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Liu Y, Dantas E, Ferrer M, Miao T, Qadiri M, Liu Y, Comjean A, Davidson EE, Perrier T, Ahmed T, Hu Y, Goncalves MD, Janowitz T, Perrimon N. Hepatic gluconeogenesis and PDK3 upregulation drive cancer cachexia in flies and mice. Nat Metab 2025; 7:823-841. [PMID: 40275022 PMCID: PMC12021660 DOI: 10.1038/s42255-025-01265-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 03/06/2025] [Indexed: 04/26/2025]
Abstract
Cachexia, a severe wasting syndrome characterized by tumour-induced metabolic dysregulation, is a leading cause of death in people with cancer, yet its underlying mechanisms remain poorly understood. Here we show that a longitudinal full-body single-nuclei-resolution transcriptome analysis in a Drosophila model of cancer cachexia captures interorgan dysregulations. Our study reveals that the tumour-secreted interleukin-like cytokine Upd3 induces fat-body expression of Pepck1 and Pdk, key regulators of gluconeogenesis, disrupting glucose metabolism and contributing to cachexia. Similarly, in mouse cancer cachexia models, we observe IL-6-JAK-STAT-signalling-mediated induction of Pck1 and Pdk3 expression in the liver. Increased expression of these genes in fly, mouse, and human correlates with poor prognosis, and hepatic expression of Pdk3 emerges as a previously unknown mechanism contributing to metabolic dysfunction in cancer cachexia. This study highlights the conserved nature of tumour-induced metabolic disruptions and identifies potential therapeutic targets to mitigate cachexia in people with cancer.
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Affiliation(s)
- Ying Liu
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
| | - Ezequiel Dantas
- Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA
| | - Miriam Ferrer
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA
| | - Ting Miao
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Mujeeb Qadiri
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Yifang Liu
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Aram Comjean
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Emma E Davidson
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA
- Ohio State University College of Medicine, Columbus, OH, USA
| | - Tiffany Perrier
- Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Tanvir Ahmed
- Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Yanhui Hu
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Marcus D Goncalves
- Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA
| | - Tobias Janowitz
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA
- Northwell Health Cancer Institute, Northwell Health, New Hyde Park, New York, NY, USA
| | - Norbert Perrimon
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
- Howard Hughes Medical Institute, Boston, MA, USA.
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Huschet LA, Kliem FP, Wienand P, Wunderlich CM, Ribeiro A, Bustos-Martínez I, Barco Á, Wunderlich FT, Lech M, Robles MS. FrozONE: quick cell nucleus enrichment for comprehensive proteomics analysis of frozen tissues. Life Sci Alliance 2025; 8:e202403130. [PMID: 39667914 PMCID: PMC11638322 DOI: 10.26508/lsa.202403130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 12/02/2024] [Accepted: 12/03/2024] [Indexed: 12/14/2024] Open
Abstract
Subcellular fractionation allows for the investigation of compartmentalized processes in individual cellular organelles. Nuclear enrichment methods commonly employ the use of density gradients combined with ultracentrifugation for freshly isolated tissues. Although it is broadly used in combination with proteomics, this approach poses several challenges when it comes to scalability and applicability for frozen material. To overcome these limitations, we developed FrozONE (Frozen Organ Nucleus Enrichment), a nucleus enrichment and proteomics workflow for frozen tissues. By extensively benchmarking our workflow against alternative methods, we showed that FrozONE is a faster, simpler, and more scalable alternative to conventional ultracentrifugation methods. FrozONE allowed for the study, profiling, and classification of nuclear proteomes in different tissues with complex cellular heterogeneity, ensuring optimal nucleus enrichment from different cell types and quantitative resolution for low abundant proteins. In addition to its performance in healthy mouse tissues, FrozONE proved to be very efficient for the characterization of liver nuclear proteome alterations in a pathological condition, diet-induced nonalcoholic steatohepatitis.
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Affiliation(s)
- Lukas A Huschet
- Institute of Medical Psychology and Biomedical Center (BMC), Faculty of Medicine, LMU, Munich, Germany
| | - Fabian P Kliem
- Institute of Medical Psychology and Biomedical Center (BMC), Faculty of Medicine, LMU, Munich, Germany
| | - Peter Wienand
- Max Planck Institute for Metabolism Research, Center for Molecular Medicine Cologne (CMMC) and Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Cologne, Germany
| | - Claudia M Wunderlich
- Max Planck Institute for Metabolism Research, Center for Molecular Medicine Cologne (CMMC) and Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Cologne, Germany
| | - Andrea Ribeiro
- LMU Klinikum, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Isabel Bustos-Martínez
- Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Alicante, Spain
| | - Ángel Barco
- Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Alicante, Spain
| | - F Thomas Wunderlich
- Max Planck Institute for Metabolism Research, Center for Molecular Medicine Cologne (CMMC) and Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Cologne, Germany
| | - Maciej Lech
- LMU Klinikum, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Maria S Robles
- Institute of Medical Psychology and Biomedical Center (BMC), Faculty of Medicine, LMU, Munich, Germany
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Felicianna, Lo EKK, Chen C, Ismaiah MJ, Zhang F, Leung HKM, El-Nezami H. Low-dose valine attenuates diet-induced metabolic dysfunction-associated steatotic liver disease (MASLD) in mice by enhancing leptin sensitivity and modulating the gut microbiome. Mol Metab 2024; 90:102059. [PMID: 39489290 PMCID: PMC11616088 DOI: 10.1016/j.molmet.2024.102059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 10/10/2024] [Accepted: 10/25/2024] [Indexed: 11/05/2024] Open
Abstract
OBJECTIVES Elevated circulating branched-chain amino acids (BCAAs) have been associated with obesity, insulin resistance, and MASLD. Nonetheless, BCAA supplementation has been shown to provide protective outcomes towards the intervention of MASLD. Currently, there is a lack of study towards the contribution of the BCAA: valine on MASLD. Herein, the effect of low-dose valine supplementation was investigated for its role in the progression of MASLD. METHODS C57BL/6J mice were fed a high-fat/high-cholesterol diet (HFD) to induce MASLD. Upon the establishment of MASLD, valine was supplemented via voluntary oral administration. Clinical and biochemical parameters associated with MASLD were measured, and molecular mechanism and gut microbiota modulation from the effect of valine were investigated. RESULTS Low-dose valine was found to attenuate the progression of MASLD, significantly reducing the gain in body weight, liver weight, and epididymal white adipose tissue (eWAT) weight, while also attenuating hyperglycemia and hyperleptinemia, and improving serum lipid profiles. Mechanistically, in the liver, genes related to hepatic lipogenesis and cholesterol biosynthesis were downregulated, while those associated with fatty acid oxidation, autophagy, and antioxidant capacity were upregulated, and AMPK pathway activity was enhanced. Liver and hypothalamic leptin resistance and inflammation were also attenuated, allowing better appetite control in mice fed a HFD and leading to reduced food intake. Additionally, metabolic flexibility in the eWAT was improved, and the gut microbiome was modulated by low-dose valine supplementation. CONCLUSION Low-dose valine supplementation attenuates MASLD by enhancing systemic leptin sensitivity and modulating the gut microbiome.
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Affiliation(s)
- Felicianna
- School of Biological Sciences, University of Hong Kong, Pokfulam 999077, Hong Kong, China
| | - Emily K K Lo
- School of Biological Sciences, University of Hong Kong, Pokfulam 999077, Hong Kong, China
| | - Congjia Chen
- School of Biological Sciences, University of Hong Kong, Pokfulam 999077, Hong Kong, China
| | - Marsena J Ismaiah
- School of Biological Sciences, University of Hong Kong, Pokfulam 999077, Hong Kong, China
| | - Fangfei Zhang
- School of Biological Sciences, University of Hong Kong, Pokfulam 999077, Hong Kong, China
| | - Hoi Kit Matthew Leung
- School of Biological Sciences, University of Hong Kong, Pokfulam 999077, Hong Kong, China
| | - Hani El-Nezami
- School of Biological Sciences, University of Hong Kong, Pokfulam 999077, Hong Kong, China; Institute of Public Health and Clinical Nutrition, School of Medicine, University of Eastern Finland, FI-70211 Kuopio, Finland.
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Liu Z, Ren J, Qiu C, Wang Y, Zhang T. Application of mesenchymal stem cells in liver fibrosis and regeneration. LIVER RESEARCH 2024; 8:246-258. [PMID: 39958916 PMCID: PMC11771278 DOI: 10.1016/j.livres.2024.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 11/20/2024] [Accepted: 11/22/2024] [Indexed: 02/18/2025]
Abstract
Liver transplantation remains the most effective treatment for end-stage liver disease (ESLD), but it is fraught with challenges such as immunosuppression, high risk and cost, and donor shortage. In recent years, stem cell transplantation has emerged as a promising new strategy for ESLD treatment, with mesenchymal stem cells (MSCs) gaining significant attention because of their unique properties. MSCs can regulate signaling pathways, including hepatocyte growth factor/c-Met, Wnt/beta (β)-catenin, Notch, transforming growth factor-β1/Smad, interleukin-6/Janus kinase/signal transducer and activator of transcription 3, and phosphatidylinositol 3-kinase/PDK/Akt, thereby influencing the progression of liver fibrosis and regeneration. As a promising stem cell type, MSCs offer numerous advantages in liver disease treatment, including low immunogenicity; ease of acquisition; unlimited proliferative ability; pluripotent differentiation potential; immunomodulatory function; and anti-inflammatory, antifibrotic, and antiapoptotic biological characteristics. This review outlines the mechanisms by which MSCs reverse liver fibrosis and promote liver regeneration. MSCs are crucial in reversing liver fibrosis and repairing liver damage through the secretion of growth factors, regulation of signaling pathways, and modulation of immune responses. MSCs have shown good therapeutic effects in preclinical and clinical studies, providing new strategies for liver disease treatment. However, challenges still exist in the clinical application of MSCs, including low differentiation efficiency and limited sources. This review provides a reference for MSC application in liver disease treatment. With the continuous progress in MSC research, MSCs are expected to achieve breakthroughs in liver disease treatment, thereby improving patient treatment outcomes.
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Affiliation(s)
- Zhenyu Liu
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Junkai Ren
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Cheng Qiu
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Ying Wang
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Tong Zhang
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, China
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Ahn SH, Lee YJ, Lim DS, Cho W, Gwon HJ, Abd El-Aty AM, Jeong JH, Jung TW. Upadacitinib counteracts hepatic lipid deposition via the repression of JAK1/STAT3 signaling and AMPK/autophagy-mediated suppression of ER stress. Biochem Biophys Res Commun 2024; 735:150829. [PMID: 39406018 DOI: 10.1016/j.bbrc.2024.150829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 10/11/2024] [Indexed: 11/05/2024]
Abstract
Upadacitinib (UPA) has been utilized to treat conditions such as rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis, Crohn's disease, ankylosing spondylitis, and axial spondyloarthritis by modulating inflammation via the JAK pathway. However, its impact on hepatic lipogenesis remains insufficiently studied. This research evaluated protein expression through Western blotting, lipid accumulation with oil red O staining, autophagosomes in hepatocytes via MDC staining, and hepatic apoptosis via cell viability and caspase 3 activity assays. This study aimed to explore the effects of UPA on hepatic lipogenesis and the underlying molecular mechanisms in in vitro models of hepatic steatosis. These findings demonstrated that UPA reduced lipid deposition, apoptosis, and ER stress in palmitate-treated hepatocytes. UPA treatment inhibited phosphorylated JAK1 and STAT3 while promoting the expression of phosphorylated AMPK and autophagy markers. AMPK siRNA negated the effects of UPA on lipogenic lipid deposition, apoptosis, JAK1/STAT3 phosphorylation, and ER stress. These results reveal that UPAmitigates ER stress through the JAK1/STAT3/AMPK pathway, thereby reducing lipid deposition and apoptosis in hyperlipidemic hepatocytes, supporting its potential as a therapeutic strategy for treating hepatic steatosis in obese individuals.
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Affiliation(s)
- Sung Ho Ahn
- Department of Family Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yong-Jik Lee
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Do Su Lim
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea; Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea
| | - Wonjun Cho
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Hyeon Ji Gwon
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea; Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea
| | - A M Abd El-Aty
- Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, 12211-Giza, Egypt; Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, 25240, Turkey.
| | - Ji Hoon Jeong
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea; Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea.
| | - Tae Woo Jung
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea.
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Zhang X, Sun Z, Sun W, Li Y, Gao F, Teng F, Han Z, Lu Y, Zhang S, Li L. Bioinformatics Analysis and Experimental Findings Reveal the Therapeutic Actions and Targets of Cyathulae Radix Against Type 2 Diabetes Mellitus. J Diabetes Res 2024; 2024:5521114. [PMID: 39534794 PMCID: PMC11557179 DOI: 10.1155/2024/5521114] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 07/15/2024] [Accepted: 09/19/2024] [Indexed: 11/16/2024] Open
Abstract
Objective: This study elucidated the mechanistic role of Cyathulae Radix (CR) in type 2 diabetes mellitus (T2DM) through bioinformatics analysis and experimental validation. Methods: Components and targets of CR were retrieved from the traditional Chinese medical systems pharmacology, while potential T2DM targets were obtained from GeneCards and Online Mendelian Inheritance in Man databases. Intersecting these datasets yielded target genes between CR and T2DM. Differential genes were used for constructing a protein-protein interaction network, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Molecular docking and dynamics simulations were performed using AutoDock and GROMACS, respectively, and in vitro experiments validated the results. Experiments evaluated the effect of CR on T2DM pancreatic β-cells. Results: Bioinformatics analysis identified four active compounds of CR, 157 related genes, and 5431 T2DM target genes, with 141 shared targets. Key targets such as JUN, MAPK1, and MAPK14 were identified through topological analysis of the PPI network. GO analysis presented 2663 entries, while KEGG analysis identified 161 pathways. The molecular docking results demonstrated favorable binding energy between the core components and the core proteins. Among them, JUN-rubrosterone, MAPK1-rubrosterone, and MAPK14-rubrosterone deserved further investigation. Molecular dynamics results indicated that all of them can form stable binding interactions. CR could inhibit the expression of JUN, MAPK1, and MAPK14, promote insulin secretion, alleviate apoptosis, and regulate autophagy in INS-1 cells. Conclusion: This study suggests CR approach to T2DM management by multitarget and multipathway provides a scientific basis for further research on the hypoglycemic effect of CR.
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Affiliation(s)
- Xi Zhang
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Zijin Sun
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Wenlong Sun
- School of Life Sciences and Medicine, Shandong University of Technology, Zibo 255049, China
| | - Yueming Li
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250014, China
| | - Fei Gao
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250014, China
| | - Fei Teng
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250014, China
| | - Zhenxu Han
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250014, China
| | - Yanting Lu
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250014, China
| | - Shuo Zhang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250014, China
| | - Lingru Li
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
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Deng F, Yang R, Yang Y, Li X, Hou J, Liu Y, Lu J, Huangfu S, Meng Y, Wu S, Zhang L. Visible light accelerates skin wound healing and alleviates scar formation in mice by adjusting STAT3 signaling. Commun Biol 2024; 7:1266. [PMID: 39367154 PMCID: PMC11452386 DOI: 10.1038/s42003-024-06973-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 09/26/2024] [Indexed: 10/06/2024] Open
Abstract
During the wound healing process, the activation of signal transducer and activator of transcription 3 (STAT3) is considered crucial for the migration and proliferation of epithelial cells, as well as for establishing the inflammatory environment. However, an excessive STAT3 activation aggravates scar formation. Here we show that 450 nm blue light and 630 nm red light can differentially regulate the phosphorylation of STAT3 (p-STAT3) and its downstream cytokines in keratinocytes. Further mechanistic studies reveal that red light promotes wound healing by activating the PI3 kinase p110 beta (PI3Kβ)/STAT3 signaling axis, while blue light inhibits p-STAT3 at the wound site by modulating cytochrome c-P450 (CYT-P450) activity and reactive oxygen species (ROS) generation. In a mouse scar model, skin wound healing can be significantly accelerated with red light followed by blue light to reduce scar formation. In summary, our study presents a potential strategy for regulating epithelial cell p-STAT3 through visible light to address skin scarring issues and elucidates the underlying mechanisms.
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Affiliation(s)
- Fangqing Deng
- Key Laboratory for Space Bioscience & Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Rong Yang
- Key Laboratory for Space Bioscience & Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Yingchun Yang
- Key Laboratory for Space Bioscience & Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.
| | - Xu Li
- Key Laboratory for Space Bioscience & Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Jing Hou
- Key Laboratory for Space Bioscience & Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Yanyan Liu
- Key Laboratory for Space Bioscience & Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Jueru Lu
- Key Laboratory for Space Bioscience & Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Shuaiqi Huangfu
- Key Laboratory for Space Bioscience & Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Yuqi Meng
- Key Laboratory for Space Bioscience & Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Si Wu
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, College of Life Science, Hunan Normal University, Changsha, China
| | - Lianbing Zhang
- Key Laboratory for Space Bioscience & Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.
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Rajesh R U, Sangeetha D. Therapeutic potentials and targeting strategies of quercetin on cancer cells: Challenges and future prospects. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 133:155902. [PMID: 39059266 DOI: 10.1016/j.phymed.2024.155902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 07/08/2024] [Accepted: 07/19/2024] [Indexed: 07/28/2024]
Abstract
BACKGROUND Every cell in the human body is vital because it maintains equilibrium and carries out a variety of tasks, including growth and development. These activities are carried out by a set of instructions carried by many different genes and organized into DNA. It is well recognized that some lifestyle decisions, like using tobacco, alcohol, UV, or multiple sexual partners, might increase one's risk of developing cancer. The advantages of natural products for any health issue are well known, and researchers are making attempts to separate flavonoid-containing substances from plants. Various parts of plants contain a phenolic compound called flavonoid. Quercetin, which belongs to the class of compounds known as flavones with chromone skeletal structure, has anti-cancer activity. PURPOSE The study was aimed at investigating the therapeutic action of the flavonoid quercetin on various cancer cells. METHODS The phrases quercetin, anti-cancer, nanoparticles, and cell line were used to search the data using online resources such as PubMed, and Google Scholar. Several critical previous studies have been included. RESULTS Quercetin inhibits various dysregulated signaling pathways that cause cancer cells to undergo apoptosis to exercise its anticancer effects. Numerous signaling pathways are impacted by quercetin, such as the Hedgehog system, Akt, NF-κB pathway, downregulated mutant p53, JAK/STAT, G1 phase arrest, Wnt/β-Catenin, and MAPK. There are downsides to quercetin, like hydrophobicity, first-pass effect, instability in the gastrointestinal tract, etc., because of which it is not well-established in the pharmaceutical industry. The solution to these drawbacks in the future is using bio-nanomaterials like chitosan, PLGA, liposomes, and silk fibroin as carriers, which can enhance the target specificity of quercetin. The first section of this review covers the specifics of flavonoids and quercetin; the second section covers the anti-cancer activity of quercetin; and the third section explains the drawbacks and conjugation of quercetin with nanoparticles for drug delivery by overcoming quercetin's drawback. CONCLUSIONS Overall, this review presented details about quercetin, which is a plant derivative with a promising molecular mechanism of action. They inhibit cancer by various mechanisms with little or no side effects. It is anticipated that plant-based materials will become increasingly relevant in the treatment of cancer.
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Affiliation(s)
- Udaya Rajesh R
- Department of Chemistry, School of Advanced Science, Vellore Institute of Technology, Vellore, 632014 Tamil Nadu, India
| | - Dhanaraj Sangeetha
- Department of Chemistry, School of Advanced Science, Vellore Institute of Technology, Vellore, 632014 Tamil Nadu, India.
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Chen X, Tao X, Wang M, Cannon RD, Chen B, Yu X, Qi H, Saffery R, Baker PN, Zhou X, Han TL, Zhang H. Circulating extracellular vesicle-derived miR-1299 disrupts hepatic glucose homeostasis by targeting the STAT3/FAM3A axis in gestational diabetes mellitus. J Nanobiotechnology 2024; 22:509. [PMID: 39182087 PMCID: PMC11344378 DOI: 10.1186/s12951-024-02766-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 08/13/2024] [Indexed: 08/27/2024] Open
Abstract
BACKGROUND Extracellular vesicles (EVs) are membrane-enclosed structures containing lipids, proteins, and RNAs that play a crucial role in cell-to-cell communication. However, the precise mechanism through which circulating EVs disrupt hepatic glucose homeostasis in gestational diabetes mellitus (GDM) remains unclear. RESULTS Circulating EVs isolated from human plasma were co-cultured with mammalian liver cells to investigate the potential induction of hepatic insulin resistance by GDM-EVs using glucose output assays, Seahorse assays, metabolomics, fluxomics, qRT-PCR, bioinformatics analyses, and luciferase assays. Our findings demonstrated that hepatocytes exposed to GDM-EVs exhibited increased gluconeogenesis, attenuated energy metabolism, and upregulated oxidative stress. Particularly noteworthy was the discovery of miR-1299 as the predominant miRNA in GDM-EVs, which directly targeting the 3'-untranslated regions (UTR) of STAT3. Our experiments involving loss- and gain-of-function revealed that miR-1299 inhibits the insulin signaling pathway by regulating the STAT3/FAM3A axis, resulting in increased insulin resistance through the modulation of mitochondrial function and oxidative stress in hepatocytes. Moreover, experiments conducted in vivo on mice inoculated with GDM-EVs confirmed the development of glucose intolerance, insulin resistance, and downregulation of STAT3 and FAM3A. CONCLUSIONS These results provide insights into the role of miR-1299 derived from circulating GDM-EVs in the progression of insulin resistance in hepatic cells via the STAT3/FAM3A axis and downstream metabolic reprogramming.
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Affiliation(s)
- Xuyang Chen
- Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016, China
- Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China
| | - Xinyi Tao
- Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016, China
- Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China
| | - Min Wang
- Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016, China
- Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China
| | - Richard D Cannon
- Department of Oral Sciences, Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand
| | - Bingnan Chen
- Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016, China
- Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China
| | - Xinyang Yu
- Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016, China
- Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China
| | - Hongbo Qi
- Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China
- Women and Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Richard Saffery
- Molecular Immunity, Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Australia
| | - Philip N Baker
- College of Life Sciences, University of Leicester, Leicester, UK
| | - Xiaobo Zhou
- Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China.
- Department of Center for Reproductive Medicine, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016, China.
| | - Ting-Li Han
- Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China.
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Chongqing Medical University, No.74 Linjiang Road, Yuzhong District, Chongqing, 400010, China.
| | - Hua Zhang
- Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016, China.
- Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China.
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10
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Nomura K, Kinoshita S, Mizusaki N, Senga Y, Sasaki T, Kitamura T, Sakaue H, Emi A, Hosooka T, Matsuo M, Okamura H, Amo T, Wolf AM, Kamimura N, Ohta S, Itoh T, Hayashi Y, Kiyonari H, Krook A, Zierath JR, Kasuga M, Ogawa W. Adaptive gene expression of alternative splicing variants of PGC-1α regulates whole-body energy metabolism. Mol Metab 2024; 86:101968. [PMID: 38885788 PMCID: PMC11254180 DOI: 10.1016/j.molmet.2024.101968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 05/23/2024] [Accepted: 06/11/2024] [Indexed: 06/20/2024] Open
Abstract
The transcriptional coactivator PGC-1α has been implicated in the regulation of multiple metabolic processes. However, the previously reported metabolic phenotypes of mice deficient in PGC-1α have been inconsistent. PGC-1α exists as multiple isoforms, including variants transcribed from an alternative first exon. We show here that alternative PGC-1α variants are the main entity that increases PGC-1α during exercise. These variants, unlike the canonical isoform of PGC-1α, are robustly upregulated in human skeletal muscle after exercise. Furthermore, the extent of this upregulation correlates with oxygen consumption. Mice lacking these variants manifest impaired energy expenditure during exercise, leading to the development of obesity and hyperinsulinemia. The alternative variants are also upregulated in brown adipose tissue in response to cold exposure, and mice lacking these variants are intolerant of a cold environment. Our findings thus indicate that an increase in PGC-1α expression, attributable mostly to upregulation of alternative variants, is pivotal for adaptive enhancement of energy expenditure and heat production and thereby essential for the regulation of whole-body energy metabolism.
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Affiliation(s)
- Kazuhiro Nomura
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden
| | - Shinichi Kinoshita
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Nao Mizusaki
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Yoko Senga
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Tsutomu Sasaki
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan
| | - Tadahiro Kitamura
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan
| | - Hiroshi Sakaue
- Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan; Diabetes Therapeutics and Research Center, University of Tokushima, Tokushima 770-8503, Japan
| | - Aki Emi
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Tetsuya Hosooka
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Laboratory of Nutritional Physiology, Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, Shizuoka 422-8526, Japan
| | - Masahiro Matsuo
- Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan
| | - Hitoshi Okamura
- Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan; Department of Neuroscience, Graduate School of Medicine, Kyoto University, Kyoto 606-8303, Japan
| | - Taku Amo
- Department of Applied Chemistry, National Defense Academy, Yokosuka 239-8686, Japan
| | - Alexander M Wolf
- Department of Biochemistry and Cell Biology, Graduate School of Medicine, Nippon Medical School, Kawasaki 211-8533, Japan
| | - Naomi Kamimura
- Department of Biochemistry and Cell Biology, Graduate School of Medicine, Nippon Medical School, Kawasaki 211-8533, Japan; Laboratory for Clinical Research, Collaborative Research Center, Nippon Medical School, Tokyo 113-8602, Japan
| | - Shigeo Ohta
- Department of Biochemistry and Cell Biology, Graduate School of Medicine, Nippon Medical School, Kawasaki 211-8533, Japan
| | - Tomoo Itoh
- Department of Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Yoshitake Hayashi
- Department of Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Hiroshi Kiyonari
- Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan
| | - Anna Krook
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden
| | - Juleen R Zierath
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden
| | - Masato Kasuga
- The Institute of Medical Science, Asahi Life Foundation, Tokyo 100-0005, Japan
| | - Wataru Ogawa
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
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11
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He J, Feng X, Liu Y, Wang Y, Ge C, Liu S, Jiang Y. Graveoline attenuates D-GalN/LPS-induced acute liver injury via inhibition of JAK1/STAT3 signaling pathway. Biomed Pharmacother 2024; 177:117163. [PMID: 39018876 DOI: 10.1016/j.biopha.2024.117163] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 07/05/2024] [Accepted: 07/15/2024] [Indexed: 07/19/2024] Open
Abstract
Graveoline exhibits various biological activities. However, only limited studies have focused on its hepatoprotective properties. This study evaluated the anti-inflammatory and hepatoprotective activities of graveoline, a minor 2-phenylquinolin-4-one alkaloid isolated from Ruta graveolens L., in a liver injury model in vitro and in vivo. A network pharmacology approach was used to investigate the potential signaling pathway associated with the hepatoprotective activity of graveoline. Subsequently, biological experiments were conducted to validate the findings. Topological analysis of the KEGG pathway enrichment revealed that graveoline mediates its hepatoprotective activity through genes associated with the hepatitis B viral infection pathway. Biological experiments demonstrated that graveoline effectively reduced the levels of alanine transaminase and aspartate transaminase in lipopolysaccharide (LPS)-induced HepG2 cells. Graveoline exerted antihepatitic activity by inhibiting the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and elevated the anti-inflammatory cytokines interleukin-4 (IL-4) and interleukin-10 (IL-10) in vitro and in vivo. Additionally, graveoline exerted its hepatoprotective activity by inhibiting JAK1 and STAT3 phosphorylation both in vitro and in vivo. In summary, graveoline can attenuate acute liver injury by inhibiting the TNF-α inflammasome, activating IL-4 and IL-10, and suppressing the JAK1/STAT3 signaling pathway. This study sheds light on the potential of graveoline as a promising therapeutic agent for treating liver injury.
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Affiliation(s)
- Jia He
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Xu Feng
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yanyang Liu
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Pharmacy, Mianyang 404 Hospital, Mianyang, Sichuan 621000, China
| | - Yuxin Wang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; College of pharmacy, Dali University, Dali, Yunan 671000, China
| | - Chengyu Ge
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Shao Liu
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
| | - Yueping Jiang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; College of Pharmacy, Changsha Medical University, Changsha, Hunan 410219, China.
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12
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Zhuang Z, Jia W, Wu L, Li Y, Lu Y, Xu M, Bai H, Bi Y, Wang Z, Chen S, Jiang Y, Chang G. Threonine Deficiency Increases Triglyceride Deposition in Primary Duck Hepatocytes by Reducing STAT3 Phosphorylation. Int J Mol Sci 2024; 25:8142. [PMID: 39125712 PMCID: PMC11312044 DOI: 10.3390/ijms25158142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 06/24/2024] [Accepted: 06/26/2024] [Indexed: 08/12/2024] Open
Abstract
Liver lipid metabolism disruption significantly contributes to excessive fat buildup in waterfowl. Research suggests that the supplementation of Threonine (Thr) in the diet can improve liver lipid metabolism disorder, while Thr deficiency can lead to such metabolic disorders in the liver. The mechanisms through which Thr regulates lipid metabolism remain unclear. STAT3 (signal transducer and activator of transcription 3), a crucial transcription factor in the JAK-STAT (Janus kinase-signal transducer and activator of transcription) pathway, participates in various biological processes, including lipid and energy metabolism. This research investigates the potential involvement of STAT3 in the increased lipid storage seen in primary duck hepatocytes as a result of a lack of Thr. Using small interfering RNA and Stattic, a specific STAT3 phosphorylation inhibitor, we explored the impact of STAT3 expression patterns on Thr-regulated lipid synthesis metabolism in hepatocytes. Through transcriptome sequencing, we uncovered pathways related to lipid synthesis and metabolism jointly regulated by Thr and STAT3. The results showed that Thr deficiency increases lipid deposition in primary duck hepatocytes (p < 0.01). The decrease in protein and phosphorylation levels of STAT3 directly caused this deposition (p < 0.01). Transcriptomic analysis revealed that Thr deficiency and STAT3 knockdown jointly altered the mRNA expression levels of pathways related to long-chain fatty acid synthesis and energy metabolism (p < 0.05). Thr deficiency, through mediating STAT3 inactivation, upregulated ELOVL7, PPARG, MMP1, MMP13, and TIMP4 mRNA levels, and downregulated PTGS2 mRNA levels (p < 0.01). In summary, these results suggest that Thr deficiency promotes lipid synthesis, reduces lipid breakdown, and leads to lipid metabolism disorders and triglyceride deposition by downregulating STAT3 activity in primary duck hepatocytes.
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Affiliation(s)
- Zhong Zhuang
- Key Laboratory for Animal Genetics & Molecular Breeding of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (Z.Z.); (W.J.); (L.W.); (Y.L.); (Y.L.); (M.X.); (Y.B.); (Z.W.); (S.C.); (G.C.)
| | - Wenqian Jia
- Key Laboratory for Animal Genetics & Molecular Breeding of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (Z.Z.); (W.J.); (L.W.); (Y.L.); (Y.L.); (M.X.); (Y.B.); (Z.W.); (S.C.); (G.C.)
| | - Lei Wu
- Key Laboratory for Animal Genetics & Molecular Breeding of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (Z.Z.); (W.J.); (L.W.); (Y.L.); (Y.L.); (M.X.); (Y.B.); (Z.W.); (S.C.); (G.C.)
| | - Yongpeng Li
- Key Laboratory for Animal Genetics & Molecular Breeding of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (Z.Z.); (W.J.); (L.W.); (Y.L.); (Y.L.); (M.X.); (Y.B.); (Z.W.); (S.C.); (G.C.)
| | - Yijia Lu
- Key Laboratory for Animal Genetics & Molecular Breeding of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (Z.Z.); (W.J.); (L.W.); (Y.L.); (Y.L.); (M.X.); (Y.B.); (Z.W.); (S.C.); (G.C.)
| | - Minghong Xu
- Key Laboratory for Animal Genetics & Molecular Breeding of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (Z.Z.); (W.J.); (L.W.); (Y.L.); (Y.L.); (M.X.); (Y.B.); (Z.W.); (S.C.); (G.C.)
| | - Hao Bai
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, The Ministry of Education of China, Institutes of Agricultural Science and Technology Development, Yangzhou University, Yangzhou 225009, China;
| | - Yulin Bi
- Key Laboratory for Animal Genetics & Molecular Breeding of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (Z.Z.); (W.J.); (L.W.); (Y.L.); (Y.L.); (M.X.); (Y.B.); (Z.W.); (S.C.); (G.C.)
| | - Zhixiu Wang
- Key Laboratory for Animal Genetics & Molecular Breeding of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (Z.Z.); (W.J.); (L.W.); (Y.L.); (Y.L.); (M.X.); (Y.B.); (Z.W.); (S.C.); (G.C.)
| | - Shihao Chen
- Key Laboratory for Animal Genetics & Molecular Breeding of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (Z.Z.); (W.J.); (L.W.); (Y.L.); (Y.L.); (M.X.); (Y.B.); (Z.W.); (S.C.); (G.C.)
| | - Yong Jiang
- Key Laboratory for Animal Genetics & Molecular Breeding of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (Z.Z.); (W.J.); (L.W.); (Y.L.); (Y.L.); (M.X.); (Y.B.); (Z.W.); (S.C.); (G.C.)
| | - Guobin Chang
- Key Laboratory for Animal Genetics & Molecular Breeding of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (Z.Z.); (W.J.); (L.W.); (Y.L.); (Y.L.); (M.X.); (Y.B.); (Z.W.); (S.C.); (G.C.)
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13
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Arneson‐Wissink PC, Mendez H, Pelz K, Dickie J, Bartlett AQ, Worley BL, Krasnow SM, Eil R, Grossberg AJ. Hepatic signal transducer and activator of transcription-3 signalling drives early-stage pancreatic cancer cachexia via suppressed ketogenesis. J Cachexia Sarcopenia Muscle 2024; 15:975-988. [PMID: 38632714 PMCID: PMC11154744 DOI: 10.1002/jcsm.13466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 03/07/2024] [Accepted: 03/19/2024] [Indexed: 04/19/2024] Open
Abstract
BACKGROUND Patients with pancreatic ductal adenocarcinoma (PDAC) often suffer from cachexia, a wasting syndrome that significantly reduces both quality of life and survival. Although advanced cachexia is associated with inflammatory signalling and elevated muscle catabolism, the early events driving wasting are poorly defined. During periods of nutritional scarcity, the body relies on hepatic ketogenesis to generate ketone bodies, and lipid metabolism via ketogenesis is thought to protect muscle from catabolizing during nutritional scarcity. METHODS We developed an orthotopic mouse model of early PDAC cachexia in 12-week-old C57BL/6J mice. Murine pancreatic cancer cells (KPC) were orthotopically implanted into the pancreas of wild-type, IL-6-/-, and hepatocyte STAT3-/- male and female mice. Mice were subject to fasting, 50% food restriction, ad libitum feeding or ketogenic diet interventions. We measured longitudinal body composition by EchoMRI, body mass and food intake. At the endpoint, we measured tissue mass, tissue gene expression by quantitative real-time polymerase chain reaction, whole-body calorimetry, circulating hormone levels, faecal protein and lipid content, hepatic lipid content and ketogenic response to medium-chain fatty acid bolus. We assessed muscle atrophy in vivo and C2C12 myotube atrophy in vitro. RESULTS Pre-cachectic PDAC mice did not preserve gastrocnemius muscle mass during 3-day food restriction (-13.1 ± 7.7% relative to food-restricted sham, P = 0.0117) and displayed impaired fatty acid oxidation during fasting, resulting in a hypoketotic state (ketogenic response to octanoate bolus, -83.0 ± 17.3%, P = 0.0328; Hmgcs2 expression, -28.3 ± 7.6%, P = 0.0004). PDAC human patients display impaired fasting ketones (-46.9 ± 7.1%, P < 0.0001) and elevated circulating interleukin-6 (IL-6) (12.4 ± 16.5-fold increase, P = 0.0001). IL-6-/- PDAC mice had improved muscle mass (+35.0 ± 3.9%, P = 0.0031) and ketogenic response (+129.4 ± 44.4%, P = 0.0033) relative to wild-type PDAC mice. Hepatocyte-specific signal transducer and activator of transcription 3 (STAT3) deletion prevented muscle loss (+9.3 ± 4.0%, P = 0.009) and improved fasting ketone levels (+52.0 ± 43.3%, P = 0.018) in PDAC mice. Without affecting tumour growth, a carbohydrate-free diet improved tibialis anterior myofibre diameter (+16.5 ± 3.5%, P = 0.0089), circulating ketone bodies (+333.0 ± 117.6%, P < 0.0001) and Hmgcs2 expression (+106.5 ± 36.1%, P < 0.0001) in PDAC mice. Ketone supplementation protected muscle against PDAC-induced atrophy in vitro (+111.0 ± 17.6%, P < 0.0001 myofibre diameter). CONCLUSIONS In early PDAC cachexia, muscle vulnerability to wasting is dependent on inflammation-driven metabolic reprogramming in the liver. PDAC suppresses lipid β-oxidation and impairs ketogenesis in the liver, which is reversed in genetically modified mouse models deficient in IL-6/STAT3 signalling or through ketogenic diet supplementation. This work establishes a direct link between skeletal muscle homeostasis and hepatic metabolism. Dietary and anti-inflammatory interventions that restore ketogenesis may be a viable preventative approach for pre-cachectic patients with pancreatic cancer.
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Affiliation(s)
| | - Heike Mendez
- Brenden‐Colson Center for Pancreatic CareOregon Health & Science UniversityPortlandORUSA
| | - Katherine Pelz
- Brenden‐Colson Center for Pancreatic CareOregon Health & Science UniversityPortlandORUSA
| | - Jessica Dickie
- Brenden‐Colson Center for Pancreatic CareOregon Health & Science UniversityPortlandORUSA
| | - Alexandra Q. Bartlett
- Division of Surgical Oncology, Department of Surgery, Knight Cancer InstituteOregon Health & Science UniversityPortlandORUSA
| | - Beth L. Worley
- Brenden‐Colson Center for Pancreatic CareOregon Health & Science UniversityPortlandORUSA
| | - Stephanie M. Krasnow
- Division of Oncological Sciences, Knight Cancer InstituteOregon Health & Science UniversityPortlandORUSA
| | - Robert Eil
- Division of Surgical Oncology, Department of Surgery, Knight Cancer InstituteOregon Health & Science UniversityPortlandORUSA
| | - Aaron J. Grossberg
- Brenden‐Colson Center for Pancreatic CareOregon Health & Science UniversityPortlandORUSA
- Department of Radiation MedicineOregon Health & Science UniversityPortlandORUSA
- Cancer Early Detection Advanced Research CenterOregon Health & Science UniversityPortlandORUSA
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14
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Lu H. Inflammatory liver diseases and susceptibility to sepsis. Clin Sci (Lond) 2024; 138:435-487. [PMID: 38571396 DOI: 10.1042/cs20230522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Revised: 01/09/2024] [Accepted: 03/12/2024] [Indexed: 04/05/2024]
Abstract
Patients with inflammatory liver diseases, particularly alcohol-associated liver disease and metabolic dysfunction-associated fatty liver disease (MAFLD), have higher incidence of infections and mortality rate due to sepsis. The current focus in the development of drugs for MAFLD is the resolution of non-alcoholic steatohepatitis and prevention of progression to cirrhosis. In patients with cirrhosis or alcoholic hepatitis, sepsis is a major cause of death. As the metabolic center and a key immune tissue, liver is the guardian, modifier, and target of sepsis. Septic patients with liver dysfunction have the highest mortality rate compared with other organ dysfunctions. In addition to maintaining metabolic homeostasis, the liver produces and secretes hepatokines and acute phase proteins (APPs) essential in tissue protection, immunomodulation, and coagulation. Inflammatory liver diseases cause profound metabolic disorder and impairment of energy metabolism, liver regeneration, and production/secretion of APPs and hepatokines. Herein, the author reviews the roles of (1) disorders in the metabolism of glucose, fatty acids, ketone bodies, and amino acids as well as the clearance of ammonia and lactate in the pathogenesis of inflammatory liver diseases and sepsis; (2) cytokines/chemokines in inflammatory liver diseases and sepsis; (3) APPs and hepatokines in the protection against tissue injury and infections; and (4) major nuclear receptors/signaling pathways underlying the metabolic disorders and tissue injuries as well as the major drug targets for inflammatory liver diseases and sepsis. Approaches that focus on the liver dysfunction and regeneration will not only treat inflammatory liver diseases but also prevent the development of severe infections and sepsis.
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Affiliation(s)
- Hong Lu
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, U.S.A
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15
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Yang S, Zhang R, Deng W, Chang S, Li Y, Li S. Pirfenidone ameliorates liver steatosis by targeting the STAT3-SCD1 axis. Inflamm Res 2023; 72:1773-1787. [PMID: 37659014 DOI: 10.1007/s00011-023-01776-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 07/14/2023] [Accepted: 07/31/2023] [Indexed: 09/05/2023] Open
Abstract
OBJECTIVE Previous studies reported that pirfenidone (PFD) is associated with liver disease. However, the effects of pirfenidone on energy metabolism and hepatic lipid accumulation are still poorly understood. METHODS In this study, C57BL/6J mice were randomly divided into two groups, and fed a normal chow diet (NCD) or a high-fat diet (HFD) for 16 weeks. At the end of the eighth week, half of the mice fed on both diets were treated with PFD. Biochemical and lipid metabolism-related indices were analyzed. Furthermore, Hepa 1-6 cells and mouse primary hepatocytes (MPHs) were incubated with PFD with or without free fatty acid (FFA) treatment. Then, stattic (a p-STAT3 inhibitor) or Ad-shSTAT3 was used to further elucidate the effects of Signal Transducer and Activator of Transcription 3 (STAT3) signaling on PFD regulation of hepatic steatosis. RESULTS PFD ameliorated obesity and hepatic lipid deposition in HFD mice by decreasing stearoyl-CoA desaturase 1 (SCD1) expression and upregulating p-STAT3 in the liver. In Hepa 1-6 cells and MPHs, PFD also down-regulated the expression of SCD1. STAT3 inhibition treatment eliminated the benefits of PFD on both SCD1 and hepatic steatosis. CONCLUSION In summary, our data reveal that PFD may play an important role in mitigating hepatic steatosis in a STAT3-SCD1-dependent manner.
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Affiliation(s)
- Shan Yang
- Department of Endocrinology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Renzi Zhang
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wenzhen Deng
- Department of Endocrinology, Qianjiang Central Hospital of Chongqing, Chongqing, 409000, China
| | - Shichuan Chang
- Oncology Department, Chongqing University Three Gorges Hospital, Chongqing, 404000, China
| | - Yang Li
- Department of Endocrinology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| | - Sheng Li
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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16
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Geng Y, Liu Z, Hu R, Ma W, Wu X, Dong H, Song K, Xu X, Huang Y, Li F, Song Y, Zhang M. Opportunities and challenges: interleukin-22 comprehensively regulates polycystic ovary syndrome from metabolic and immune aspects. J Ovarian Res 2023; 16:149. [PMID: 37525285 PMCID: PMC10388558 DOI: 10.1186/s13048-023-01236-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Accepted: 07/13/2023] [Indexed: 08/02/2023] Open
Abstract
Polycystic ovary syndrome (PCOS) is known as a prevalent but complicated gynecologic disease throughout the reproductive period. Typically, it is characterized by phenotypic manifestations of hyperandrogenism, polycystic ovary morphology, and persistent anovulation. For now, the therapeutic modality of PCOS is still a formidable challenge. Metabolic aberrations and immune challenge of chronic low-grade inflammatory state are significant in PCOS individuals. Recently, interleukin-22 (IL-22) has been shown to be therapeutically effective in immunological dysfunction and metabolic diseases, which suggests a role in the treatment of PCOS. In this review, we outline the potential mechanisms and limitations of IL-22 therapy in PCOS-related metabolic disorders including its regulation of insulin resistance, gut barrier, systemic inflammation, and hepatic steatosis to generate insights into developing novel strategies in clinical practice.
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Affiliation(s)
- Yuli Geng
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Zhuo Liu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Runan Hu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Wenwen Ma
- Department of Traditional Chinese Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Xiao Wu
- Department of Traditional Chinese Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Haoxu Dong
- Department of Traditional Chinese Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Kunkun Song
- Department of Traditional Chinese Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Xiaohu Xu
- Department of Traditional Chinese Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Yanjing Huang
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Fan Li
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Yufan Song
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China.
- Department of Traditional Chinese Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China.
| | - Mingmin Zhang
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China.
- Department of Traditional Chinese Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China.
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17
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Li JH, Hepworth MR, O'Sullivan TE. Regulation of systemic metabolism by tissue-resident immune cell circuits. Immunity 2023; 56:1168-1186. [PMID: 37315533 PMCID: PMC10321269 DOI: 10.1016/j.immuni.2023.05.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 04/11/2023] [Accepted: 05/02/2023] [Indexed: 06/16/2023]
Abstract
Recent studies have demonstrated that tissue homeostasis and metabolic function are dependent on distinct tissue-resident immune cells that form functional cell circuits with structural cells. Within these cell circuits, immune cells integrate cues from dietary contents and commensal microbes in addition to endocrine and neuronal signals present in the tissue microenvironment to regulate structural cell metabolism. These tissue-resident immune circuits can become dysregulated during inflammation and dietary overnutrition, contributing to metabolic diseases. Here, we review the evidence describing key cellular networks within and between the liver, gastrointestinal tract, and adipose tissue that control systemic metabolism and how these cell circuits become dysregulated during certain metabolic diseases. We also identify open questions in the field that have the potential to enhance our understanding of metabolic health and disease.
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Affiliation(s)
- Joey H Li
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 900953, USA; Medical Scientist Training Program, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Matthew R Hepworth
- Division of Immunology, Immunity to Infection and Respiratory Medicine, Faculty of Biology, Medicine and Health, Manchester Collaborative Centre for Inflammation Research, Lydia Becker Institute of Immunology and Inflammation, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
| | - Timothy E O'Sullivan
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 900953, USA.
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18
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Liu Y, Dantas E, Ferrer M, Liu Y, Comjean A, Davidson EE, Hu Y, Goncalves MD, Janowitz T, Perrimon N. Tumor Cytokine-Induced Hepatic Gluconeogenesis Contributes to Cancer Cachexia: Insights from Full Body Single Nuclei Sequencing. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.15.540823. [PMID: 37292804 PMCID: PMC10245574 DOI: 10.1101/2023.05.15.540823] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
A primary cause of death in cancer patients is cachexia, a wasting syndrome attributed to tumor-induced metabolic dysregulation. Despite the major impact of cachexia on the treatment, quality of life, and survival of cancer patients, relatively little is known about the underlying pathogenic mechanisms. Hyperglycemia detected in glucose tolerance test is one of the earliest metabolic abnormalities observed in cancer patients; however, the pathogenesis by which tumors influence blood sugar levels remains poorly understood. Here, utilizing a Drosophila model, we demonstrate that the tumor secreted interleukin-like cytokine Upd3 induces fat body expression of Pepck1 and Pdk, two key regulatory enzymes of gluconeogenesis, contributing to hyperglycemia. Our data further indicate a conserved regulation of these genes by IL-6/JAK-STAT signaling in mouse models. Importantly, in both fly and mouse cancer cachexia models, elevated gluconeogenesis gene levels are associated with poor prognosis. Altogether, our study uncovers a conserved role of Upd3/IL-6/JAK-STAT signaling in inducing tumor-associated hyperglycemia, which provides insights into the pathogenesis of IL-6 signaling in cancer cachexia.
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Affiliation(s)
- Ying Liu
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Harvard University, Boston, MA 02115, USA
| | - Ezequiel Dantas
- Division of Endocrinology, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA
| | - Miriam Ferrer
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY 11724 USA
| | - Yifang Liu
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Harvard University, Boston, MA 02115, USA
| | - Aram Comjean
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Harvard University, Boston, MA 02115, USA
| | - Emma E. Davidson
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY 11724 USA
| | - Yanhui Hu
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Harvard University, Boston, MA 02115, USA
| | - Marcus D. Goncalves
- Division of Endocrinology, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA
| | - Tobias Janowitz
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY 11724 USA
- Northwell Health Cancer Institute, Northwell Health, New Hyde Park, New York, NY 11042 USA
| | - Norbert Perrimon
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Harvard University, Boston, MA 02115, USA
- Howard Hughes Medical Institute, Boston, MA, USA
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19
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Yang H, Zhang P, Wang Q, Cheng K, Zhao Y. The research development of STAT3 in hepatic ischemia-reperfusion injury. Front Immunol 2023; 14:1066222. [PMID: 36761734 PMCID: PMC9902876 DOI: 10.3389/fimmu.2023.1066222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 01/10/2023] [Indexed: 01/25/2023] Open
Abstract
Ischemia-reperfusion injury (IRI) is a common complication of surgery, which can cause rapid deterioration of the liver function, increase the risk of graft rejection, and seriously affect the prognosis of patients. The signal transducer and activator of transcription 3 (STAT3) protein has been implicated in pathogenesis of IRI. STAT3 influences the mitochondria through multiple pathways and is also involved in apoptosis and other forms of programmed cell death. STAT3 is associated with Janus kinase (JAK), phosphoinositide-3 kinase (PI3K), and heme oxygenase-1 (HO-1) in liver IRI. The STAT3 pathway plays a dual role in IRI as it can also regulate lipid metabolism which may have potential for treating IRI fatty liver. In this review, we summarize research on the function of STAT3 in liver IRI to provide references for its application in the clinic.
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Affiliation(s)
| | | | | | | | - Yujun Zhao
- Engineering and Technology Research Center for Transplantation Medicine of National Health Comission, Third Xiangya Hospital, Central South University, Changsha, China
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20
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Inaba Y, Hashiuchi E, Watanabe H, Kimura K, Oshima Y, Tsuchiya K, Murai S, Takahashi C, Matsumoto M, Kitajima S, Yamamoto Y, Honda M, Asahara SI, Ravnskjaer K, Horike SI, Kaneko S, Kasuga M, Nakano H, Harada K, Inoue H. The transcription factor ATF3 switches cell death from apoptosis to necroptosis in hepatic steatosis in male mice. Nat Commun 2023; 14:167. [PMID: 36690638 PMCID: PMC9871012 DOI: 10.1038/s41467-023-35804-w] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 01/03/2023] [Indexed: 01/24/2023] Open
Abstract
Hepatocellular death increases with hepatic steatosis aggravation, although its regulation remains unclear. Here we show that hepatic steatosis aggravation shifts the hepatocellular death mode from apoptosis to necroptosis, causing increased hepatocellular death. Our results reveal that the transcription factor ATF3 acts as a master regulator in this shift by inducing expression of RIPK3, a regulator of necroptosis. In severe hepatic steatosis, after partial hepatectomy, hepatic ATF3-deficient or -overexpressing mice display decreased or increased RIPK3 expression and necroptosis, respectively. In cultured hepatocytes, ATF3 changes TNFα-dependent cell death mode from apoptosis to necroptosis, as revealed by live-cell imaging. In non-alcoholic steatohepatitis (NASH) mice, hepatic ATF3 deficiency suppresses RIPK3 expression and hepatocellular death. In human NASH, hepatocellular damage is correlated with the frequency of hepatocytes expressing ATF3 or RIPK3, which overlap frequently. ATF3-dependent RIPK3 induction, causing a modal shift of hepatocellular death, can be a therapeutic target for steatosis-induced liver damage, including NASH.
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Affiliation(s)
- Yuka Inaba
- Metabolism and Nutrition Research Unit, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, Japan
- Department of Physiology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Emi Hashiuchi
- Department of Physiology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Hitoshi Watanabe
- Metabolism and Nutrition Research Unit, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, Japan
| | - Kumi Kimura
- Department of Biochemistry and Molecular Vascular Biology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Yu Oshima
- Department of Biochemistry and Molecular Vascular Biology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Kohsuke Tsuchiya
- Division of Immunology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Shin Murai
- Department of Biochemistry, Toho University School of Medicine, Tokyo, Japan
| | - Chiaki Takahashi
- Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Michihiro Matsumoto
- Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Shigetaka Kitajima
- Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yasuhiko Yamamoto
- Department of Biochemistry and Molecular Vascular Biology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Masao Honda
- Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
- Department of Clinical Laboratory Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
| | - Shun-Ichiro Asahara
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kim Ravnskjaer
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, Denmark
- Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, Odense M, Denmark
| | - Shin-Ichi Horike
- Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Masato Kasuga
- The Institute of Medical Science, Asahi Life Foundation, Tokyo, Japan
| | - Hiroyasu Nakano
- Department of Biochemistry, Toho University School of Medicine, Tokyo, Japan
| | - Kenichi Harada
- Departments of Human Pathology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Hiroshi Inoue
- Metabolism and Nutrition Research Unit, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, Japan.
- Department of Physiology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
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21
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Di-Iacovo N, Pieroni S, Piobbico D, Castelli M, Scopetti D, Ferracchiato S, Della-Fazia MA, Servillo G. Liver Regeneration and Immunity: A Tale to Tell. Int J Mol Sci 2023; 24:1176. [PMID: 36674692 PMCID: PMC9864482 DOI: 10.3390/ijms24021176] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 12/28/2022] [Accepted: 12/30/2022] [Indexed: 01/11/2023] Open
Abstract
The physiological importance of the liver is demonstrated by its unique and essential ability to regenerate following extensive injuries affecting its function. By regenerating, the liver reacts to hepatic damage and thus enables homeostasis to be restored. The aim of this review is to add new findings that integrate the regenerative pathway to the current knowledge. An optimal regeneration is achieved through the integration of two main pathways: IL-6/JAK/STAT3, which promotes hepatocyte proliferation, and PI3K/PDK1/Akt, which in turn enhances cell growth. Proliferation and cell growth are events that must be balanced during the three phases of the regenerative process: initiation, proliferation and termination. Achieving the correct liver/body weight ratio is ensured by several pathways as extracellular matrix signalling, apoptosis through caspase-3 activation, and molecules including transforming growth factor-beta, and cyclic adenosine monophosphate. The actors involved in the regenerative process are numerous and many of them are also pivotal players in both the immune and non-immune inflammatory process, that is observed in the early stages of hepatic regeneration. Balance of Th17/Treg is important in liver inflammatory process outcomes. Knowledge of liver regeneration will allow a more detailed characterisation of the molecular mechanisms that are crucial in the interplay between proliferation and inflammation.
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Affiliation(s)
- Nicola Di-Iacovo
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Stefania Pieroni
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Danilo Piobbico
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Marilena Castelli
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Damiano Scopetti
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Simona Ferracchiato
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Maria Agnese Della-Fazia
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Giuseppe Servillo
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
- Centro Universitario di Ricerca sulla Genomica Funzionale (C.U.R.Ge.F.), University of Perugia, 06123 Perugia, Italy
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22
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Jiang Y, Zhuang Z, Jia W, Wen Z, Xie M, Bai H, Bi Y, Wang Z, Chang G, Hou S, Chen G. Proteomic and phosphoproteomic analysis reveal threonine deficiency increases hepatic lipid deposition in Pekin ducks via reducing STAT phosphorylation. ANIMAL NUTRITION 2023; 13:249-260. [PMID: 37168449 PMCID: PMC10164787 DOI: 10.1016/j.aninu.2023.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 01/16/2023] [Accepted: 01/19/2023] [Indexed: 01/24/2023]
Abstract
Dietary threonine (Thr) deficiency enhances triglyceride (TG) deposition in the liver of Pekin ducks, which injures hepatic function and impairs growth performance. However, the underlying molecular mechanisms remain unclear. In the present study, we investigated the effects of dietary Thr deficiency on the expressions of proteins and phosphoproteins in liver of Pekin ducks, to identify the underlying molecular changes. A total of 300 one-day-old ducklings were divided into 3 groups with 10 replicates of 10 birds. All ducks were fed corn-wheat-peanut meal diets containing 0.46%, 0.71%, and 0.96% Thr, respectively, from 1 to 21 days of age. Growth performance, serum parameters, hepatic TG content, and expression of genes involved in lipid metabolism of Pekin ducks were determined. A Thr deficiency group (Thr-D, 0.46% Thr) and a Thr sufficiency group (Thr-S, 0.71% Thr) were selected for subsequent proteomic and phosphoproteomic analysis. The results showed that Thr-D reduced the growth performance (P < 0.001), and increased the plasma concentrations of cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and hepatic TG (P < 0.05). Thr-D increased gene expression related to fatty acid and TG synthesis (P < 0.05). A total of 176 proteins and 259 phosphosites (containing 198 phosphoproteins) were observed to be differentially expressed as a result of Thr-D. The upregulated proteins were enriched in the pathway related to amino acid metabolism, peroxisome. The downregulated proteins were enriched in linolenic and arachidonic acid metabolism, and the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. The upregulated phosphoproteins were enriched in the pathways related to fatty acid biosynthesis, fructose and mannose metabolism, and glycolysis/gluconeogenesis. Thr-D reduced the phosphorylation of STAT1 at S729 and STAT3 at S728, and expression of STAT5B. In contrast, Thr-D increased non-receptor tyrosine-protein kinase (TYK2) expression and STAT1 phosphorylation at S649. Taken together, dietary Thr-D increased hepatic TG accumulation by upregulating the expression of genes and proteins, and phosphoproteins related to fatty acid and triglyceride synthesis. Furthermore, these processes might be regulated by the JAK-STAT signaling pathway, especially the phosphorylation of STAT1 and STAT3.
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23
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Douglas K, Logan SM, Storey KB. Status of the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway in liver and skin of the freeze tolerant wood frog. Cryobiology 2022; 108:27-33. [PMID: 36100073 DOI: 10.1016/j.cryobiol.2022.08.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 07/21/2022] [Accepted: 08/19/2022] [Indexed: 11/03/2022]
Abstract
The wood frog (Rana sylvatica) has adapted full-body freezing and thawing as a means of sub-zero winter survival and early-breeding in ephemeral pools. One such protective process implicated recently in freeze-thaw tolerance is that of anti-apoptotic signaling, which has been proposed to play a cytoprotective role by modulating stress-induced death signals. This study employed the use of immunoblotting to examine response of a potent cell cycle and apoptosis regulator, known as the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, to freezing and thawing in the liver and skin of the wood frog. This pathway demonstrably exhibits factor- and tissue-specific changes between non-frozen, 24 h-frozen, and 8 h-thawed conditions. There were few changes in JAK-STAT proteins in frozen frogs, but protective changes were observed upon thaw: Elevated levels of pJAK3 and nuclear localization of pSTAT3 and pSTAT5 suggested an increase in anti-apoptotic signaling after thaw. By contrast, both STAT1 and STAT3 signaling appeared to increase in frozen skin, suggesting frogs use homeostatic regulation of apoptotic- and anti-apoptotic signals, in an antagonistic and compensatory manner. As such, these findings support that JAK-STAT pathway signaling modulation is a plausible adaptation that contributes to fast and reversible manipulation of anti-apoptotic signals, thus assisting in freeze survival of the wood frog.
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Affiliation(s)
- Kurtis Douglas
- Institute of Biochemistry & Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, ON, K1S 5B6, Canada
| | - Samantha M Logan
- Institute of Biochemistry & Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, ON, K1S 5B6, Canada
| | - Kenneth B Storey
- Institute of Biochemistry & Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, ON, K1S 5B6, Canada.
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24
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The Molecular Mechanisms of Panax ginseng in Treating Type 2 Diabetes Mellitus: Network Pharmacology Analysis and Molecular Docking Validation. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:3082109. [PMID: 36159557 PMCID: PMC9507733 DOI: 10.1155/2022/3082109] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 08/07/2022] [Accepted: 08/17/2022] [Indexed: 11/18/2022]
Abstract
Background Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder with a high global incidence. Panax ginseng has been used to treat T2DM in traditional medicine, with previous in vitro, in vivo, and clinical trial studies demonstrating its efficacy. This study aimed to determine the mechanism of P. ginseng in treating T2DM by network pharmacology. Methods The bioactive compounds of P. ginseng and corresponding targets of P. ginseng-T2DM were retrieved across multiple databases. The protein-protein interaction network was established using the STRING database and topological analysis helped identify the core target. Using the DAVID tool, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Finally, we checked the binding of core targets and bioactive compounds using molecular docking. Results The P. ginseng-T2DM networks mainly contained 22 bioactive compounds and 314 overlapping targets. The five most significant core targets were SRC, STAT3, MAPK1, AKT1, and PIK3R1. There were 244 GO terms and 95 KEGG pathways (adjusted p < 0.01) that were strongly correlated with diabetes-related signaling pathways, such as insulin resistance, the HIF-1 signaling pathway, the PI3K/Akt signaling pathway, the prolactin signaling pathway, the Rap1 signaling pathway, the Ras signaling pathway, the calcium signaling pathway, and the FoxO signaling pathway. Molecular docking results revealed that the top five core targets had a high binding affinity with the bioactive compounds of P. ginseng. Conclusion The bioactive compounds and targets in P. ginseng ameliorate T2DM by regulating insulin resistance and multiple signaling pathways.
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25
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Signaling pathways in obesity: mechanisms and therapeutic interventions. Signal Transduct Target Ther 2022; 7:298. [PMID: 36031641 PMCID: PMC9420733 DOI: 10.1038/s41392-022-01149-x] [Citation(s) in RCA: 171] [Impact Index Per Article: 57.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/26/2022] [Accepted: 08/08/2022] [Indexed: 12/19/2022] Open
Abstract
Obesity is a complex, chronic disease and global public health challenge. Characterized by excessive fat accumulation in the body, obesity sharply increases the risk of several diseases, such as type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease, and is linked to lower life expectancy. Although lifestyle intervention (diet and exercise) has remarkable effects on weight management, achieving long-term success at weight loss is extremely challenging, and the prevalence of obesity continues to rise worldwide. Over the past decades, the pathophysiology of obesity has been extensively investigated, and an increasing number of signal transduction pathways have been implicated in obesity, making it possible to fight obesity in a more effective and precise way. In this review, we summarize recent advances in the pathogenesis of obesity from both experimental and clinical studies, focusing on signaling pathways and their roles in the regulation of food intake, glucose homeostasis, adipogenesis, thermogenesis, and chronic inflammation. We also discuss the current anti-obesity drugs, as well as weight loss compounds in clinical trials, that target these signals. The evolving knowledge of signaling transduction may shed light on the future direction of obesity research, as we move into a new era of precision medicine.
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26
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Kim HY, Yoo YH. The Role of STAMP2 in Pathogenesis of Chronic Diseases Focusing on Nonalcoholic Fatty Liver Disease: A Review. Biomedicines 2022; 10:biomedicines10092082. [PMID: 36140186 PMCID: PMC9495648 DOI: 10.3390/biomedicines10092082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/16/2022] [Accepted: 08/24/2022] [Indexed: 11/16/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a major health issue. NAFLD can progress from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH). NASH can progress to cirrhosis or hepatocellular carcinoma. Unfortunately, there is no currently approved pharmacologic therapy for NAFLD patients. The six transmembrane protein of prostate 2 (STAMP2), a metalloreductase involved in iron and copper homeostasis, is well known for its critical role in the coordination of glucose/lipid metabolism and inflammation in metabolic tissues. We previously demonstrated that hepatic STAMP2 could be a suitable therapeutic target for NAFLD. In this review, we discuss the emerging role of STAMP2 in the dysregulation of iron metabolism events leading to NAFLD and suggest therapeutic strategies targeting STAMP2.
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27
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Tao Y, Jiang Q, Wang Q. Adipose tissue macrophages in remote modulation of hepatic glucose production. Front Immunol 2022; 13:998947. [PMID: 36091076 PMCID: PMC9449693 DOI: 10.3389/fimmu.2022.998947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 08/03/2022] [Indexed: 11/16/2022] Open
Abstract
Hepatic glucose production (HGP) is fine-regulated via glycogenolysis or gluconeogenesis to maintain physiological concentration of blood glucose during fasting-feeding cycle. Aberrant HGP leads to hyperglycemia in obesity-associated diabetes. Adipose tissue cooperates with the liver to regulate glycolipid metabolism. During these processes, adipose tissue macrophages (ATMs) change their profiles with various physio-pathological settings, producing diverse effects on HGP. Here, we briefly review the distinct phenotypes of ATMs under different nutrition states including feeding, fasting or overnutrition, and detail their effects on HGP. We discuss several pathways by which ATMs regulate hepatic gluconeogenesis or glycogenolysis, leading to favorable or unfavorable metabolic consequences. Furthermore, we summarize emerging therapeutic targets to correct metabolic disorders in morbid obesity or diabetes based on ATM-HGP axis. This review puts forward the importance and flexibility of ATMs in regulating HGP, proposing ATM-based HGP modulation as a potential therapeutic approach for obesity-associated metabolic dysfunction.
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Affiliation(s)
| | | | - Qun Wang
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
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28
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Janssen JAMJL. New Insights into the Role of Insulin and Hypothalamic-Pituitary-Adrenal (HPA) Axis in the Metabolic Syndrome. Int J Mol Sci 2022; 23:ijms23158178. [PMID: 35897752 PMCID: PMC9331414 DOI: 10.3390/ijms23158178] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 07/17/2022] [Accepted: 07/21/2022] [Indexed: 11/16/2022] Open
Abstract
Recent data suggests that (pre)diabetes onset is preceded by a period of hyperinsulinemia. Consumption of the "modern" Western diet, over-nutrition, genetic background, decreased hepatic insulin clearance, and fetal/metabolic programming may increase insulin secretion, thereby causing chronic hyperinsulinemia. Hyperinsulinemia is an important etiological factor in the development of metabolic syndrome, type 2 diabetes, cardiovascular disease, polycystic ovarian syndrome, and Alzheimer's disease. Recent data suggests that the onset of prediabetes and diabetes are preceded by a variable period of hyperinsulinemia. Emerging data suggest that chromic hyperinsulinemia is also a driving force for increased activation of the hypothalamic-adrenal-pituitary (HPA) axis in subjects with the metabolic syndrome, leading to a state of "functional hypercortisolism". This "functional hypercortisolism" by antagonizing insulin actions may prevent hypoglycemia. It also disturbs energy balance by shifting energy fluxes away from muscles toward abdominal fat stores. Synergistic effects of hyperinsulinemia and "functional hypercortisolism" promote abdominal visceral obesity and insulin resistance which are core pathophysiological components of the metabolic syndrome. It is hypothesized that hyperinsulinemia-induced increased activation of the HPA axis plays an important etiological role in the development of the metabolic syndrome and its consequences. Numerous studies have demonstrated reversibility of hyperinsulinemia with lifestyle, surgical, and pharmaceutical-based therapies. Longitudinal studies should be performed to investigate whether strategies that reduce hyperinsulinemia at an early stage are successfully in preventing increased activation of the HPA axis and the metabolic syndrome.
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Affiliation(s)
- Joseph A M J L Janssen
- Department of Internal Medicine, Erasmus Medical Center, Room Rg527, 3015 GD Rotterdam, The Netherlands
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Huang X, He Q, Zhu H, Fang Z, Che L, Lin Y, Xu S, Zhuo Y, Hua L, Wang J, Zou Y, Huang C, Li L, Xu H, Wu D, Feng B. Hepatic Leptin Signaling Improves Hyperglycemia by Stimulating MAPK Phosphatase-3 Protein Degradation via STAT3. Cell Mol Gastroenterol Hepatol 2022; 14:983-1001. [PMID: 35863745 PMCID: PMC9490031 DOI: 10.1016/j.jcmgh.2022.07.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 07/12/2022] [Accepted: 07/12/2022] [Indexed: 01/31/2023]
Abstract
BACKGROUND & AIMS Obesity-related hyperglycemia, with hepatic insulin resistance, has become an epidemic disease. Central neural leptin signaling was reported to improve hyperglycemia. The aim of this study was to investigate the effect of hepatic leptin signaling on controlling hyperglycemia. METHODS First, the effect of leptin signaling on gluconeogenesis was investigated in primary mouse hepatocytes and hepatoma cells. Second, glucose tolerance, insulin tolerance, blood glucose levels, and hepatic gluconeogenic gene expression were analyzed in obese mice overexpressing hepatic OBRb. Third, expression of mitogen-activated protein kinase phosphatase (MKP)-3, phosphorylation level of signal transducer and activator of transcription (STAT) 3, and extracellular regulated protein kinase (ERK) were analyzed in hepatocytes and mouse liver. Fourth, the role of MKP-3 in hepatic leptin signaling regulating gluconeogenesis was analyzed. Lastly, the role of ERK and STAT3 in the regulation of MKP-3 protein by leptin signaling was analyzed. RESULTS Activation of hepatic leptin signaling suppressed gluconeogenesis in both hepatocytes and obese mouse liver, and improved hyperglycemia, insulin tolerance, and glucose tolerance in obese mice. The protein level of MKP-3, which can promote gluconeogenesis, was decreased by leptin signaling in both hepatocytes and mouse liver. Mkp-3 deficiency abolished the effect of hepatic leptin signaling on suppressing gluconeogenesis in hepatocytes. STAT3 decreased the MKP-3 protein level, while inactivation of STAT3 abolished the effect of leptin signaling on reducing the MKP-3 protein level in hepatocytes. Moreover, STAT3 could combine with MKP-3 and phospho-ERK1/2, which induced the degradation of MKP-3, and leptin signaling enhanced the combination. CONCLUSIONS Hepatic leptin signaling could suppress gluconeogenesis at least partially by decreasing the MKP-3 protein level via STAT3-enhanced MKP-3 and ERK1/2 combination.
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Affiliation(s)
- Xiaohua Huang
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, China,Key Laboratory of Animal Disease-Resistant Nutrition of Ministry of Education, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Qin He
- Hallett Center for Diabetes and Endocrinology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island,School of international education, Xihua University, Chengdu, Sichuan, China
| | - Heng Zhu
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Zhengfeng Fang
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, China,Key Laboratory for Food Science and Human Health, College of Food Science, Sichuan Agricultural University, Ya’an, Sichuan, China
| | - Lianqiang Che
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Yan Lin
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Shengyu Xu
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Yong Zhuo
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Lun Hua
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Jianping Wang
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Yuanfeng Zou
- College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Chao Huang
- College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Lixia Li
- College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Haiyan Xu
- Hallett Center for Diabetes and Endocrinology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island,Department of Quantitative Biosciences, Merck & Co., Inc., Boston, Massachusetts
| | - De Wu
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, China,Key Laboratory of Animal Disease-Resistant Nutrition of Ministry of Education, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Bin Feng
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, China,Key Laboratory of Animal Disease-Resistant Nutrition of Ministry of Education, Sichuan Agricultural University, Chengdu, Sichuan, China,Hallett Center for Diabetes and Endocrinology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island,Key Laboratory for Food Science and Human Health, College of Food Science, Sichuan Agricultural University, Ya’an, Sichuan, China,Correspondence Address correspondence to: Bin Feng, PhD, Sichuan Agricultural University, 211 Huimin Road, Wenjiang District, Chengdu 611130, China. fax: (86) 028-82652669.
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Yuan Y, Li K, Teng F, Wang W, Zhou B, Zhou X, Lin J, Ye X, Deng Y, Liu W, Luo S, Zhang P, Liu D, Zheng M, Li J, Lu Y, Zhang H. Leukemia inhibitory factor protects against liver steatosis in nonalcoholic fatty liver disease patients and obese mice. J Biol Chem 2022; 298:101946. [PMID: 35447114 PMCID: PMC9123280 DOI: 10.1016/j.jbc.2022.101946] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 03/26/2022] [Accepted: 03/28/2022] [Indexed: 01/27/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. However, the molecular mechanisms that promote dysregulation of hepatic triglyceride metabolism and lead to NAFLD are poorly understood, and effective treatments are limited. Leukemia inhibitory factor (LIF) is a member of the interleukin-6 cytokine family and has been shown to regulate a variety of physiological processes, although its role in hepatic triglyceride metabolism remains unknown. In the present study, we measured circulating LIF levels by ELISA in 214 patients with biopsy-diagnosed NAFLD as well as 314 normal control patients. We further investigated the potential role and mechanism of LIF on hepatic lipid metabolism in obese mice. We found that circulating LIF levels correlated with the severity of liver steatosis. Patients with ballooning, fibrosis, lobular inflammation, and abnormally elevated liver injury markers alanine transaminase and aspartate aminotransferase also had higher levels of serum LIF than control patients. Furthermore, animal studies showed that white adipose tissue-derived LIF could ameliorate liver steatosis through activation of hepatic LIF receptor signaling pathways. Together, our results suggested that targeting LIF-LIF receptor signaling might be a promising strategy for treating NAFLD.
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Affiliation(s)
- Youwen Yuan
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Shock and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Kangli Li
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Shock and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Fei Teng
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Shock and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Weiwei Wang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Shock and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Bing Zhou
- The Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xuan Zhou
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Shock and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiayang Lin
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Shock and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xueru Ye
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Shock and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yajuan Deng
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Shock and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wenhui Liu
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Shock and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shenjian Luo
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Shock and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Peizhen Zhang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Shock and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Deying Liu
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Shock and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Minghua Zheng
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease, Zhejiang Province, Wenzhou, Zhejiang, China
| | - Jin Li
- Division of Endocrinology, Department of Medicine, Shanxi Medical University affiliated Second Hospital, Taiyuan, China
| | - Yan Lu
- The Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Huijie Zhang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Shock and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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Downton P, Sanna F, Maidstone R, Poolman TM, Hayter EA, Dickson SH, Ciccone NA, Early JO, Adamson A, Spiller DG, Simpkins DA, Baxter M, Fischer R, Rattray M, Loudon ASI, Gibbs JE, Bechtold DA, Ray DW. Chronic inflammatory arthritis drives systemic changes in circadian energy metabolism. Proc Natl Acad Sci U S A 2022; 119:e2112781119. [PMID: 35482925 PMCID: PMC9170023 DOI: 10.1073/pnas.2112781119] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 03/01/2022] [Indexed: 11/22/2022] Open
Abstract
Chronic inflammation underpins many human diseases. Morbidity and mortality associated with chronic inflammation are often mediated through metabolic dysfunction. Inflammatory and metabolic processes vary through circadian time, suggesting an important temporal crosstalk between these systems. Using an established mouse model of rheumatoid arthritis, we show that chronic inflammatory arthritis results in rhythmic joint inflammation and drives major changes in muscle and liver energy metabolism and rhythmic gene expression. Transcriptional and phosphoproteomic analyses revealed alterations in lipid metabolism and mitochondrial function associated with increased EGFR-JAK-STAT3 signaling. Metabolomic analyses confirmed rhythmic metabolic rewiring with impaired β-oxidation and lipid handling and revealed a pronounced shunt toward sphingolipid and ceramide accumulation. The arthritis-related production of ceramides was most pronounced during the day, which is the time of peak inflammation and increased reliance on fatty acid oxidation. Thus, our data demonstrate that localized joint inflammation drives a time-of-day–dependent build-up of bioactive lipid species driven by rhythmic inflammation and altered EGFR-STAT signaling.
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Affiliation(s)
- Polly Downton
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, United Kingdom
| | - Fabio Sanna
- National Institute for Health Research Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, OX3 9DU, United Kingdom
| | - Robert Maidstone
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, United Kingdom
- National Institute for Health Research Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, OX3 9DU, United Kingdom
| | - Toryn M. Poolman
- National Institute for Health Research Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, OX3 9DU, United Kingdom
| | - Edward A. Hayter
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, United Kingdom
| | - Suzanna H. Dickson
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, United Kingdom
| | - Nick A. Ciccone
- National Institute for Health Research Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, OX3 9DU, United Kingdom
| | - James O. Early
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, United Kingdom
| | - Antony Adamson
- Genome Editing Unit, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, United Kingdom
| | - David G. Spiller
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, United Kingdom
| | - Devin A. Simpkins
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, United Kingdom
| | - Matthew Baxter
- National Institute for Health Research Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, OX3 9DU, United Kingdom
| | - Roman Fischer
- Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, OX3 7FZ, United Kingdom
| | - Magnus Rattray
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, United Kingdom
| | - Andrew S. I. Loudon
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, United Kingdom
| | - Julie E. Gibbs
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, United Kingdom
| | - David A. Bechtold
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, United Kingdom
| | - David W. Ray
- National Institute for Health Research Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, OX3 9DU, United Kingdom
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Bini S, Pecce V, Di Costanzo A, Polito L, Ghadiri A, Minicocci I, Tambaro F, Covino S, Arca M, D’Erasmo L. The Fibrinogen-like Domain of ANGPTL3 Facilitates Lipolysis in 3T3-L1 Cells by Activating the Intracellular Erk Pathway. Biomolecules 2022; 12:biom12040585. [PMID: 35454174 PMCID: PMC9028860 DOI: 10.3390/biom12040585] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 04/13/2022] [Accepted: 04/14/2022] [Indexed: 12/18/2022] Open
Abstract
Background: ANGPTL3 stimulates lipolysis in adipocytes, but the underlying molecular mechanism is yet unknown. The C-terminal fibrinogen-like domain of ANGPTL3 (ANGPTL3-Fld) activates the AKT pathway in endothelial cells. Hence, we evaluated whether ANGPTL3-Fld stimulates lipolysis in adipocytes through the MAPK kinase pathway. Materials and Methods: 3T3-L1 adipocytes were treated with isoproterenol (ISO), ANGPTL3-Fld, or both. Lipolysis was evaluated through the release of free fatty acids (FFAs) in the culture medium. The activation status of intracellular kinases was evaluated with and without the inhibition of the BRAF–ERK arm of the MAPK pathway. Results: ANGPTL3-Fld alone was not able to activate lipolysis, while the combination of ANGPTL3-Fld and ISO determined a 10-fold enrichment of the FFA concentration in the culture medium with an incremental effect (twofold) when compared with ISO alone. ANGPTL3-Fld alone inhibited hormone-sensitive lipase (HSL), whereas the treatment with ISO induced the activation of HSL. The net balance of ANGPTL3-Fld and ISO cotreatment resulted in HSL activation. The results indicate that ANGPTL3-Fld generated an intracellular activation signal involving the MAPK–ERK pathway, possibly through the PDGFRβ—PLCγ-AMPK axis. Conclusion: ANGPTL3-Fld appears to act as a facilitator of lipolysis in adipocytes, and this effect was driven by a signal mediated by a pathway that is different from the canonical β-adrenergic stimulus.
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Zhuang L, Jia K, Chen C, Li Z, Zhao J, Hu J, Zhang H, Fan Q, Huang C, Xie H, Lu L, Shen W, Ning G, Wang J, Zhang R, Chen K, Yan X. DYRK1B-STAT3 Drives Cardiac Hypertrophy and Heart Failure by Impairing Mitochondrial Bioenergetics. Circulation 2022; 145:829-846. [PMID: 35235343 DOI: 10.1161/circulationaha.121.055727] [Citation(s) in RCA: 86] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Heart failure is a global public health issue that is associated with increasing morbidity and mortality. Previous studies have suggested that mitochondrial dysfunction plays critical roles in the progression of heart failure; however, the underlying mechanisms remain unclear. Because kinases have been reported to modulate mitochondrial function, we investigated the effects of DYRK1B (dual-specificity tyrosine-regulated kinase 1B) on mitochondrial bioenergetics, cardiac hypertrophy, and heart failure. METHODS We engineered DYRK1B transgenic and knockout mice and used transverse aortic constriction to produce an in vivo model of cardiac hypertrophy. The effects of DYRK1B and its downstream mediators were subsequently elucidated using RNA-sequencing analysis and mitochondrial functional analysis. RESULTS We found that DYRK1B expression was clearly upregulated in failing human myocardium and in hypertrophic murine hearts, as well. Cardiac-specific DYRK1B overexpression resulted in cardiac dysfunction accompanied by a decline in the left ventricular ejection fraction, fraction shortening, and increased cardiac fibrosis. In striking contrast to DYRK1B overexpression, the deletion of DYRK1B mitigated transverse aortic constriction-induced cardiac hypertrophy and heart failure. Mechanistically, DYRK1B was positively associated with impaired mitochondrial bioenergetics by directly binding with STAT3 to increase its phosphorylation and nuclear accumulation, ultimately contributing toward the downregulation of PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1α). Furthermore, the inhibition of DYRK1B or STAT3 activity using specific inhibitors was able to restore cardiac performance by rejuvenating mitochondrial bioenergetics. CONCLUSIONS Taken together, the findings of this study provide new insights into the previously unrecognized role of DYRK1B in mitochondrial bioenergetics and the progression of cardiac hypertrophy and heart failure. Consequently, these findings may provide new therapeutic options for patients with heart failure.
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Affiliation(s)
- Lingfang Zhuang
- Department of Cardiovascular Medicine (L.Z., K..J., Z.L., J.Z., J.H., H.Z., Q.F., C.H., H.X., L.L., W.S., R.Z., K.C., X.Y.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Ruijin Hospital, Institute of Cardiovascular Diseases (L.Z., K..J., Z.L., J.Z., J.H., H.Z., Q.F., C.H., H.X., L.L., W.S., R.Z., X.Y.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Kangni Jia
- Department of Cardiovascular Medicine (L.Z., K..J., Z.L., J.Z., J.H., H.Z., Q.F., C.H., H.X., L.L., W.S., R.Z., K.C., X.Y.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Ruijin Hospital, Institute of Cardiovascular Diseases (L.Z., K..J., Z.L., J.Z., J.H., H.Z., Q.F., C.H., H.X., L.L., W.S., R.Z., X.Y.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Chen Chen
- Department of Cardiovascular Medicine (L.Z., K..J., Z.L., J.Z., J.H., H.Z., Q.F., C.H., H.X., L.L., W.S., R.Z., K.C., X.Y.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (C.C.)
| | - Zhigang Li
- Department of Cardiovascular Medicine (L.Z., K..J., Z.L., J.Z., J.H., H.Z., Q.F., C.H., H.X., L.L., W.S., R.Z., K.C., X.Y.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Ruijin Hospital, Institute of Cardiovascular Diseases (L.Z., K..J., Z.L., J.Z., J.H., H.Z., Q.F., C.H., H.X., L.L., W.S., R.Z., X.Y.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Jiaxin Zhao
- Department of Cardiovascular Medicine (L.Z., K..J., Z.L., J.Z., J.H., H.Z., Q.F., C.H., H.X., L.L., W.S., R.Z., K.C., X.Y.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases (G.N., J.W.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Jian Hu
- Department of Cardiovascular Medicine (L.Z., K..J., Z.L., J.Z., J.H., H.Z., Q.F., C.H., H.X., L.L., W.S., R.Z., K.C., X.Y.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases (G.N., J.W.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Hang Zhang
- Department of Cardiovascular Medicine (L.Z., K..J., Z.L., J.Z., J.H., H.Z., Q.F., C.H., H.X., L.L., W.S., R.Z., K.C., X.Y.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases (G.N., J.W.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Qin Fan
- Department of Cardiovascular Medicine (L.Z., K..J., Z.L., J.Z., J.H., H.Z., Q.F., C.H., H.X., L.L., W.S., R.Z., K.C., X.Y.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Ruijin Hospital, Institute of Cardiovascular Diseases (L.Z., K..J., Z.L., J.Z., J.H., H.Z., Q.F., C.H., H.X., L.L., W.S., R.Z., X.Y.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Chunkai Huang
- Department of Cardiovascular Medicine (L.Z., K..J., Z.L., J.Z., J.H., H.Z., Q.F., C.H., H.X., L.L., W.S., R.Z., K.C., X.Y.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases (G.N., J.W.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Hongyang Xie
- Department of Cardiovascular Medicine (L.Z., K..J., Z.L., J.Z., J.H., H.Z., Q.F., C.H., H.X., L.L., W.S., R.Z., K.C., X.Y.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Ruijin Hospital, Institute of Cardiovascular Diseases (L.Z., K..J., Z.L., J.Z., J.H., H.Z., Q.F., C.H., H.X., L.L., W.S., R.Z., X.Y.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Lin Lu
- Department of Cardiovascular Medicine (L.Z., K..J., Z.L., J.Z., J.H., H.Z., Q.F., C.H., H.X., L.L., W.S., R.Z., K.C., X.Y.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Ruijin Hospital, Institute of Cardiovascular Diseases (L.Z., K..J., Z.L., J.Z., J.H., H.Z., Q.F., C.H., H.X., L.L., W.S., R.Z., X.Y.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Weifeng Shen
- Department of Cardiovascular Medicine (L.Z., K..J., Z.L., J.Z., J.H., H.Z., Q.F., C.H., H.X., L.L., W.S., R.Z., K.C., X.Y.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Ruijin Hospital, Institute of Cardiovascular Diseases (L.Z., K..J., Z.L., J.Z., J.H., H.Z., Q.F., C.H., H.X., L.L., W.S., R.Z., X.Y.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Guang Ning
- Department of Cardiovascular Medicine (L.Z., K..J., Z.L., J.Z., J.H., H.Z., Q.F., C.H., H.X., L.L., W.S., R.Z., K.C., X.Y.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases (G.N., J.W.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Jiqiu Wang
- Department of Cardiovascular Medicine (L.Z., K..J., Z.L., J.Z., J.H., H.Z., Q.F., C.H., H.X., L.L., W.S., R.Z., K.C., X.Y.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases (G.N., J.W.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Ruiyan Zhang
- Department of Cardiovascular Medicine (L.Z., K..J., Z.L., J.Z., J.H., H.Z., Q.F., C.H., H.X., L.L., W.S., R.Z., K.C., X.Y.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases (G.N., J.W.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Kang Chen
- Department of Cardiovascular Medicine (L.Z., K..J., Z.L., J.Z., J.H., H.Z., Q.F., C.H., H.X., L.L., W.S., R.Z., K.C., X.Y.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Xiaoxiang Yan
- Department of Cardiovascular Medicine (L.Z., K..J., Z.L., J.Z., J.H., H.Z., Q.F., C.H., H.X., L.L., W.S., R.Z., K.C., X.Y.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Ruijin Hospital, Institute of Cardiovascular Diseases (L.Z., K..J., Z.L., J.Z., J.H., H.Z., Q.F., C.H., H.X., L.L., W.S., R.Z., X.Y.), Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
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Matsubara Y, Kiyohara H, Teratani T, Mikami Y, Kanai T. Organ and brain crosstalk: The liver-brain axis in gastrointestinal, liver, and pancreatic diseases. Neuropharmacology 2021; 205:108915. [PMID: 34919906 DOI: 10.1016/j.neuropharm.2021.108915] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 12/01/2021] [Accepted: 12/06/2021] [Indexed: 12/15/2022]
Abstract
The liver is the largest organ in the human body and is responsible for the metabolism and storage of the three principal nutrients: carbohydrates, fats, and proteins. In addition, the liver contributes to the breakdown and excretion of alcohol, medicinal agents, and toxic substances and the production and secretion of bile. In addition to its role as a metabolic centre, the liver has recently attracted attention for its function in the liver-brain axis, which interacts closely with the central nervous system via the autonomic nervous system, including the vagus nerve. The liver-brain axis influences the control of eating behaviour in the central nervous system through stimuli from the liver. Conversely, neural signals from the central nervous system influence glucose, lipid, and protein metabolism in the liver. The liver also receives a constant influx of nutrients and hormones from the intestinal tract and compounds of bacterial origin via the portal system. As a result, the intestinal tract and liver are involved in various immunological interactions. A good example is the co-occurrence of primary sclerosing cholangitis and ulcerative colitis. These heterogeneous roles of the liver-brain axis are mediated via the vagus nerve in an asymmetrical manner. In this review, we provide an overview of these interactions, mainly with the liver but also with the brain and gut.
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Affiliation(s)
- Yuta Matsubara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Hiroki Kiyohara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Toshiaki Teratani
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Yohei Mikami
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan; AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, 100-0004, Japan.
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Abstract
Janus protein tyrosine kinase (JAK) has the ability to activate signal transducer and activator of transcription (STAT). STAT3 is a valued member of the JAK/STAT signaling pathway. In recent years, several studies have documented that STAT3 is closely related to the occurrence and development of liver fibrosis caused by various factors. Activation of STAT3 can play anti- or pro-inflammatory roles in the pathogenesis of liver fibrosis. This article reviewed the recent studies on STAT3 in the development of various liver fibrosis to find a more effective method to relieve and cure liver diseases, such as hepatitis B virus (HBV), non-alcoholic fatty liver disease (NAFLD), schistosomiasis, and chemical liver injury.
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Jia R, Fu Y, Xu L, Li H, Li Y, Liu L, Ma Z, Sun D, Han B. Associations between polymorphisms of SLC22A7, NGFR, ARNTL and PPP2R2B genes and Milk production traits in Chinese Holstein. BMC Genom Data 2021; 22:47. [PMID: 34732138 PMCID: PMC8567656 DOI: 10.1186/s12863-021-01002-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 10/22/2021] [Indexed: 12/27/2022] Open
Abstract
Background Our preliminary work confirmed that, SLC22A7 (solute carrier family 22 member 7), NGFR (nerve growth factor receptor), ARNTL (aryl hydrocarbon receptor nuclear translocator like) and PPP2R2B (protein phosphatase 2 regulatory subunit Bβ) genes were differentially expressed in dairy cows during different stages of lactation, and involved in the lipid metabolism through insulin, PI3K-Akt, MAPK, AMPK, mTOR, and PPAR signaling pathways, so we considered these four genes as the candidates affecting milk production traits. In this study, we detected polymorphisms of the four genes and verified their genetic effects on milk yield and composition traits in a Chinese Holstein cow population. Results By resequencing the whole coding region and part of the flanking region of SLC22A7, NGFR, ARNTL and PPP2R2B, we totally found 20 SNPs, of which five were located in SLC22A7, eight in NGFR, three in ARNTL, and four in PPP2R2B. Using Haploview4.2, we found three haplotype blocks including five SNPs in SLC22A7, eight in NGFR and three in ARNTL. Single-SNP association analysis showed that 19 out of 20 SNPs were significantly associated with at least one of milk yield, fat yield, fat percentage, protein yield or protein percentage in the first and second lactations (P < 0.05). Haplotype-based association analysis showed that the three haplotypes were significantly associated with at least one of milk yield, fat yield, fat percentage, protein yield or protein percentage (P < 0.05). Further, we used SOPMA software to predict a SNP, 19:g.37095131C > T in NGFR, changed the structure of NGFR protein. In addition, we used Jaspar software to found that four SNPs, 19:g.37113872C > G,19:g.37113157C > T, and 19:g.37112276C > T in NGFR and 15:g.39320936A > G in ARNTL, could change the transcription factor binding sites and might affect the expression of the corresponding genes. These five SNPs might be the potential functional mutations for milk production traits in dairy cattle. Conclusions In summary, we proved that SLC22A7, NGFR, ARNTL and PPP2R2B have significant genetic effects on milk production traits. The valuable SNPs can be used as candidate genetic markers for genomic selection of dairy cattle, and the effects of these SNPs on other traits need to be further verified. Supplementary Information The online version contains supplementary material available at 10.1186/s12863-021-01002-0.
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Affiliation(s)
- Ruike Jia
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs, National Engineering Laboratory for Animal Breeding, China Agricultural University, No. 2 Yuanmingyuan West Road, Haidian District, Beijing, 100193, China
| | - Yihan Fu
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs, National Engineering Laboratory for Animal Breeding, China Agricultural University, No. 2 Yuanmingyuan West Road, Haidian District, Beijing, 100193, China
| | - Lingna Xu
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs, National Engineering Laboratory for Animal Breeding, China Agricultural University, No. 2 Yuanmingyuan West Road, Haidian District, Beijing, 100193, China
| | - Houcheng Li
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs, National Engineering Laboratory for Animal Breeding, China Agricultural University, No. 2 Yuanmingyuan West Road, Haidian District, Beijing, 100193, China
| | - Yanhua Li
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs, National Engineering Laboratory for Animal Breeding, China Agricultural University, No. 2 Yuanmingyuan West Road, Haidian District, Beijing, 100193, China.,Beijing Dairy Cattle Center, Beijing, 100192, China
| | - Lin Liu
- Beijing Dairy Cattle Center, Beijing, 100192, China
| | - Zhu Ma
- Beijing Dairy Cattle Center, Beijing, 100192, China
| | - Dongxiao Sun
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs, National Engineering Laboratory for Animal Breeding, China Agricultural University, No. 2 Yuanmingyuan West Road, Haidian District, Beijing, 100193, China
| | - Bo Han
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs, National Engineering Laboratory for Animal Breeding, China Agricultural University, No. 2 Yuanmingyuan West Road, Haidian District, Beijing, 100193, China.
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Goon DE, Ab-Rahim S, Mohd Sakri AH, Mazlan M, Tan JK, Abdul Aziz M, Mohd Noor N, Ibrahim E, Sheikh Abdul Kadir SH. Untargeted serum metabolites profiling in high-fat diet mice supplemented with enhanced palm tocotrienol-rich fraction using UHPLC-MS. Sci Rep 2021; 11:21001. [PMID: 34697380 PMCID: PMC8546078 DOI: 10.1038/s41598-021-00454-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 10/01/2021] [Indexed: 01/14/2023] Open
Abstract
Excessive high fat dietary intake promotes risk of developing non-alcoholic fatty liver disease (NAFLD) and predisposed with oxidative stress. Palm based tocotrienol-rich fraction (TRF) has been reported able to ameliorate oxidative stress but exhibited poor bioavailability. Thus, we investigated whether an enhanced formulation of TRF in combination with palm kernel oil (medium-chain triglycerides) (ETRF) could ameliorate the effect of high-fat diet (HFD) on leptin-deficient male mice. All the animals were divided into HFD only (HFD group), HFD supplemented with ETRF (ETRF group) and HFD supplemented with TRF (TRF group) and HFD supplemented with PKO (PKO group). After 6 weeks, sera were collected for untargeted metabolite profiling using UHPLC-Orbitrap MS. Univariate analysis unveiled alternation in metabolites for bile acids, amino acids, fatty acids, sphingolipids, and alkaloids. Bile acids, lysine, arachidonic acid, and sphingolipids were downregulated while xanthine and hypoxanthine were upregulated in TRF and ETRF group. The regulation of these metabolites suggests that ETRF may promote better fatty acid oxidation, reduce oxidative stress and pro-inflammatory metabolites and acts as anti-inflammatory in fatty liver compared to TRF. Metabolites regulated by ETRF also provide insight of its role in fatty liver. However, further investigation is warranted to identify the mechanisms involved.
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Affiliation(s)
- Danial Efendy Goon
- Institute of Medical Molecular Biotechnology (IMMB), Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia
- Department of Biochemistry, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia
| | - Sharaniza Ab-Rahim
- Department of Biochemistry, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia.
| | - Amir Hakimi Mohd Sakri
- Institute of Medical Molecular Biotechnology (IMMB), Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia
- Department of Physiology, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia
| | - Musalmah Mazlan
- Department of Biochemistry, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia
| | - Jen Kit Tan
- Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, 56000, Kuala Lumpur, Malaysia
| | - Mardiana Abdul Aziz
- Department of Pathology, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, 47000, Sungai Buloh, Selangor, Malaysia
| | - Norizal Mohd Noor
- Department of Pathology, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, 47000, Sungai Buloh, Selangor, Malaysia
| | - Effendi Ibrahim
- Department of Physiology, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia
| | - Siti Hamimah Sheikh Abdul Kadir
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia.
- Department of Biochemistry, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia.
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Shriki A, Lanton T, Sonnenblick A, Levkovitch-Siany O, Eidelshtein D, Abramovitch R, Rosenberg N, Pappo O, Elgavish S, Nevo Y, Safadi R, Peled A, Rose-John S, Galun E, Axelrod JH. Multiple Roles of IL6 in Hepatic Injury, Steatosis, and Senescence Aggregate to Suppress Tumorigenesis. Cancer Res 2021; 81:4766-4777. [PMID: 34117031 DOI: 10.1158/0008-5472.can-21-0321] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 05/05/2021] [Accepted: 06/10/2021] [Indexed: 11/16/2022]
Abstract
Hepatocellular carcinoma (HCC) typically develops on a background of chronic hepatitis for which the proinflammatory cytokine IL6 is conventionally considered a crucial driving factor. Paradoxically, IL6 also acts as a hepatoprotective factor in chronic liver injury. Here we used the multidrug-resistant gene 2 knockout (Mdr2-/-) mouse model to elucidate potential roles of IL6 in chronic hepatitis-associated liver cancer. Long-term analysis of three separate IL6/Stat3 signaling-deficient Mdr2-/- strains revealed aggravated liver injury with increased dysplastic nodule formation and significantly accelerated tumorigenesis in all strains. Tumorigenesis in the IL6/Stat3-perturbed models was strongly associated with enhanced macrophage accumulation and hepatosteatosis, phenotypes of nonalcoholic steatohepatitis (NASH), as well as with significant reductions in senescence and the senescence-associated secretory phenotype (SASP) accompanied by increased hepatocyte proliferation. These findings reveal a crucial suppressive role for IL6/Stat3 signaling in chronic hepatitis-associated hepatocarcinogenesis by impeding protumorigenic NASH-associated phenotypes and by reinforcing the antitumorigenic effects of the SASP. SIGNIFICANCE: These findings describe a context-dependent role of IL6 signaling in hepatocarcinogenesis and predict that increased IL6-neutralizing sgp130 levels in some patients with NASH may herald early HCC development.See related commentary by Huynh and Ernst, p. 4671.
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Affiliation(s)
- Anat Shriki
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Tali Lanton
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Amir Sonnenblick
- Oncology Division, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Orr Levkovitch-Siany
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Dana Eidelshtein
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Rinat Abramovitch
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
- The Wohl Institute for Translational Medicine, Human Biology Research Center, Hadassah University Medical Center, Jerusalem, Israel
| | - Nofar Rosenberg
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Orit Pappo
- Department of Pathology, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Sharona Elgavish
- Bioinformatics Unit, The Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Hadassah Medical School, Ein Karem, Jerusalem, Israel
| | - Yuval Nevo
- Bioinformatics Unit, The Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Hadassah Medical School, Ein Karem, Jerusalem, Israel
| | - Rifaat Safadi
- Liver Unit, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Amnon Peled
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Stefan Rose-John
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
| | - Eithan Galun
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
| | - Jonathan H Axelrod
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
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Song CC, Chen GH, Zhong CC, Chen F, Chen SW, Luo Z. Transcriptional responses of four slc30a/znt family members and their roles in Zn homeostatic modulation in yellow catfish Pelteobagrus fulvidraco. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2021; 1864:194723. [PMID: 34116248 DOI: 10.1016/j.bbagrm.2021.194723] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 05/09/2021] [Accepted: 05/29/2021] [Indexed: 12/12/2022]
Abstract
The study characterized their regulatory functions of four znt members (znt1, znt2, znt6 and znt8) in Zn homeostasis in vertebrates. We found that the -1281/-1296 bp locus on the znt1 promoter, the -1/-16 bp locus on the znt2 promoter, the -825/-839 bp locus on the znt6 promoter, the -165/-180 bp locus and the -274/-292 bp STAT3 locus on the znt8 promoter were functional MTF-1 binding sites and had metal responsive element (MRE). Zn incubation increased activities of four znt promoters, which was mediated by MRE sites on znt1, znt2, znt6 and znt8 promoters and by STAT3 binding site on znt8 promoter. Moreover, Zn activated the transcription of these znts genes through MTF-1-MRE-dependent pathway. Zn incubation up-regulated the mRNA and total protein expression of ZnT1, ZnT2 and ZnT8 at both 24 h and 48 h. Overall, for the first time, this study offered novel insights for regulatory mechanism of Zn homeostasis in vertebrates.
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Affiliation(s)
- Chang-Chun Song
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Fishery College, Huazhong Agricultural University, Wuhan 430070, China
| | - Guang-Hui Chen
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Fishery College, Huazhong Agricultural University, Wuhan 430070, China
| | - Chong-Chao Zhong
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Fishery College, Huazhong Agricultural University, Wuhan 430070, China
| | - Fang Chen
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Fishery College, Huazhong Agricultural University, Wuhan 430070, China
| | - Shu-Wei Chen
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Fishery College, Huazhong Agricultural University, Wuhan 430070, China
| | - Zhi Luo
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Fishery College, Huazhong Agricultural University, Wuhan 430070, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China.
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Wei D, Wu S, Liu J, Zhang X, Guan X, Gao L, Xu Z. Theobromine ameliorates nonalcoholic fatty liver disease by regulating hepatic lipid metabolism via mTOR signaling pathway in vivo and in vitro. Can J Physiol Pharmacol 2021; 99:775-785. [PMID: 33290156 DOI: 10.1139/cjpp-2020-0259] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Theobromine, a methylxanthine present in cocoa, has been shown to possess many beneficial pharmacological properties such as anti-oxidative stress, anti-inflammatory property, and anti-microbial activity. In this study, we investigated the effects of theobromine on nonalcoholic fatty liver disease (NAFLD) and the possible underlying mechanisms in vivo and in vitro. The results showed that theobromine reduced body weight and fat mass and improved dyslipidemia. Theobromine mitigated liver injury and significantly reduced hepatic triglyceride level in mice with obesity. Histological examinations also showed hepatic steatosis was alleviated after theobromine treatment. Furthermore, theobromine reversed the elevated mRNA and protein expression of SREBP-1c, FASN, CD36, FABP4, and the suppressed expression of PPARα and CPT1a in the liver of mice with obesity, which were responsible for lipogenesis, fatty acid uptake, and fatty acid oxidation respectively. In vitro, theobromine also downregulated SREBP-1c, FASN, CD36, FABP4 and upregulated PPARα and CPT1a mRNA and protein levels in hepatocytes in a dose-dependent manner, while these changes were reversed by L-leucine, a mammalian target of rapamycin (mTOR) agonist. The present study demonstrated that theobromine improved NAFLD by inhibiting lipogenesis and fatty acid uptake and promoting fatty acid oxidation in the liver and hepatocytes, which might be associated with its suppression of mTOR signaling pathway. Novelty: Theobromine protects against high-fat diet - induced NAFLD. Theobromine inhibits lipogenesis and fatty acid uptake and promotes fatty acid oxidation in the liver and hepatocytes via inhibiting mTOR signaling pathway.
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Affiliation(s)
- Dan Wei
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China
| | - Shaofei Wu
- Department of Hepatology, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China
| | - Jie Liu
- Department of Public Health, Tengzhou Central People's Hospital, Zaozhuang, Shandong, China
| | - Xiaoqian Zhang
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China
| | - Xiaoling Guan
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China
| | - Li Gao
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China
| | - Zhipeng Xu
- Department of Urology, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China
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Abstract
The immune and endocrine systems collectively control homeostasis in the body. The endocrine system ensures that values of essential factors and nutrients such as glucose, electrolytes and vitamins are maintained within threshold values. The immune system resolves local disruptions in tissue homeostasis, caused by pathogens or malfunctioning cells. The immediate goals of these two systems do not always align. The immune system benefits from optimal access to nutrients for itself and restriction of nutrient availability to all other organs to limit pathogen replication. The endocrine system aims to ensure optimal nutrient access for all organs, limited only by the nutrients stores that the body has available. The actual state of homeostatic parameters such as blood glucose levels represents a careful balance based on regulatory signals from the immune and endocrine systems. This state is not static but continuously adjusted in response to changes in the current metabolic needs of the body, the amount of resources it has available and the level of threats it encounters. This balance is maintained by the ability of the immune and endocrine systems to interact and co-regulate systemic metabolism. In context of metabolic disease, this system is disrupted, which impairs functionality of both systems. The failure of the endocrine system to retain levels of nutrients such as glucose within threshold values impairs functionality of the immune system. In addition, metabolic stress of organs in context of obesity is perceived by the immune system as a disruption in local homeostasis, which it tries to resolve by the excretion of factors which further disrupt normal metabolic control. In this chapter, we will discuss how the immune and endocrine systems interact under homeostatic conditions and during infection with a focus on blood glucose regulation. In addition, we will discuss how this system fails in the context of metabolic disease.
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Wang YN, Liu S, Jia T, Feng Y, Xu X, Zhang D. T Cell Protein Tyrosine Phosphatase in Glucose Metabolism. Front Cell Dev Biol 2021; 9:682947. [PMID: 34268308 PMCID: PMC8276021 DOI: 10.3389/fcell.2021.682947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 06/09/2021] [Indexed: 11/17/2022] Open
Abstract
T cell protein tyrosine phosphatase (TCPTP), a vital regulator in glucose metabolism, inflammatory responses, and tumor processes, is increasingly considered a promising target for disease treatments and illness control. This review discusses the structure, substrates and main biological functions of TCPTP, as well as its regulatory effect in glucose metabolism, as an attempt to be referenced for formulating treatment strategies of metabolic disorders. Given the complicated regulation functions in different tissues and organs of TCPTP, the development of drugs inhibiting TCPTP with a higher specificity and a better biocompatibility is recognized as a promising therapeutic strategy for diabetes or obesity. Besides, treatments targeting TCPTP in a specific tissue or organ are suggested to be considerably promising.
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Affiliation(s)
- Ya-Nan Wang
- Department of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Key Laboratory of Oral Tissue Regeneration, Jinan, China.,Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Shiyue Liu
- Shandong Key Laboratory of Oral Tissue Regeneration, Jinan, China.,Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China.,Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Tingting Jia
- Department of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Key Laboratory of Oral Tissue Regeneration, Jinan, China.,Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Yao Feng
- Department of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Key Laboratory of Oral Tissue Regeneration, Jinan, China.,Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Xin Xu
- Department of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Key Laboratory of Oral Tissue Regeneration, Jinan, China.,Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Dongjiao Zhang
- Department of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Key Laboratory of Oral Tissue Regeneration, Jinan, China.,Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
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Endocrine role of bone in the regulation of energy metabolism. Bone Res 2021; 9:25. [PMID: 34016950 PMCID: PMC8137703 DOI: 10.1038/s41413-021-00142-4] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 12/20/2020] [Accepted: 01/12/2021] [Indexed: 02/06/2023] Open
Abstract
Bone mainly functions as a supportive framework for the whole body and is the major regulator of calcium homeostasis and hematopoietic function. Recently, an increasing number of studies have characterized the significance of bone as an endocrine organ, suggesting that bone-derived factors regulate local bone metabolism and metabolic functions. In addition, these factors can regulate global energy homeostasis by altering insulin sensitivity, feeding behavior, and adipocyte commitment. These findings may provide a new pathological mechanism for related metabolic diseases or be used in the diagnosis, treatment, and prevention of metabolic diseases such as osteoporosis, obesity, and diabetes mellitus. In this review, we summarize the regulatory effect of bone and bone-derived factors on energy metabolism and discuss directions for future research.
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44
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Adewale Q, Khan AF, Carbonell F, Iturria-Medina Y, Alzheimer's Disease Neuroimaging Initiative. Integrated transcriptomic and neuroimaging brain model decodes biological mechanisms in aging and Alzheimer's disease. eLife 2021; 10:e62589. [PMID: 34002691 PMCID: PMC8131100 DOI: 10.7554/elife.62589] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 03/24/2021] [Indexed: 02/07/2023] Open
Abstract
Both healthy aging and Alzheimer's disease (AD) are characterized by concurrent alterations in several biological factors. However, generative brain models of aging and AD are limited in incorporating the measures of these biological factors at different spatial resolutions. Here, we propose a personalized bottom-up spatiotemporal brain model that accounts for the direct interplay between hundreds of RNA transcripts and multiple macroscopic neuroimaging modalities (PET, MRI). In normal elderly and AD participants, the model identifies top genes modulating tau and amyloid-β burdens, vascular flow, glucose metabolism, functional activity, and atrophy to drive cognitive decline. The results also revealed that AD and healthy aging share specific biological mechanisms, even though AD is a separate entity with considerably more altered pathways. Overall, this personalized model offers novel insights into the multiscale alterations in the elderly brain, with important implications for identifying effective genetic targets for extending healthy aging and treating AD progression.
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Affiliation(s)
- Quadri Adewale
- Neurology and Neurosurgery Department, Montreal Neurological Institute, McGill UniversityMontrealCanada
- McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill UniversityMontrealCanada
- Ludmer Centre for Neuroinformatics and Mental Health, McGill UniversityMontrealCanada
| | - Ahmed F Khan
- Neurology and Neurosurgery Department, Montreal Neurological Institute, McGill UniversityMontrealCanada
- McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill UniversityMontrealCanada
- Ludmer Centre for Neuroinformatics and Mental Health, McGill UniversityMontrealCanada
| | | | - Yasser Iturria-Medina
- Neurology and Neurosurgery Department, Montreal Neurological Institute, McGill UniversityMontrealCanada
- McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill UniversityMontrealCanada
- Ludmer Centre for Neuroinformatics and Mental Health, McGill UniversityMontrealCanada
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45
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Reilly SM, Abu-Odeh M, Ameka M, DeLuca JH, Naber MC, Dadpey B, Ebadat N, Gomez AV, Peng X, Poirier B, Walk E, Potthoff MJ, Saltiel AR. FGF21 is required for the metabolic benefits of IKKε/TBK1 inhibition. J Clin Invest 2021; 131:145546. [PMID: 33822771 DOI: 10.1172/jci145546] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 03/23/2021] [Indexed: 12/15/2022] Open
Abstract
The protein kinases IKKε and TBK1 are activated in liver and fat in mouse models of obesity. We have previously demonstrated that treatment with the IKKε/TBK1 inhibitor amlexanox produces weight loss and relieves insulin resistance in obese animals and patients. While amlexanox treatment caused a transient reduction in food intake, long-term weight loss was attributable to increased energy expenditure via FGF21-dependent beiging of white adipose tissue (WAT). Amlexanox increased FGF21 synthesis and secretion in several tissues. Interestingly, although hepatic secretion determined circulating levels, it was dispensable for regulating energy expenditure. In contrast, adipocyte-secreted FGF21 may have acted as an autocrine factor that led to adipose tissue browning and weight loss in obese mice. Moreover, increased energy expenditure was an important determinant of improved insulin sensitivity by amlexanox. Conversely, the immediate reductions in fasting blood glucose observed with acute amlexanox treatment were mediated by the suppression of hepatic glucose production via activation of STAT3 by adipocyte-secreted IL-6. These findings demonstrate that amlexanox improved metabolic health via FGF21 action in adipocytes to increase energy expenditure via WAT beiging and that adipocyte-derived IL-6 has an endocrine role in decreasing gluconeogenesis via hepatic STAT3 activation, thereby producing a coordinated improvement in metabolic parameters.
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Affiliation(s)
- Shannon M Reilly
- Division of Metabolism and Endocrinology, Department of Medicine, UCSD, La Jolla, California, USA.,Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA
| | - Mohammad Abu-Odeh
- Division of Metabolism and Endocrinology, Department of Medicine, UCSD, La Jolla, California, USA
| | - Magdalene Ameka
- Department of Neuroscience and Pharmacology and.,Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
| | - Julia H DeLuca
- Division of Metabolism and Endocrinology, Department of Medicine, UCSD, La Jolla, California, USA
| | - Meghan C Naber
- Department of Neuroscience and Pharmacology and.,Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
| | - Benyamin Dadpey
- Division of Metabolism and Endocrinology, Department of Medicine, UCSD, La Jolla, California, USA
| | - Nima Ebadat
- Division of Metabolism and Endocrinology, Department of Medicine, UCSD, La Jolla, California, USA
| | - Andrew V Gomez
- Division of Metabolism and Endocrinology, Department of Medicine, UCSD, La Jolla, California, USA
| | - Xiaoling Peng
- Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA
| | - BreAnne Poirier
- Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA
| | - Elyse Walk
- Division of Metabolism and Endocrinology, Department of Medicine, UCSD, La Jolla, California, USA
| | - Matthew J Potthoff
- Department of Neuroscience and Pharmacology and.,Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
| | - Alan R Saltiel
- Division of Metabolism and Endocrinology, Department of Medicine, UCSD, La Jolla, California, USA.,Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA
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46
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Zhang C, Biehl Rudkjær LC, Cachón MF, Falkenhahn M, Theis S, Schmidt T, Vrang N, Jelsing J, Rigbolt K. Transcriptomic changes in pancreatic islets, adipose and liver after Roux-en-Y gastric bypass in a diet-induced obese rat model. Peptides 2021; 136:170467. [PMID: 33253774 DOI: 10.1016/j.peptides.2020.170467] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 10/28/2020] [Accepted: 11/21/2020] [Indexed: 12/28/2022]
Abstract
Roux-en-Y gastric bypass (RYGB) is the most efficient intervention in morbid obesity and promotes metabolic improvements in several peripheral tissues. However, the underlying molecular mechanisms are still poorly understood. To further understand the effects of RYGB on peripheral tissues transcriptomes, we determined transcriptome signatures in pancreatic islets, adipose and liver tissue from diet-induced obese (DIO) rats model following RYGB. Whereas RYGB led to discrete gene expression changes in pancreatic islets, substantial transcriptome changes were observed in metabolic and immune signaling pathways in adipose tissue and the liver, indicating major gene adaptive responses in fat-storing tissues. Compared to RYGB DIO rats, peripheral tissue transcriptome signatures were markedly different in caloric restricted weight matching DIO rats, implying that caloric restriction paradigms do not reflect transcriptomic regulations of RYGB induced weight loss. The present gene expression study may serve as a basis for further investigations into molecular regulatory effects in peripheral tissues following RYGB-induced weight loss.
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Affiliation(s)
| | | | | | | | - Stefan Theis
- Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany
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47
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Kim H, Lee DS, An TH, Park TJ, Lee EW, Han BS, Kim WK, Lee CH, Lee SC, Oh KJ, Bae KH. GADD45β Regulates Hepatic Gluconeogenesis via Modulating the Protein Stability of FoxO1. Biomedicines 2021; 9:biomedicines9010050. [PMID: 33435535 PMCID: PMC7827134 DOI: 10.3390/biomedicines9010050] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 12/26/2020] [Accepted: 01/07/2021] [Indexed: 01/07/2023] Open
Abstract
Increased hepatic gluconeogenesis is one of the main contributors to the development of type 2 diabetes. Recently, it has been reported that growth arrest and DNA damage-inducible 45 beta (GADD45β) is induced under both fasting and high-fat diet (HFD) conditions that stimulate hepatic gluconeogenesis. Here, this study aimed to establish the molecular mechanisms underlying the novel role of GADD45β in hepatic gluconeogenesis. Both whole-body knockout (KO) mice and adenovirus-mediated knockdown (KD) mice of GADD45β exhibited decreased hepatic gluconeogenic gene expression concomitant with reduced blood glucose levels under fasting and HFD conditions, but showed a more pronounced effect in GADD45β KD mice. Further, in primary hepatocytes, GADD45β KD reduced glucose output, whereas GADD45β overexpression increased it. Mechanistically, GADD45β did not affect Akt-mediated forkhead box protein O1 (FoxO1) phosphorylation and forskolin-induced cAMP response element-binding protein (CREB) phosphorylation. Rather it increased FoxO1 transcriptional activity via enhanced protein stability of FoxO1. Further, GADD45β colocalized and physically interacted with FoxO1. Additionally, GADD45β deficiency potentiated insulin-mediated suppression of hepatic gluconeogenic genes, and it were impeded by the restoration of GADD45β expression. Our finding demonstrates GADD45β as a novel and essential regulator of hepatic gluconeogenesis. It will provide a deeper understanding of the FoxO1-mediated gluconeogenesis.
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Affiliation(s)
- Hyunmi Kim
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea; (H.K.); (D.S.L.); (T.H.A.); (T.-J.P.); (E.-W.L.); (B.S.H.); (W.K.K.); (S.C.L.)
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34141, Korea
| | - Da Som Lee
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea; (H.K.); (D.S.L.); (T.H.A.); (T.-J.P.); (E.-W.L.); (B.S.H.); (W.K.K.); (S.C.L.)
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34141, Korea
| | - Tae Hyeon An
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea; (H.K.); (D.S.L.); (T.H.A.); (T.-J.P.); (E.-W.L.); (B.S.H.); (W.K.K.); (S.C.L.)
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34141, Korea
| | - Tae-Jun Park
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea; (H.K.); (D.S.L.); (T.H.A.); (T.-J.P.); (E.-W.L.); (B.S.H.); (W.K.K.); (S.C.L.)
| | - Eun-Woo Lee
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea; (H.K.); (D.S.L.); (T.H.A.); (T.-J.P.); (E.-W.L.); (B.S.H.); (W.K.K.); (S.C.L.)
| | - Baek Soo Han
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea; (H.K.); (D.S.L.); (T.H.A.); (T.-J.P.); (E.-W.L.); (B.S.H.); (W.K.K.); (S.C.L.)
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34141, Korea
| | - Won Kon Kim
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea; (H.K.); (D.S.L.); (T.H.A.); (T.-J.P.); (E.-W.L.); (B.S.H.); (W.K.K.); (S.C.L.)
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34141, Korea
| | - Chul-Ho Lee
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea;
| | - Sang Chul Lee
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea; (H.K.); (D.S.L.); (T.H.A.); (T.-J.P.); (E.-W.L.); (B.S.H.); (W.K.K.); (S.C.L.)
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34141, Korea
| | - Kyoung-Jin Oh
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea; (H.K.); (D.S.L.); (T.H.A.); (T.-J.P.); (E.-W.L.); (B.S.H.); (W.K.K.); (S.C.L.)
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34141, Korea
- Correspondence: (K.-J.O.); (K.-H.B.)
| | - Kwang-Hee Bae
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea; (H.K.); (D.S.L.); (T.H.A.); (T.-J.P.); (E.-W.L.); (B.S.H.); (W.K.K.); (S.C.L.)
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34141, Korea
- Correspondence: (K.-J.O.); (K.-H.B.)
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48
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Abduraman MA, Azizan NA, Teoh SH, Tan ML. Ketogenesis and SIRT1 as a tool in managing obesity. Obes Res Clin Pract 2020; 15:10-18. [PMID: 33371997 DOI: 10.1016/j.orcp.2020.12.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 10/21/2020] [Accepted: 12/01/2020] [Indexed: 12/14/2022]
Abstract
Obesity is a serious chronic disease and a public health concern in both developing and developed countries. Managing obesity has been a great challenge for both health care professionals and patients alike. Among the various diet programs aimed at promoting weight loss, the ketogenic diet, a diet high in fat and low in carbohydrates, has been at the forefront recently and its mechanism in weight loss is much debated. Activation of Sirtuin 1 or SIRT1 is able to circumvent various diseases, including metabolic syndrome and obesity and is thought to be a potentially reliable treatment target for both of them. Augmentation of SIRT1 may be carried out using dietary means such as nicotinamide adenine dinucleotide (NAD) supplementation and/or ketogenic diet. Although ketogenic diet may augment SIRT1 activation in people affected by obesity, recent studies have indicated that the relationship between SIRT1 and ketogenesis is unpredictable. The exact circumstances and mechanisms of SIRT1, NAD and ketogenesis in the clinical setting as an intervention tool in managing obesity remained uncertain. Although several recent literatures have documented significant weight-loss following ketogenic diet interventions, there were limitations with regards to duration of trial, choice and the number of trial subjects. Studies investigating the safety of ketogenic diet in the long term, beyond 46 weeks and related mechanism and pathways are still lacking and the sustainability of this diet remains to be determined. This review explores the recent progress on ketogenic diet and its relationships with SIRT1 as a tool in managing obesity and relevant clinical implications.
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Affiliation(s)
- Muhammad Asyraf Abduraman
- Advanced Medical & Dental Institute, SAINS@BERTAM, Universiti Sains Malaysia, 13200 Kepala Batas, Pulau Pinang, Malaysia
| | - Nurul Ain Azizan
- Advanced Medical & Dental Institute, SAINS@BERTAM, Universiti Sains Malaysia, 13200 Kepala Batas, Pulau Pinang, Malaysia; Center for Population Health, Dept. Social and Preventive Medicine, Faculty of Medicine, University Malaya, 50603 Kuala Lumpur, Malaysia
| | - Soo Huat Teoh
- Advanced Medical & Dental Institute, SAINS@BERTAM, Universiti Sains Malaysia, 13200 Kepala Batas, Pulau Pinang, Malaysia
| | - Mei Lan Tan
- Advanced Medical & Dental Institute, SAINS@BERTAM, Universiti Sains Malaysia, 13200 Kepala Batas, Pulau Pinang, Malaysia; School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Universiti Sains Malaysia, Pulau Pinang, Malaysia.
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49
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Xiao Y, Kim M, Lazar MA. Nuclear receptors and transcriptional regulation in non-alcoholic fatty liver disease. Mol Metab 2020; 50:101119. [PMID: 33220489 PMCID: PMC8324695 DOI: 10.1016/j.molmet.2020.101119] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 11/13/2020] [Accepted: 11/16/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND As a result of a sedentary lifestyle and excess food consumption in modern society, non-alcoholic fatty liver disease (NAFLD) characterized by fat accumulation in the liver is becoming a major disease burden. Non-alcoholic steatohepatitis (NASH) is an advanced form of NAFLD characterized by inflammation and fibrosis that can lead to hepatocellular carcinoma and liver failure. Nuclear receptors (NRs) are a family of ligand-regulated transcription factors that closely control multiple aspects of metabolism. Their transcriptional activity is modulated by various ligands, including hormones and lipids. NRs serve as potential pharmacological targets for NAFLD/NASH and other metabolic diseases. SCOPE OF REVIEW In this review, we provide a comprehensive overview of NRs that have been studied in the context of NAFLD/NASH with a focus on their transcriptional regulation, function in preclinical models, and studies of their clinical utility. MAJOR CONCLUSIONS The transcriptional regulation of NRs is context-dependent. During the dynamic progression of NAFLD/NASH, NRs play diverse roles in multiple organs and different cell types in the liver, which highlights the necessity of targeting NRs in a stage-specific and cell-type-specific manner to enhance the efficacy and safety of treatment methods.
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Affiliation(s)
- Yang Xiao
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Mindy Kim
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Mitchell A Lazar
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
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50
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Saik OV, Klimontov VV. Bioinformatic Reconstruction and Analysis of Gene Networks Related to Glucose Variability in Diabetes and Its Complications. Int J Mol Sci 2020; 21:ijms21228691. [PMID: 33217980 PMCID: PMC7698756 DOI: 10.3390/ijms21228691] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 11/06/2020] [Accepted: 11/16/2020] [Indexed: 02/06/2023] Open
Abstract
Glucose variability (GV) has been recognized recently as a promoter of complications and therapeutic targets in diabetes. The aim of this study was to reconstruct and analyze gene networks related to GV in diabetes and its complications. For network analysis, we used the ANDSystem that provides automatic network reconstruction and analysis based on text mining. The network of GV consisted of 37 genes/proteins associated with both hyperglycemia and hypoglycemia. Cardiovascular system, pancreas, adipose and muscle tissues, gastrointestinal tract, and kidney were recognized as the loci with the highest expression of GV-related genes. According to Gene Ontology enrichment analysis, these genes are associated with insulin secretion, glucose metabolism, glycogen biosynthesis, gluconeogenesis, MAPK and JAK-STAT cascades, protein kinase B signaling, cell proliferation, nitric oxide biosynthesis, etc. GV-related genes were found to occupy central positions in the networks of diabetes complications (cardiovascular disease, diabetic nephropathy, retinopathy, and neuropathy) and were associated with response to hypoxia. Gene prioritization analysis identified new gene candidates (THBS1, FN1, HSP90AA1, EGFR, MAPK1, STAT3, TP53, EGF, GSK3B, and PTEN) potentially involved in GV. The results expand the understanding of the molecular mechanisms of the GV phenomenon in diabetes and provide molecular markers and therapeutic targets for future research.
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Affiliation(s)
- Olga V. Saik
- Laboratory of Endocrinology, Research Institute of Clinical and Experimental Lymphology—Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL—Branch of IC&G SB RAS), 630060 Novosibirsk, Russia;
- Laboratory of Computer Proteomics, Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences (ICG SB RAS), 630090 Novosibirsk, Russia
- Correspondence:
| | - Vadim V. Klimontov
- Laboratory of Endocrinology, Research Institute of Clinical and Experimental Lymphology—Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL—Branch of IC&G SB RAS), 630060 Novosibirsk, Russia;
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