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Hegazy MA, Ahmed SM, Sultan SM, Afifi OF, Mohamed MA, Azab AE, Hassanen MA, Zaben RK. Metabolic dysfunction-associated steatotic liver disease and omega-6 polyunsaturated fatty acids: Friends or foes. World J Hepatol 2025; 17:102286. [DOI: 10.4254/wjh.v17.i3.102286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 02/20/2025] [Accepted: 03/05/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide. Its prevalence is closely linked to the dramatic rise in obesity and non-communicable diseases. MASLD exhibits a progressive trajectory that may culminate in development of hepatic cirrhosis, thereby predisposing affected individuals to an elevated likelihood of hepatocarcinogenesis. Diet, especially dietary fatty acids, serves as a key link between nutrient intake and MASLD pathogenesis.
AIM To explore the impact of various omega-6 fatty acid subtypes on the pathogenesis and therapeutic strategies of MASLD.
METHODS A systematic literature search was conducted across Web of Science, PubMed, Cochrane Central, Scopus, and Embase databases from inception through June 2024 to identify all original studies linking different subtypes of omega-6 polyunsaturated fatty acids to the pathogenesis and management of MASLD. The search strategy explored the linkage between omega-6 polyunsaturated fatty acids and their subtypes, including linoleic acid (LA), gamma-linolenic acid (GLA), arachidonic acid, conjugated LA, and docosapentaenoic acid, in relation to MASLD and cardiometabolic risk.
RESULTS By employing the specified search strategy, a total of 83 articles were identified as potentially eligible. During the title, abstract, and full-text screening phases, 27 duplicate records were removed, leaving 56 records for relevance screening. Of these, 43 records were excluded for reasons such as irrelevance and language restrictions (limited to English), resulting in 13 full-text articles being included for detailed assessment (10 human studies,1 animal study, and 2 review articles). Although certain subtypes, as GLA, dihomo-GLA, omega-6-derived oxylipins, and most arachidonic acid-derived eicosanoids, exhibit pro-inflammatory effects, our findings suggest that other subtypes such as LA, cis-9, trans-11 conjugated LA, and docosapentaenoic acid have beneficial effects on fatty liver, cardiometabolic risk factors, and inflammation, even at high intake levels.
CONCLUSION The varying health effects of omega-6 fatty acids, ranging from anti-inflammatory to pro-inflammatory impacts on the liver, leave the question of their recommendation for MASLD patients unresolved. This underscores the importance of careful selection when considering omega-6 supplementation.
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Affiliation(s)
- Mona A Hegazy
- Department of Internal Medicine, Kasr Aliny Hospital, Faculty of Medicine, Cairo University, Cairo 12556, Egypt
| | - Safaa M Ahmed
- Department of Neonatology, Mounira General Hospital, Cairo 4262130, Egypt
| | - Shaimaa M Sultan
- Department of Maternal and Pediatric Health, Shubra Elkhema Medical Administration, Qalyubia 13768, Egypt
| | - Osama F Afifi
- Department of Neonatology, Ashmoun Hospital, Menofia 32811, Egypt
| | - Manal A Mohamed
- Department of Internal Medicine, Elnasr Hospital, Helwan 11731, Egypt
| | - Alshimaa E Azab
- Department of Anesthesia, Al Helal Insurance Hospital, Qism Shebin 32514, Egypt
| | - Mohamed A Hassanen
- Department of Clinical Nutrition, Egyptian Fellowship, Cairo 11559, Egypt
| | - Rakan K Zaben
- Department of Clinical Nutrition, Egyptian Fellowship, Cairo 11559, Egypt
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Li J, Chen X, Song S, Jiang W, Geng T, Wang T, Xu Y, Zhu Y, Lu J, Xia Y, Wang R. Hexokinase 2-mediated metabolic stress and inflammation burden of liver macrophages via histone lactylation in MASLD. Cell Rep 2025; 44:115350. [PMID: 40014451 DOI: 10.1016/j.celrep.2025.115350] [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: 08/06/2024] [Revised: 01/07/2025] [Accepted: 02/04/2025] [Indexed: 03/01/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by metabolic dysfunction and inflammation burden, involving a significant enhancement of cellular glycolytic activity. Here, we elucidate how a positive feedback loop in liver macrophages drives MASLD pathogenesis and demonstrate that disrupting this cycle mitigates metabolic stress and macrophage M1 activation during MASLD. We detect elevated expression of hexokinase 2 (HK2) and H3K18la in liver macrophages from patients with MASLD and MASLD mice. This lactate-dependent histone lactylation promotes glycolysis and liver macrophage M1 polarization by enriching the promoters of glycolytic genes and activating transcription. Ultimately, the HK2/glycolysis/H3K18la positive feedback loop exacerbates the vicious cycle of enhancing metabolic dysregulation and histone lactylation and the inflammatory phenotype of liver macrophages. Myeloid-specific deletion of Hk2 or pharmacological inhibition of the transcription factor HIF-1α significantly disrupts this deleterious cycle. Therefore, our study illustrates that targeting this amplified pathogenic loop may offer a promising therapeutic strategy for MASLD.
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Affiliation(s)
- Jinyang Li
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu 210046, China; Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu 210029, China; NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Xiancheng Chen
- Department of Critical Care Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210029, China
| | - Shiyu Song
- Nanjing Lupine (YuShanDou) Biomedical Research Institute, Nanjing, Jiangsu 210046, China
| | - Wangjie Jiang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu 210029, China; NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Tianjiao Geng
- Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
| | - Tiantian Wang
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu 210046, China
| | - Yan Xu
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu 210046, China
| | - Yongqiang Zhu
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu 210046, China.
| | - Jun Lu
- Department of Intensive Care Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu 210029, China.
| | - Yongxiang Xia
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu 210029, China; NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
| | - Rong Wang
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu 210046, China; Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, Hunan 410219, China.
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Zhang Q, Su T, Pan Y, Wang X, Zhang C, Qin H, Li M, Li Q, Li X, Guo J, Wu L, Qin L, Liu T. Malus hupehensis leaves: a functional beverage for alleviating hepatic inflammation and modulating gut microbiota in diabetic mice. Food Funct 2025. [PMID: 40126388 DOI: 10.1039/d4fo05325g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/25/2025]
Abstract
Malus hupehensis leaves (MHL), consumed as a daily beverage in Chinese folk tradition and recently recognized as a new food material, are abundant in polyphenols and bioactive compounds that demonstrate hypoglycemic, lipid-lowering, and anti-inflammatory effects. However, the antidiabetic mechanisms have not been fully elucidated. This study aimed to investigate the protective mechanisms of Malus hupehensis leaves' extract (MHLE) against type 2 diabetes mellitus (T2DM). The results showed that MHLE effectively ameliorated glucose and lipid metabolic abnormalities in db/db mice, and attenuated hepatic macrophage activation. Transcriptomic analysis of the liver revealed that MHLE primarily affects genes involved in inflammatory responses and inhibited the TLR4/MAPK pathway to reduce hepatic inflammation. Metagenomic sequencing identified changes in gut microbiota composition and showed that MHLE restored the abundance of Lachnospiraceae bacterium, Oscillospiraceae bacterium, and Clostridia bacterium while reducing the abundance of Escherichia coli, thereby ameliorating gut dysbiosis. The integrated regulation of metabolism, immune response, and the microbial environment by MHLE significantly alleviated symptoms of T2DM. This study offers strong scientific evidence for the potential use of MHL as a functional food.
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Affiliation(s)
- Qiue Zhang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 102488, China
- Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, 102488, China.
| | - Tong Su
- Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, 102488, China.
- Dongfang Hospital of Beijing University of Chinese Medicine, Beijing, 100078, China
| | - Yajing Pan
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Xiaomeng Wang
- Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, 102488, China.
| | - Chengfei Zhang
- Dongfang Hospital of Beijing University of Chinese Medicine, Beijing, 100078, China
| | - Huizhao Qin
- Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, 102488, China.
- Dongfang Hospital of Beijing University of Chinese Medicine, Beijing, 100078, China
| | - Mingxiu Li
- Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, 102488, China.
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Qingsong Li
- Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, 102488, China.
- Shaanxi University of Chinese Medicine, Xianyang, 712046, China
| | - Xiaochen Li
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 102488, China
- Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, 102488, China.
| | - Jiangfan Guo
- Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, 102488, China.
- Shaanxi University of Chinese Medicine, Xianyang, 712046, China
| | - Lili Wu
- Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, 102488, China.
| | - Lingling Qin
- Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, 102488, China.
| | - Tonghua Liu
- Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, 102488, China.
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Isiklar A, Denizoglu N, Buyukcam F, Ozer Etik D. Does platelet to lymphocyte ratio predict the ultrasound stage in hepatosteatosis? Acta Radiol 2025:2841851251322480. [PMID: 40091566 DOI: 10.1177/02841851251322480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
BackgroundThe prevalence of hepatosteatosis, or fatty liver disease, has been increasing globally in recent years largely due to increasing rates of obesity, diabetes, and metabolic syndrome.PurposeTo examine the platelet to lymphocyte ratio (PLR) reflection on the hepatosteatosis stage.Material and MethodsWe evaluated healthy individuals who applied to the check-up department in our hospital. The platelet and lymphocyte counts from blood tests, along with upper abdominal ultrasound results obtained as part of routine diagnostic check-ups, results recorded retrospectively, between November 2022 and April 2024.ResultsA total 748 participants were included in the study. All participants were divided in three groups according to hepatosteatosis stages.The PLR levels were highest in the stage 1 hepatosteatosis group. There was statistical significance in PLR levels between stage 1 and 3 hepatosteatosis (P = 0003). In addition, PLR levels were higher in stage 2 than in stage 3, which was also statistically significant (P = 0037).ConclusionThese results could help in early detection and monitoring of disease progression in patients with hepatoteatosis. Lower PLR values (<115.26) in advanced stages might prompt closer monitoring or more aggressive interventions to prevent progression to fibrosis.
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Affiliation(s)
- Aysun Isiklar
- Department of Internal Medicine, Acibadem Atasehir Hospital, Istanbul, Turkey
| | - Nurper Denizoglu
- Department of Radiology, Acibadem Atasehir Hospital, Istanbul, Turkey
| | - Fatih Buyukcam
- Department of Emergency Medicine, Acibadem Atasehir Hospital, Istanbul, Turkey
| | - Didem Ozer Etik
- Department of Gastroenterology, Acibadem Atasehir Hospital, Istanbul, Turkey
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Leszczynska A, Alle T, Kaufmann B, Sung H, Stoess C, Reca A, Kim A, Kim S, Tran C, Oukoloff K, Monti L, Lucero B, Gertsman I, Momper JD, Hartmann P, Feldstein AE, Dohil R, Ballatore C. d 4-Cystamine: A Deuterated Cystamine Derivative with Improved Anti-Inflammatory and Anti-Fibrotic Activities in a Murine Model of Fibrosing Steatohepatitis. ACS Pharmacol Transl Sci 2025; 8:885-898. [PMID: 40109735 PMCID: PMC11915185 DOI: 10.1021/acsptsci.4c00738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 01/27/2025] [Accepted: 02/03/2025] [Indexed: 03/22/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial chronic disease that can progress to metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis, ultimately leading to liver cirrhosis and hepatocellular carcinoma. Oxidative stress is believed to play an important role in the development of MASH. Small aminothiol compounds such as cysteamine and its oxidized precursor, cystamine, are known pleiotropic compounds that exhibit relatively potent antioxidant and other effects. Herein, we evaluate the efficacy of cystamine, as well as two deuterated derivatives, in a choline-deficient, L-amino acid-defined, high-fat-diet (CDAA-HFD) mouse model of rapidly progressing liver fibrosis. Compared to control mice, daily oral administration of isotopically reinforced cystamine derivatives (200 mg/kg) led to a significant reduction of liver fibrosis and inflammation as well as oxidative stress. Moreover, the efficacy of treatment appeared to increase with the deuteration state of cystamine, with the tetradeuterated derivative, d 4 -cystamine, being the most effective. These results indicate that deuterated cystamine derivatives hold promise as potential candidates for the treatment of MASH.
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Affiliation(s)
- Aleksandra Leszczynska
- Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Thibault Alle
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Benedikt Kaufmann
- Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Hana Sung
- Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Christian Stoess
- Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Agustina Reca
- Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Andrea Kim
- Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Sun Kim
- Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Chelsea Tran
- Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Killian Oukoloff
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Ludovica Monti
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Bobby Lucero
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Ilya Gertsman
- Clarus Analytical LLC, 8545 Arjons Dr. Suite A, San Diego, California 92126, United States
| | - Jeremiah D Momper
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Phillipp Hartmann
- Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Ariel E Feldstein
- Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
- Global Drug Discovery, Novo Nordisk, Copenhagen DK-2880, Denmark
| | - Ranjan Dohil
- Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Carlo Ballatore
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
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Li S, Zhu H, Zhai Q, Hou Y, Yang Y, Lan H, Jiang M, Xuan J. Exploring Mechanisms of Lang Qing Ata in Non-Alcoholic Steatohepatitis Based on Metabolomics, Network Pharmacological Analysis, and Experimental Validation. Drug Des Devel Ther 2025; 19:1681-1701. [PMID: 40098906 PMCID: PMC11911237 DOI: 10.2147/dddt.s503757] [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: 11/26/2024] [Accepted: 02/28/2025] [Indexed: 03/19/2025] Open
Abstract
Background Non-alcoholic steatohepatitis (NASH), as a progressive form of Non-alcoholic fatty liver disease (NAFLD), poses a significant threat to human health as a prevalent and common condition, with a lack of safe and effective therapeutic options. However, the therapeutic effects and potential mechanisms of Lang Qing Ata (LQAtta) against NASH remain elusive. Materials and Methods The components of LQAtta were identified using Ultra-High Performance Liquid Chromatography-Tandem Mass Spectrometry (UHPLC-MS/MS). Subsequently, we employed network construction and analysis approaches within the field of network pharmacology. By integrating known databases and target prediction algorithms, which encompassed database-based target prediction, protein-protein interaction networks, as well as Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, we unveiled the potential key targets and signaling pathways that these bioactive components might engage with. These discoveries were further validated in subsequent mouse models. An HFHC-induced NASH mouse model was used to validate the therapeutic effects and potential mechanisms of LQAtta on NASH. Results From the UHPLC-MS/MS analysis of LQAtta, a total of 1518 chemical components were identified, with 106 of them being absorbed into the bloodstream. Additionally, based on the acquisition of targets from both LQAtta and the NASH database, a total of 160 common targets were screened. KEGG enrichment analysis indicated that LQAtta may alleviate NASH by modulating pathways such as the Toll-like receptor signaling pathway, the NF-κB signaling pathway, and inflammation-related pathways. In vivo experimental results demonstrated that LQAtta could alleviate liver injury, steatosis, and inflammation induced by NASH, thereby slowing down the disease process. Additionally, LQAtta inhibited the expression and phosphorylation of NF-κB protein, playing a role in preventing NASH. Conclusion In this study, the combination of mass spectrometry analysis, network pharmacology, and animal experiments preliminarily elucidated the potential of LQAtta to treat NASH through NF-κB pathways.
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Affiliation(s)
- Shupei Li
- Department of Gastroenterology, Jinling Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China
| | - Hanlong Zhu
- Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
| | - Qi Zhai
- Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
| | - Yu Hou
- Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
| | - Ya Yang
- Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
| | - Haifeng Lan
- Department of Gastroenterology, Jinling Clinical Medical College, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China
| | - Mingzuo Jiang
- Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
| | - Ji Xuan
- Department of Gastroenterology, Jinling Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China
- Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
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Qiao M, Ni J, Qing H, Qiu Y, Quan Z. Role of Peripheral NLRP3 Inflammasome in Cognitive Impairments: Insights of Non-central Factors. Mol Neurobiol 2025:10.1007/s12035-025-04779-8. [PMID: 40000575 DOI: 10.1007/s12035-025-04779-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 02/13/2025] [Indexed: 02/27/2025]
Abstract
Cognitive impairments are common clinical manifestation of Alzheimer's disease, vascular dementia, type 2 diabetes mellitus, and autoimmune diseases. Emerging evidence has suggested a strong correlation between peripheral chronic inflammation and cognitive impairments. For example, nearly 40% of individuals with inflammatory bowel disease also suffer from cognitive impairments. In this condition, NLRP3 inflammasome (NLRP3-I) generating pro-inflammatory cytokines like IL-1β serves as a significant effector, and its persistence exerts adverse effects to both periphery and the brain. Moreover, investigations on serum biomarkers of mild cognitive impairments have shown NLRP3-I components' upregulation, suggesting the involvement of peripheral inflammasome pathway in this disorder. Here, we systematically reviewed the current knowledge of NLRP3-I in inflammatory disease to uncover its potential role in bridging peripheral chronic inflammation and cognitive impairments. This review summarizes the molecular features and ignition process of NLRP3-I in inflammatory response. Meanwhile, various effects of NLRP3-I involved in peripheral inflammation-associated disease are also reviewed, especially its chronic disturbances to brain homeostasis and cognitive function through routes including gut-brain, liver-brain, and kidney-brain axes. In addition, current promising compounds and their targets relative to NLRP3-I are discussed in the context of cognitive impairments. Through the detailed investigation, this review highlights the critical role of peripheral NLRP3-I in the pathogenesis of cognitive disorders, and offers novel perspectives for developing effective therapeutic interventions for diseases associated with cognitive impairments. The present review outlines the current knowledge on the ignition of NLRP3-I in inflammatory disease and more importantly, emphasizes the role of peripheral NLRP3-I as a causal pathway in the development of cognitive disorders. Although major efforts to restrain cognitive decline are mainly focused on the central nervous system, it has become clear that disturbances from peripheral immune are closely associated with the dysfunctional brain. Therefore, attenuation of these inflammatory changes through inhibiting the NLRP3-I pathway in early inflammatory disease may reduce future risk of cognitive impairments, and in the meantime, considerations on such pathogenesis for combined drug therapy will be required in the clinical evaluation of cognitive disorders.
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Affiliation(s)
- Mengfan Qiao
- Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, 100081, China
| | - Junjun Ni
- Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, 100081, China
| | - Hong Qing
- Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, 100081, China
- Department of Biology, Shenzhen MSU-BIT University, Shenzhen, 518172, China
| | - Yunjie Qiu
- Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, 100081, China.
| | - Zhenzhen Quan
- Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, 100081, China.
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Song J, Wang H, Gao X, Yang F, Zhu X, Qiao G, Gan T, Tao J. The serum hepcidin and the hepcidin/ferritin ratio in NAFLD: a systematic review and meta-analysis. BMC Gastroenterol 2025; 25:62. [PMID: 39915727 PMCID: PMC11804044 DOI: 10.1186/s12876-025-03620-9] [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: 09/06/2024] [Accepted: 01/15/2025] [Indexed: 02/09/2025] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a spectrum of chronic liver diseases characterized by hepatic steatosis exceeding 5% in the absence of alcohol and other liver-damaging factors. Clinical studies have identified a potential link between abnormal iron metabolism and the high incidence of NAFLD; however, the results from clinical trials remain inconsistent. This meta-analysis aims to compare serum hepcidin levels and the hepcidin/ferritin ratio between adults with NAFLD and those without to explore their potential relationship with NAFLD. METHODS A systematic search was conducted across the Web of Science platform, Cochrane, Scopus, Embase, and PubMed databases from their inception until December 18, 2024. The analysis primarily focused on serum hepcidin levels and the hepcidin/ferritin ratio. Observational studies comparing serum hepcidin levels and the hepcidin/ferritin ratio between individuals with NAFLD and control groups were included. A random-effects model was employed to calculate effect estimates, and outcomes were reported as standardized mean differences (SMD) with 95% confidence intervals (95% CI). RESULTS Following the systematic review, a total of 19 studies, comprising 2216 patients and 2125 controls, were included. The findings revealed a statistically significant difference in both hepcidin levels (SMD = 1.03, 95% CI: 0.49 to 1.56, p < 0.001) and the hepcidin/ferritin ratio (SMD = -1.13, 95% CI: -1.79 to -0.46, p < 0.001) between NAFLD and controls. Significant heterogeneity was observed across studies for both hepcidin (I² = 98.2%) and the hepcidin/ferritin ratio (I² = 93.3%), and the limited number of studies on hepcidin/ferritin were acknowledged as key limitations. Subgroup analysis revealed that patients with obesity exhibited higher levels of hepcidin (SMD = 1.12, 95% CI: 0.40 to 1.97) than overweight (SMD = 0.88, 95% CI: 0.05 to 1.72). Meta-regression analysis identified the hepcidin measurement method (p < 0.01), male-to-female ratio (p < 0.01), and study quality (p < 0.01) as significant moderators of the observed heterogeneity. CONCLUSION This meta-analysis revealed a significant association between hepcidin levels, the hepcidin/ferritin ratio and NAFLD in adults. Further investigations are needed to fully elucidate the role of these variables in iron metabolism and their potential impact on the diagnosis, prevention, and management of NAFLD.
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Affiliation(s)
- Jingmin Song
- School of Nursing, Hubei University of Chinese Medicine, Wuhan, 430065, China
| | - Heqing Wang
- School of Nursing, Hubei University of Chinese Medicine, Wuhan, 430065, China
| | - Xiaolian Gao
- School of Nursing, Hubei University of Chinese Medicine, Wuhan, 430065, China.
- Hubei Shizhen Laboratory, Wuhan, 430065, China.
| | - Fen Yang
- School of Nursing, Hubei University of Chinese Medicine, Wuhan, 430065, China
- Hubei Shizhen Laboratory, Wuhan, 430065, China
| | - Xinhong Zhu
- School of Nursing, Hubei University of Chinese Medicine, Wuhan, 430065, China
- Hubei Shizhen Laboratory, Wuhan, 430065, China
| | - Guiyuan Qiao
- School of Nursing, Hubei University of Chinese Medicine, Wuhan, 430065, China
- Hubei Shizhen Laboratory, Wuhan, 430065, China
| | - Ting Gan
- School of Nursing, Hubei University of Chinese Medicine, Wuhan, 430065, China
- Hubei Shizhen Laboratory, Wuhan, 430065, China
| | - Junxiu Tao
- Hepatic Disease Institute, Hubei Key Laboratory of Theoretical and Applied Research of Liver and Kidney in Traditional Chinese Medicine, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, 430061, China.
- Affiliated Hospital of Hubei University of Chinese Medicine, Wuhan, 430074, China.
- Hubei Province Academy of Traditional Chinese Medicine, Wuhan, 430074, China.
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9
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Luo J, Yang Y, Liu H, Tan Z, Chen C, Li W, Yang R. Ellagic acid alleviates high-fructose diet-induced non-alcoholic fatty liver disease by modulating liver metabolic profiles and gut microbiota. Int J Food Sci Nutr 2025; 76:47-61. [PMID: 39627026 DOI: 10.1080/09637486.2024.2435849] [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: 07/06/2024] [Revised: 10/30/2024] [Accepted: 11/25/2024] [Indexed: 02/12/2025]
Abstract
This study integrated analyses of gut microbiota and metabolomics to investigate the impact of ellagic acid (EA) on non-alcoholic fatty liver disease (NAFLD). Compared to the high-fructose diet (HFruD) group, the EA group exhibited reduced body weight and fat mass, alongside improvements in blood glucose and lipid metabolism. Liver metabolomics analysis revealed that EA increased the abundance of metabolites in pathways related to unsaturated fatty acids, amino acids and bile acids. Furthermore, EA induced alterations in the composition and structure of gut microbiota, notably decreasing bacterial genera enriched by HFruD while promoting beneficial bacteria such as Faecalibaculum. Correlation analysis demonstrated significant associations among NAFLD markers, gut microbiota and liver metabolites influenced by EA. This study provides new insights into the anti-NAFLD effects of EA, suggesting EA as a promising nutraceutical for improving NAFLD.
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Affiliation(s)
- Jinxin Luo
- Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou, China
| | - Yuzhe Yang
- Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou, China
| | - Hui Liu
- Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou, China
| | - Zhaolun Tan
- Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou, China
| | - Chunlian Chen
- Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou, China
| | - Wu Li
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, China
| | - Ruili Yang
- Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou, China
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
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10
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Perez-Ternero C, Li W, Aubdool AA, Goldin RD, Loy J, Devalia K, Alazawi W, Hobbs AJ. Endogenous C-type natriuretic peptide offsets the pathogenesis of steatohepatitis, hepatic fibrosis, and portal hypertension. PNAS NEXUS 2025; 4:pgae579. [PMID: 39816244 PMCID: PMC11734523 DOI: 10.1093/pnasnexus/pgae579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 12/20/2024] [Indexed: 01/18/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), hepatic fibrosis, and portal hypertension constitute an increasing public health problem due to the growing prevalence of obesity and diabetes. C-type natriuretic peptide (CNP) is an endogenous regulator of cardiovascular homeostasis, immune cell reactivity, and fibrotic disease. Thus, we investigated a role for CNP in the pathogenesis of MASLD. Wild-type (WT), global CNP (gbCNP-/-), and natriuretic peptide receptor-C (NPR-C-/-) knockout mice were fed a choline-deficient defined amino acid diet or administered CCl4. Liver damage was assessed by histological and biochemical analyses, with steatosis and portal vein size determined by ultrasound. Portal vein pressure and reactivity were measured in vivo and ex vivo, respectively. Pharmacological CNP delivery was used to evaluate prospective therapeutic benefit, and plasma CNP concentration was compared in controls and patients with cirrhosis. Circulating CNP concentration was lower in patients with cirrhosis compared with controls. gbCNP-/- mice were more susceptible, versus WT, to advanced steatohepatitis and hepatic fibrosis, characterized by increased immune cell infiltration, fibrosis, ballooning, plasma alanine aminotransferase concentration, and up-regulation of markers driving these processes. gbCNP-/- mice had increased portal vein diameter and pressure, underpinned by CNP insensitivity. NPR-C-/- animals recapitulated, comparatively, the exaggerated pathogenic phenotype in gbCNP-/- mice, whereas CNP reduced hepatic stellate cell proliferation via NPR-B-dependent inhibition of extracellular signal-related kinase 1/2. Administration of CNP reversed many aspects of disease severity. These data define a new intrinsic role for CNP in offsetting the pathogenesis of MASLD, hepatic fibrosis, and portal hypertension and the potential for targeting CNP signaling for treating these disorders.
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Affiliation(s)
- Cristina Perez-Ternero
- Faculty of Medicine and Dentistry, William Harvey Research Institute, Barts and The London, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom
| | - Wenhao Li
- Barts Liver Centre, Blizard Institute, Queen Mary University of London, 4 Newark Street, London E1 2AT, United Kingdom
| | - Aisah A Aubdool
- Faculty of Medicine and Dentistry, William Harvey Research Institute, Barts and The London, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom
| | - Robert D Goldin
- Centre for Pathology, St Mary’s Hospital, Imperial College, London W2 1NY, United Kingdom
| | - John Loy
- Bariatric Surgery Department, Homerton University Hospital, Homerton Row, London E9 6SR, United Kingdom
| | - Kalpana Devalia
- Bariatric Surgery Department, Homerton University Hospital, Homerton Row, London E9 6SR, United Kingdom
| | - William Alazawi
- Barts Liver Centre, Blizard Institute, Queen Mary University of London, 4 Newark Street, London E1 2AT, United Kingdom
| | - Adrian J Hobbs
- Faculty of Medicine and Dentistry, William Harvey Research Institute, Barts and The London, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom
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11
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Salamoun JM, Krinos EL, Foutz MA, Hargett SR, Beretta M, Shrestha R, Hoehn KL, Santos WL. Design, synthesis, and biological evaluation of imidazo[4,5-b]pyridine mitochondrial uncouplers for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). Eur J Med Chem 2024; 280:116916. [PMID: 39406121 PMCID: PMC11585420 DOI: 10.1016/j.ejmech.2024.116916] [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: 08/02/2024] [Revised: 09/24/2024] [Accepted: 09/25/2024] [Indexed: 11/09/2024]
Abstract
Small molecule mitochondrial uncouplers have gained traction for their potential therapeutic use against metabolic dysfunction-associated steatohepatitis (MASH). Herein, we report a novel imidazo[4,5-b]pyridine scaffold derived from iterative modifications of the potent uncoupler BAM15. Our structure-activity relationship (SAR) study demonstrated that this promising scaffold has a range of tolerated substitutions that allows for the modulation of uncoupling activity and in vivo pharmacokinetic properties. Specifically, compound SHS206 displayed an EC50 of 830 nM in L6 myoblasts and, importantly, showed no cytotoxicity in vitro or adverse effects in mice up to 1000 mg/kg. SHS206 was administered orally at 100 and 300 mg/kg in a GAN mouse model of MASH and was observed to lower liver triglyceride levels while food intake, body weight, temperature, organ weights, and cholesterol levels remained unaltered. Together, these findings illuminate imidazo[4,5-b]pyridine as a promising scaffold for the future development of mitochondrial uncouplers.
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Affiliation(s)
- Joseph M Salamoun
- Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA, 24061, United States
| | - Emily L Krinos
- Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA, 24061, United States
| | - Mary A Foutz
- Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA, 24061, United States
| | - Stefan R Hargett
- Department of Pharmacology, University of Virginia, Charlottesville, VA, 22908, United States
| | - Martina Beretta
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, NSW, 2033, Australia
| | - Riya Shrestha
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, NSW, 2033, Australia
| | - Kyle L Hoehn
- Department of Pharmacology, University of Virginia, Charlottesville, VA, 22908, United States; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, NSW, 2033, Australia.
| | - Webster L Santos
- Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA, 24061, United States.
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12
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Foutz MA, Krinos EL, Beretta M, Hargett SR, Shrestha R, Murray JH, Duerre E, Salamoun JM, McCarter K, Shah DP, Hoehn KL, Santos WL. Design, Synthesis, and Biological Evaluation of [1,2,5]Oxadiazolo[3,4- b]pyridin-7-ol as Mitochondrial Uncouplers for the Treatment of Obesity and Metabolic Dysfunction-Associated Steatohepatitis. J Med Chem 2024; 67:21486-21504. [PMID: 39614818 DOI: 10.1021/acs.jmedchem.4c02366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2024]
Abstract
Mitochondrial uncouplers are small molecule protonophores that act to dissipate the proton motive force independent of adenosine triphosphate (ATP) synthase. Mitochondrial uncouplers such as BAM15 increase respiration and energy expenditure and have potential in treating a variety of metabolic diseases. In this study, we disclose the structure-activity relationship profile of 6-substituted [1,2,5]oxadiazolo[3,4-b]pyridin-7-ol derivatives of BAM15. Utilizing an oxygen consumption rate assay as a measure of increased cellular respiration, SHO1122147 (7m) displayed an EC50 of 3.6 μM in L6 myoblasts. Pharmacokinetic studies indicated a half-life of 2 h, Cmax of 35 μM, and no observed adverse effects at 1,000 mg kg-1 dose in mice. In a Gubra-Amylin (GAN) mouse model of MASH, SHO1122147 was efficacious in decreasing body weight and liver triglyceride levels at 200 mg kg-1 day-1 without changes in body temperature. These findings indicate the potential of utilizing novel [1,2,5]oxadiazolo[3,4-b]pyridin-7-ol mitochondrial uncouplers for treatment of fatty liver disease and obesity.
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Affiliation(s)
- Mary A Foutz
- Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States
| | - Emily L Krinos
- Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States
| | - Martina Beretta
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, NSW 2033, Australia
| | - Stefan R Hargett
- Departments of Pharmacology and Medicine, University of Virginia, Charlottesville, Virginia 22908, United States
| | - Riya Shrestha
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, NSW 2033, Australia
| | - Jacob H Murray
- Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States
| | - Ethan Duerre
- Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States
| | - Joseph M Salamoun
- Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States
| | - Katrina McCarter
- Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States
| | - Divya P Shah
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, NSW 2033, Australia
| | - Kyle L Hoehn
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, NSW 2033, Australia
- Departments of Pharmacology and Medicine, University of Virginia, Charlottesville, Virginia 22908, United States
| | - Webster L Santos
- Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States
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13
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Zhang Y, Wei Q, Geng X, Fang G. Long-Term Aerobic Exercise Enhances Hepatoprotection in MAFLD by Modulating Exosomal miR-324 via ROCK1. Metabolites 2024; 14:692. [PMID: 39728473 DOI: 10.3390/metabo14120692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 11/27/2024] [Accepted: 12/04/2024] [Indexed: 12/28/2024] Open
Abstract
BACKGROUND Insulin resistance (IR) is central to the progression of non-alcoholic fatty liver disease (MAFLD). While aerobic exercise reduces hepatic fat and enhances insulin sensitivity, the specific mechanisms-particularly those involving exosomal pathways-are not fully elucidated. METHOD Exosomes were isolated from 15 MAFLD patients' plasma following the final session of a 12-week aerobic exercise intervention. Liver fat content was measured using MRI-PDFF, and metabolic parameters were assessed via OGTT, HOMA-IR, QUICKI, and VO2 max. Co-culture experiments evaluated the effects of exercise-derived exosomes on IR signaling pathways. miRNA microarray analysis identified miR-324, which was quantified in high-fat diet (HFD) mice with and without exercise and compared between athletes and sedentary controls. Functional assays assessed miR-324's role in glucose and lipid metabolism, while luciferase reporter and Western blot assays confirmed ROCK1 as its direct target. RESULT Aerobic exercise significantly reduced liver fat and improved insulin sensitivity in both MAFLD patients and HFD mice. Notably, exosomal miR-324 levels were lower in athletes than sedentary controls, indicating an inverse association with insulin sensitivity. Post-exercise, precursor and mature miR-324 increased in adipose tissue and decreased in muscle, suggesting its adipose origin and inverse regulation. Functional assays demonstrated that miR-324 modulates insulin resistance by targeting ROCK1. CONCLUSION Exercise-induced exosomal miR-324 from adipose tissue targets ROCK1, revealing a novel mechanism by which aerobic exercise confers hepatoprotection against insulin resistance in MAFLD. These findings enhance our understanding of how exercise influences metabolic health and may inform future therapeutic strategies for managing MAFLD and related conditions.
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Affiliation(s)
- Yang Zhang
- Exercise Biological Research Center, China Institute of Sport Science, Beijing 100061, China
| | - Qiangman Wei
- Exercise Biological Research Center, China Institute of Sport Science, Beijing 100061, China
| | - Xue Geng
- Exercise Biological Research Center, China Institute of Sport Science, Beijing 100061, China
| | - Guoliang Fang
- Exercise Biological Research Center, China Institute of Sport Science, Beijing 100061, China
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14
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Do A, Zahrawi F, Mehal WZ. Therapeutic landscape of metabolic dysfunction-associated steatohepatitis (MASH). Nat Rev Drug Discov 2024:10.1038/s41573-024-01084-2. [PMID: 39609545 DOI: 10.1038/s41573-024-01084-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/28/2024] [Indexed: 11/30/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) and its severe subgroup metabolic dysfunction-associated steatohepatitis (MASH) have become a global epidemic and are driven by chronic overnutrition and multiple genetic susceptibility factors. The physiological outcomes include hepatocyte death, liver inflammation and cirrhosis. The first therapeutic for MASLD and MASH, resmetirom, has recently been approved for clinical use and has energized this therapeutic space. However, there is still much to learn in clinical studies of MASH, such as the scale of placebo responses, optimal trial end points, the time required for fibrosis reversal and side effect profiles. This Review introduces aspects of disease pathogenesis related to drug development and discusses two main therapeutic approaches. Thyroid hormone receptor-β agonists, such as resmetirom, as well as fatty acid synthase inhibitors, target the liver and enable it to function within a toxic metabolic environment. In parallel, incretin analogues such as semaglutide improve metabolism, allowing the liver to self-regulate and reversing many aspects of MASH. We also discuss how combinations of therapeutics could potentially be used to treat patients.
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Affiliation(s)
- Albert Do
- Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
- Division of Gastroenterology, University of California, Davis, Davis, USA
| | - Frhaan Zahrawi
- Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Wajahat Z Mehal
- Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
- West Haven Veterans Hospital, West Haven, CT, USA.
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15
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Yan M, Man S, Ma L, Guo L, Huang L, Gao W. Immunological mechanisms in steatotic liver diseases: An overview and clinical perspectives. Clin Mol Hepatol 2024; 30:620-648. [PMID: 38988278 PMCID: PMC11540396 DOI: 10.3350/cmh.2024.0315] [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: 04/28/2024] [Revised: 07/10/2024] [Accepted: 07/10/2024] [Indexed: 07/12/2024] Open
Abstract
Steatotic liver diseases (SLD) are the principal worldwide cause of cirrhosis and end-stage liver cancer, affecting nearly a quarter of the global population. SLD includes metabolic dysfunction-associated alcoholic liver disease (MetALD) and metabolic dysfunction-associated steatotic liver disease (MASLD), resulting in asymptomatic liver steatosis, fibrosis, cirrhosis and associated complications. The immune processes include gut dysbiosis, adiposeliver organ crosstalk, hepatocyte death and immune cell-mediated inflammatory processes. Notably, various immune cells such as B cells, plasma cells, dendritic cells, conventional CD4+ and CD8+ T cells, innate-like T cells, platelets, neutrophils and macrophages play vital roles in the development of MetALD and MASLD. Immunological modulations targeting hepatocyte death, inflammatory reactions and gut microbiome include N-acetylcysteine, selonsertib, F-652, prednisone, pentoxifylline, anakinra, JKB-121, HA35, obeticholic acid, probiotics, prebiotics, antibiotics and fecal microbiota transplantation. Understanding the immunological mechanisms underlying SLD is crucial for advancing clinical therapeutic strategies.
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Affiliation(s)
- Mengyao Yan
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin, China
| | - Shuli Man
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin, China
| | - Long Ma
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin, China
| | - Lanping Guo
- National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Luqi Huang
- National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Wenyuan Gao
- Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Weijin Road, Tianjin, China
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16
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Somabattini RA, Sherin S, Siva B, Chowdhury N, Nanjappan SK. Unravelling the complexities of non-alcoholic steatohepatitis: The role of metabolism, transporters, and herb-drug interactions. Life Sci 2024; 351:122806. [PMID: 38852799 DOI: 10.1016/j.lfs.2024.122806] [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: 03/27/2024] [Revised: 05/24/2024] [Accepted: 06/04/2024] [Indexed: 06/11/2024]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a mainstream halting liver disease with high prevalence in North America, Europe, and other world regions. It is an advanced form of NAFLD caused by the amassing of fat in the liver and can progress to the more severe form known as non-alcoholic steatohepatitis (NASH). Until recently, there was no authorized pharmacotherapy reported for NASH, and to improve the patient's metabolic syndrome, the focus is mainly on lifestyle modification, weight loss, ensuring a healthy diet, and increased physical activity; however, the recent approval of Rezdiffra (Resmetirom) by the US FDA may change this narrative. As per the reported studies, there is an increased articulation of uptake and efflux transporters of the liver, including OATP and MRP, in NASH, leading to changes in the drug's pharmacokinetic properties. This increase leads to alterations in the pharmacokinetic properties of drugs. Furthermore, modifications in Cytochrome P450 (CYP) enzymes can have a significant impact on these properties. Xenobiotics are metabolized primarily in the liver and constitute liver enzymes and transporters. This review aims to delve into the role of metabolism, transport, and potential herb-drug interactions in the context of NASH.
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Affiliation(s)
- Ravi Adinarayan Somabattini
- Department of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER), Kolkata, Chunilal Bhawan, 168, Maniktala Main Road, Kolkata 700054, West Bengal, India
| | - Sahla Sherin
- Department of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER), Kolkata, Chunilal Bhawan, 168, Maniktala Main Road, Kolkata 700054, West Bengal, India
| | - Bhukya Siva
- Department of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER), Kolkata, Chunilal Bhawan, 168, Maniktala Main Road, Kolkata 700054, West Bengal, India
| | - Neelanjan Chowdhury
- Department of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER), Kolkata, Chunilal Bhawan, 168, Maniktala Main Road, Kolkata 700054, West Bengal, India
| | - Satheesh Kumar Nanjappan
- Department of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER), Kolkata, Chunilal Bhawan, 168, Maniktala Main Road, Kolkata 700054, West Bengal, India.
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17
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Giuffrè M, Merli N, Pugliatti M, Moretti R. The Metabolic Impact of Nonalcoholic Fatty Liver Disease on Cognitive Dysfunction: A Comprehensive Clinical and Pathophysiological Review. Int J Mol Sci 2024; 25:3337. [PMID: 38542310 PMCID: PMC10970252 DOI: 10.3390/ijms25063337] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 03/08/2024] [Accepted: 03/09/2024] [Indexed: 01/03/2025] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) exponentially affects the global healthcare burden, and it is currently gaining increasing interest in relation to its potential impact on central nervous system (CNS) diseases, especially concerning cognitive deterioration and dementias. Overall, scientific research nowadays extends to different levels, exploring NAFLD's putative proinflammatory mechanism of such dysmetabolic conditions, spreading out from the liver to a multisystemic involvement. The aim of this review is to analyze the most recent scientific literature on cognitive involvement in NAFLD, as well as understand its underlying potential background processes, i.e., neuroinflammation, the role of microbiota in the brain-liver-gut axis, hyperammonemia neurotoxicity, insulin resistance, free fatty acids, and vitamins.
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Affiliation(s)
- Mauro Giuffrè
- Department of Internal Medicine (Digestive Diseases), Yale School of Medicine, New Haven, CT 06511, USA
| | - Nicola Merli
- Department of Neuroscience and Rehabilitation, University of Ferrara, 44124 Ferrara, Italy; (N.M.); (M.P.)
| | - Maura Pugliatti
- Department of Neuroscience and Rehabilitation, University of Ferrara, 44124 Ferrara, Italy; (N.M.); (M.P.)
- Interdepartmental Research Center for Multiple Sclerosis and Other Inflammatory and Degenerative Disorders of the Nervous System, University of Ferrara, 44124 Ferrara, Italy
| | - Rita Moretti
- Department of Clinical, Medical and Surgical Sciences, University of Trieste, 34149 Trieste, Italy
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18
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Gong P, Long H, Guo Y, Wang Z, Yao W, Wang J, Yang W, Li N, Xie J, Chen F. Chinese herbal medicines: The modulator of nonalcoholic fatty liver disease targeting oxidative stress. JOURNAL OF ETHNOPHARMACOLOGY 2024; 318:116927. [PMID: 37532073 DOI: 10.1016/j.jep.2023.116927] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 07/05/2023] [Accepted: 07/14/2023] [Indexed: 08/04/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Plants are a natural treasure trove; their secondary metabolites participate in several pharmacological processes, making them a crucial component in the synthesis of novel pharmaceuticals and serving as a reserve resource foundation in this process. Nonalcoholic fatty liver disease (NAFLD) is associated with the risk of progression to hepatitis and liver cancer. The "Treatise on Febrile Diseases," "Compendium of Materia Medica," and "Thousand Golden Prescriptions" have listed herbal remedies to treat liver diseases. AIM OF THE REVIEW Chinese herbal medicines have been widely used for the prevention and treatment of NAFLD owing to their efficacy and low side effects. The production of reactive oxygen species (ROS) during NAFLD, and the impact and potential mechanism of ROS on the pathogenesis of NAFLD are discussed in this review. Furthermore, common foods and herbs that can be used to prevent NAFLD, as well as the structure-activity relationships and potential mechanisms, are discussed. METHODS Web of Science, PubMed, CNKI database, Google Scholar, and WanFang database were searched for natural products that have been used to treat or prevent NAFLD in the past five years. The primary search was performed using the following keywords in different combinations in full articles: NAFLD, herb, natural products, medicine, and ROS. More than 400 research papers and review articles were found and analyzed in this review. RESULTS By classifying and discussing the literature, we obtained 86 herbaceous plants, 28 of which were derived from food and 58 from Chinese herbal medicines. The mechanism of NAFLD was proposed through experimental studies on thirteen natural compounds (quercetin, hesperidin, rutin, curcumin, resveratrol, epigallocatechin-3-gallate, salvianolic acid B, paeoniflorin, ginsenoside Rg1, ursolic acid, berberine, honokiol, emodin). The occurrence and progression of NAFLD could be prevented by natural antioxidants through several pathways to prevent ROS accumulation and reduce hepatic cell injuries caused by excessive ROS. CONCLUSION This review summarizes the natural products and routinely used herbs (prescription) in the prevention and treatment of NAFLD. Firstly, the mechanisms by which natural products improve NAFLD through antioxidant pathways are elucidated. Secondly, the potential of traditional Chinese medicine theory in improving NAFLD is discussed, highlighting the safety of food-medicine homology and the broader clinical potential of multi-component formulations in improving NAFLD. Aiming to provide theoretical basis for the prevention and treatment of NAFLD.
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Affiliation(s)
- Pin Gong
- School of Food and Biotechnological Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, China
| | - Hui Long
- School of Food and Biotechnological Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, China
| | - Yuxi Guo
- School of Food and Biotechnological Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, China
| | - Zhineng Wang
- School of Food and Biotechnological Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, China
| | - Wenbo Yao
- School of Food and Biotechnological Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, China
| | - Jing Wang
- School of Food and Biotechnological Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, China
| | - Wenjuan Yang
- School of Food and Biotechnological Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, China
| | - Nan Li
- School of Food and Biotechnological Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, China
| | - Jianwu Xie
- School of Food and Biotechnological Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, China.
| | - Fuxin Chen
- School of Chemistry and Chemical Engineering, Xi'an University of Science and Technology, Xi'an, 710054, China.
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Yang L, Ma Q, Chen J, Kong X, Yu X, Wang W. Foxa2 attenuates steatosis and inhibits the NF-κB/IKK signaling pathway in nonalcoholic fatty liver disease. PeerJ 2023; 11:e16466. [PMID: 38084145 PMCID: PMC10710773 DOI: 10.7717/peerj.16466] [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: 08/03/2023] [Accepted: 10/24/2023] [Indexed: 12/18/2023] Open
Abstract
Objective Forkhead box a2 (Foxa2) is proven to be an insulin-sensitive transcriptional regulator and affects hepatic steatosis. This study aims to investigate the mechanism by which Foxa2 affects nonalcoholic fatty liver disease (NAFLD). Methods Animal and cellular models of NAFLD were constructed using high-fat diet (HFD) feeding and oleic acid (OA) stimulation, respectively. NAFLD mice received tail vein injections of either an overexpressing negative control (oe-NC) or Foxa2 (oe-Foxa2) for four weeks. HepG2 cells were transfected with oe-NC and oe-Foxa2 for 48 h before OA stimulation. Histological changes and lipid accumulation were assessed using hematoxylin-eosin staining and oil red O staining, respectively. Expression of Foxa2, NF-κB/IKK pathway proteins, lipid synthesis proteins, and fatty acid β-oxidation protein in HFD mice and OA-induced HepG2 cells was detected using western blot. Results Foxa2 expression was downregulated in HFD mice and OA-induced HepG2 cells. Foxa2 overexpression attenuated lipid accumulation and liver injury, and reduced the levels of aspartate aminotransferase, alanine aminotransferase, total cholesterol, or triglyceride in HFD mice and OA-induced HepG2 cells. Moreover, Foxa2 overexpression decreased the expression of lipid synthesis proteins and increased fatty acid β-oxidation protein expression in the liver tissues. Furthermore, overexpression of Foxa2 downregulated the expression of p-NF-κB/NF-κB and p-IKK/IKK in OA-induced HepG2 cells. Additionally, lipopolysaccharide (NF-κB/IKK pathway activator) administration reversed the downregulation of lipid synthesis proteins and the upregulation of fatty acid β-oxidation protein. Conclusion Foxa2 expression is downregulated in NAFLD. Foxa2 ameliorated hepatic steatosis and inhibited the activation of the NF-κB/IKK signaling pathway.
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Affiliation(s)
- Li Yang
- Northwest Minzu University, Lanzhou, Gansu, China
| | - Qiang Ma
- Department of Gastroenterology, 940th Hospital of Joint Support Force, Lanzhou, Gansu, China
| | - Jiayu Chen
- Department of Gastroenterology, 940th Hospital of Joint Support Force, Lanzhou, Gansu, China
| | - Xiangcai Kong
- Department of Gastroenterology, 940th Hospital of Joint Support Force, Lanzhou, Gansu, China
| | - Xiaohui Yu
- Department of Gastroenterology, 940th Hospital of Joint Support Force, Lanzhou, Gansu, China
| | - Wei Wang
- Department of Gastroenterology, 940th Hospital of Joint Support Force, Lanzhou, Gansu, China
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Biagioli M, Marchianò S, Di Giorgio C, Bordoni M, Urbani G, Bellini R, Massa C, Sami Ullah Khan R, Roselli R, Chiara Monti M, Morretta E, Giordano A, Vellecco V, Bucci M, Jilani Iqbal A, Saviano A, Ab Mansour A, Ricci P, Distrutti E, Zampella A, Cieri E, Cirino G, Fiorucci S. Activation of GPBAR1 attenuates vascular inflammation and atherosclerosis in a mouse model of NAFLD-related cardiovascular disease. Biochem Pharmacol 2023; 218:115900. [PMID: 37926268 DOI: 10.1016/j.bcp.2023.115900] [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: 08/29/2023] [Revised: 10/16/2023] [Accepted: 10/26/2023] [Indexed: 11/07/2023]
Abstract
While patients with nonalcoholic fatty liver disease (NAFLD) are at increased risk to develop clinically meaningful cardiovascular diseases (CVD), there are no approved drug designed to target the liver and CVD component of NAFLD. GPBAR1, also known as TGR5, is a G protein coupled receptor for secondary bile acids. In this study we have investigated the effect of GPBAR1 activation by BAR501, a selective GPBAR1 agonist, in Apolipoprotein E deficient (ApoE-/-) mice fed a high fat diet and fructose (Western diet), a validated model of NAFLD-associated atherosclerosis. Using aortic samples from patients who underwent surgery for abdominal aneurism, and ex vivo experiments with endothelial cells and human macrophages, we were able to co-localize the expression of GPBAR1 in CD14+ and PECAM1+ cells. Similar findings were observed in the aortic plaques from ApoE-/- mice. Treating ApoE-/- mice with BAR501, 30 mg/kg for 14 weeks, attenuated the body weight gain while ameliorated the insulin sensitivity by increasing the plasma concentrations of GLP-1 and FGF15. Activation of GPBAR1 reduced the aorta thickness and severity of atherosclerotic lesions and decreased the amount of plaques macrophages. Treating ApoE-/- mice reshaped the aortic transcriptome promoting the expression of anti-inflammatory genes, including IL-10, as also confirmed by tSNE analysis of spleen-derived macrophages. Feeding ApoE-/- mice with BAR501 redirected the bile acid synthesis and the composition of the intestinal microbiota. In conclusion, GPBAR1 agonism attenuates systemic inflammation and improve metabolic profile in a genetic/dietetic model of atherosclerosis. BAR501 might be of utility in the treatment for NAFLD-related CVD.
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Affiliation(s)
- Michele Biagioli
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Silvia Marchianò
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | - Martina Bordoni
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Ginevra Urbani
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Rachele Bellini
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Carmen Massa
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | - Rosalinda Roselli
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | | | - Elva Morretta
- Department of Pharmacy, University of Salerno, Salerno, Italy
| | - Antonino Giordano
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | | | - Asif Jilani Iqbal
- Institute of Cardiovascular Sciences (ICVS), College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Anella Saviano
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Adel Ab Mansour
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Patrizia Ricci
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | - Angela Zampella
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Enrico Cieri
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Giuseppe Cirino
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Stefano Fiorucci
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
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21
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Sawada K, Chung H, Softic S, Moreno-Fernandez ME, Divanovic S. The bidirectional immune crosstalk in metabolic dysfunction-associated steatotic liver disease. Cell Metab 2023; 35:1852-1871. [PMID: 37939656 PMCID: PMC10680147 DOI: 10.1016/j.cmet.2023.10.009] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 10/13/2023] [Accepted: 10/13/2023] [Indexed: 11/10/2023]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is an unabated risk factor for end-stage liver diseases with no available therapies. Dysregulated immune responses are critical culprits of MASLD pathogenesis. Independent contributions from either the innate or adaptive arms of the immune system or their unidirectional interplay are commonly studied in MASLD. However, the bidirectional communication between innate and adaptive immune systems and its impact on MASLD remain insufficiently understood. Given that both innate and adaptive immune cells are indispensable for the development and progression of inflammation in MASLD, elucidating pathogenic contributions stemming from the bidirectional interplay between these two arms holds potential for development of novel therapeutics for MASLD. Here, we review the immune cell types and bidirectional pathways that influence the pathogenesis of MASLD and highlight potential pharmacologic approaches to combat MASLD based on current knowledge of this bidirectional crosstalk.
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Affiliation(s)
- Keisuke Sawada
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
| | - Hak Chung
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Samir Softic
- Department of Pediatrics and Gastroenterology, University of Kentucky, Lexington, KY 40536, USA; Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA
| | - Maria E Moreno-Fernandez
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
| | - Senad Divanovic
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
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22
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Sosa RA, Terry AQ, Ito T, Naini BV, Zheng Y, Pickering H, Nevarez-Mejia J, Busuttil RW, Gjertson DW, Kupiec-Weglinski JW, Reed EF, Kaldas FM. Immune Features of Disparate Liver Transplant Outcomes in Female Hispanics With Nonalcoholic Steatohepatitis. Transplant Direct 2023; 9:e1550. [PMID: 37876917 PMCID: PMC10593264 DOI: 10.1097/txd.0000000000001550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 08/26/2023] [Indexed: 10/26/2023] Open
Abstract
Background Nonalcoholic steatohepatitis (NASH) is a severe immune-mediated stage of nonalcoholic fatty liver disease that is rapidly becoming the most common etiology requiring liver transplantation (LT), with Hispanics bearing a disproportionate burden. This study aimed to uncover the underlying immune mechanisms of the disparities experienced by Hispanic patients undergoing LT for NASH. Methods We enrolled 164 LT recipients in our institutional review board-approved study, 33 of whom presented with NASH as the primary etiology of LT (20%), with 16 self-reported as Hispanic (48%). We investigated the histopathology of prereperfusion and postreperfusion biopsies, clinical liver function tests, longitudinal soluble cytokines via 38-plex Luminex, and immune cell phenotypes generated by prereperfusion and postreperfusion blood using 14-color flow cytometry and enzyme-linked immunosorbent assay. Results Hispanic LT recipients transplanted for NASH were disproportionately female (81%) and disproportionately suffered poor outcomes in the first year posttransplant, including rejection (26%) and death (38%). Clinically, we observed increased pro-inflammatory and apoptotic histopathological features in biopsies, increased AST/international normalized ratio early posttransplantation, and a higher incidence of presensitization to mismatched HLA antigens expressed by the donor allograft. Experimental investigations revealed that blood from female Hispanic NASH patients showed significantly increased levels of leukocyte-attracting chemokines, innate-to-adaptive switching cytokines and growth factors, HMGB1 release, and TLR4/TLR8/TLR9/NOD1 activation, and produced a pro-inflammatory, pro-apoptotic macrophage phenotype with reduced CD14/CD68/CD66a/TIM-3 and increased CD16/CD11b/HLA-DR/CD80. Conclusions A personalized approach to reducing immunological risk factors is urgently needed for this endotype in Hispanics with NASH requiring LT, particularly in females.
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Affiliation(s)
- Rebecca A. Sosa
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
- UCLA Immunogenetics Center, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, Los Angeles, CA
| | - Allyson Q. Terry
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Takahiro Ito
- Dumont-UCLA Transplantation Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Bita V. Naini
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Ying Zheng
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
- UCLA Immunogenetics Center, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, Los Angeles, CA
| | - Harry Pickering
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Jessica Nevarez-Mejia
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Ronald W. Busuttil
- Dumont-UCLA Transplantation Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - David W. Gjertson
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
- UCLA Immunogenetics Center, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, Los Angeles, CA
| | - Jerzy W. Kupiec-Weglinski
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
- Dumont-UCLA Transplantation Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Elaine F. Reed
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
- UCLA Immunogenetics Center, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, Los Angeles, CA
| | - Fady M. Kaldas
- Dumont-UCLA Transplantation Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
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23
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Goand UK, Patel I, Verma S, Yadav S, Maity D, Singh N, Vishwakarma S, Rathaur S, Garg R, Gayen JR. Immunometabolic impact of pancreastatin inhibitor PSTi8 in MCD induced mouse model of oxidative stress and steatohepatitis. Cytokine 2023; 171:156354. [PMID: 37672864 DOI: 10.1016/j.cyto.2023.156354] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 08/25/2023] [Accepted: 08/28/2023] [Indexed: 09/08/2023]
Abstract
AIM Pancreastatin, a dysglycemic hormone that encourages inflammation and steatosis in a variety of metabolic disorder animal models. The purpose of this study is to determine the effect of the pancreastatin inhibitor PSTi8 on immunometabolic changes in the liver of MCD-induced NASH mice. MAIN METHODS Methionine and choline-deficient (MCD) diet was used for the development of NASH. Liver enzymes like SGOT, SGPT, and ALP and lipid profiles were also performed in the serum. Further, immunophenotyping study was performed in the liver through flowcytometer. Subsequently, Hematoxylin and Eosin, Picro Sirius Red and Masson's Trichrome staining were done to check the liver morphology and collagen staining, respectively. Inflammatory cytokines were measured through ELISA and gene expression through RT-PCR. The expression of α-SMA was examined using immunohistochemistry and immunofluorescence staining. KEY FINDINGS PSTi8 inhibited the expression of lipogenic genes in the liver and attenuated bad cholesterol, SGOT, SGPT, and ALP in the serum. PSTi8 improved the liver morphology and attenuated collagen deposition. Subsequently, PSTi8 attenuated inflammatory M1-macrophages, CD8+T, CD4+T cells and increased anti-inflammatory M2 macrophages, T-reg and eosinophil populations in the liver. It also attenuated the expression of pro-inflammatory genes like Mcp1, Tnfα, and Il6. Apart from this, PSTi8 attenuated the oxidative stress marker, like ROS, and MDA and fibrosis marker α-SMA in the liver. It also decreased the apoptosis and ROS and MDA level in the liver. SIGNIFICANCE Overall, these compressive studies revealed that PSTi8 exhibited beneficial effect on the liver of MCD-induced NASH mice by attenuating inflammation and oxidative stress.
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Affiliation(s)
- Umesh K Goand
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Inklisan Patel
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Saurabh Verma
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Shubhi Yadav
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Debalina Maity
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Naveen Singh
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Sachin Vishwakarma
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Shivam Rathaur
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Richa Garg
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Jiaur R Gayen
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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24
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Sheu MJ, Yeh MC, Tsai MC, Wang CC, Chang YL, Wang CJ, Huang HP. Glucosinolates Extracts from Brassica juncea Ameliorate HFD-Induced Non-Alcoholic Steatohepatitis. Nutrients 2023; 15:3497. [PMID: 37630688 PMCID: PMC10458563 DOI: 10.3390/nu15163497] [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: 05/16/2023] [Revised: 07/26/2023] [Accepted: 08/03/2023] [Indexed: 08/27/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is mainly characterized by excessive fat accumulation in the liver. It spans a spectrum of diseases from hepatic steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Brassica juncea is rich in glucosinolates and has been proven to possess many potential pharmacological properties, including hypoglycemic, anti-oxidation, anti-inflammatory, and anti-carcinogenic activities. This study aims to investigate whether whole-plant Brassica juncea (WBJ) and its glucosinolates extracts (BGE) have hepatoprotective effects against a high-fat diet (HFD)-induced NAFLD and further explore the mechanism underlying this process in vivo and in vitro. WBJ treatment significantly reduced body fat, dyslipidemia, hepatic steatosis, liver injury, and inflammation; WBJ treatment also reversed the antioxidant enzyme activity to attenuate oxidative stress in HFD-fed rat liver. Moreover, WBJ and BGE enhanced the activation of AMPK to reduce SREBPs, fatty acid synthase, and HMG-CoA reductase but increased the expression of CPT-I and PPARα to improve hepatic steatosis. In addition, WBJ and BGE could ameliorate NAFLD by inhibiting TNF-α and NF-κB. Based on the above results, this study demonstrates that WBJ and BGE ameliorate HFD-induced hepatic steatosis and liver injury. Therefore, these treatments could represent an unprecedented hope toward improved strategies for NAFLD.
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Affiliation(s)
- Ming-Jen Sheu
- Division of Hepatogastroenterology, Department of Internal Medicine, Chi Mei Medical Center, No. 901, Zhonghua Rd. Yongkang Dist., Tainan City 71004, Taiwan;
| | - Mei-Chen Yeh
- Division of Metabolism and Endocrinology, Department of Internal Medicine, Chi Mei Medical Center, Tainan 71004, Taiwan;
| | - Ming-Chang Tsai
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan; (M.-C.T.); (C.-C.W.); (Y.-L.C.)
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Chi-Chih Wang
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan; (M.-C.T.); (C.-C.W.); (Y.-L.C.)
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Yen-Ling Chang
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan; (M.-C.T.); (C.-C.W.); (Y.-L.C.)
| | - Chau-Jong Wang
- Department of Health Industry Technology Management, Chung Shan Medical University, Taichung 402, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Hui-Pei Huang
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan
- Department of Biochemistry, School of Medicine, Chung Shan Medical University, Taichung 40242, Taiwan
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Chai R, Li Y, Shui L, Ni L, Zhang A. The role of pyroptosis in inflammatory diseases. Front Cell Dev Biol 2023; 11:1173235. [PMID: 37250902 PMCID: PMC10213465 DOI: 10.3389/fcell.2023.1173235] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 04/18/2023] [Indexed: 05/31/2023] Open
Abstract
Programmed cell death has crucial roles in the physiological maturation of an organism, the maintenance of metabolism, and disease progression. Pyroptosis, a form of programmed cell death which has recently received much attention, is closely related to inflammation and occurs via canonical, non-canonical, caspase-3-dependent, and unclassified pathways. The pore-forming gasdermin proteins mediate pyroptosis by promoting cell lysis, contributing to the outflow of large amounts of inflammatory cytokines and cellular contents. Although the inflammatory response is critical for the body's defense against pathogens, uncontrolled inflammation can cause tissue damage and is a vital factor in the occurrence and progression of various diseases. In this review, we briefly summarize the major signaling pathways of pyroptosis and discuss current research on the pathological function of pyroptosis in autoinflammatory diseases and sterile inflammatory diseases.
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Affiliation(s)
| | | | | | - Longxing Ni
- *Correspondence: Longxing Ni, ; Ansheng Zhang,
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26
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Lee SJ, Kim YR, Lee YH, Yoon KH. US Attenuation Imaging for the Evaluation and Diagnosis of Fatty Liver Disease. JOURNAL OF THE KOREAN SOCIETY OF RADIOLOGY 2023; 84:666-675. [PMID: 37324990 PMCID: PMC10265227 DOI: 10.3348/jksr.2022.0053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 06/30/2022] [Accepted: 10/14/2022] [Indexed: 06/17/2023]
Abstract
Purpose This study aimed to determine whether the attenuation coefficient (AC) from attenuation imaging (ATI) was correlated with visual US assessment in patients with hepatic steatosis. Moreover, it aimed to assess whether the patient's blood chemistry results and CT attenuation were correlated with AC. Materials and Methods Patients who underwent abdominal US with ATI between April 2018 and December 2018 were included in this study. Patients with chronic liver disease or cirrhosis were excluded. The correlation between AC and other parameters, such as visual US assessment, blood chemistry results, liver attenuation, and liver-to-spleen (L/S) ratio, were analyzed. AC values according to visual US assessment grades were compared using analysis of variance. Results A total of 161 patients were included in this study. The correlation coefficient between US assessment and AC was 0.814 (p < 0.001). The mean AC values for the normal, mild, moderate, and severe grades were 0.56, 0.66, 0.74, and 0.85, respectively (p < 0.001). Alanine aminotransferase levels were significantly correlated with AC (r = 0.317, p < 0.001). The correlation coefficients between liver attenuation and AC and between L/S ratio and AC were -0.702 and -0.626, respectively (p < 0.001). Conclusion Visual US assessment and AC showed a strong positive correlation with the discriminative value between the groups. Computed tomography attenuation and AC showed a strong negative correlation.
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27
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Abdollahi A, Narayanan SK, Frankovich A, Lai YC, Zhang Y, Henderson GC. Albumin Deficiency Reduces Hepatic Steatosis and Improves Glucose Metabolism in a Mouse Model of Diet-Induced Obesity. Nutrients 2023; 15:2060. [PMID: 37432201 PMCID: PMC10181153 DOI: 10.3390/nu15092060] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/14/2023] [Accepted: 04/20/2023] [Indexed: 06/23/2023] Open
Abstract
Serum albumin facilitates the transport of free fatty acids (FFAs) from adipose tissue to other organs. It was not known if impeding this process could protect from hepatic steatosis and metabolic dysfunction in obesity. We tested whether albumin knockout (Alb-/-) mice would exhibit a reduction in plasma FFA concentration, reduced hepatic lipid accumulation, and improved glucoregulation as compared to wild-type (WT) mice. Male homozygous albumin knockout mice (Alb-/-) and WT controls were fed a low-fat diet (LFD) or high-fat diet (HFD). Alb-/- mice exhibited a similar body weight gain and body composition as WT on both diets. Despite HFD-induced obesity, Alb-/- mice were protected from various comorbidities. Compared to WT mice on the HFD, Alb-/- exhibited lower plasma FFA levels, lower blood glucose levels during glucose tolerance and insulin tolerance tests, and lower hepatic steatosis and inflammation. Alb-/- mice on HFD also exhibited elevated expression of multiple genes in the liver and adipose tissues, such as peroxisome proliferator-activated receptor α in both tissues, as well as glucose transporter-4 and adiponectin in adipose tissues. The results indicate that albumin's FFA transport function may be involved in the development of hepatic lipid accumulation and dysregulated glucose metabolism in obesity.
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Affiliation(s)
- Afsoun Abdollahi
- Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA
| | - Sanjeev K. Narayanan
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA
| | - Alexandra Frankovich
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA
| | - Yen-Chun Lai
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Yi Zhang
- Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA
| | - Gregory C. Henderson
- Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA
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28
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Wikan N, Tocharus J, Oka C, Sivasinprasasn S, Chaichompoo W, Suksamrarn A, Tocharus C. The capsaicinoid nonivamide suppresses the inflammatory response and attenuates the progression of steatosis in a NAFLD-rat model. J Biochem Mol Toxicol 2023; 37:e23279. [PMID: 36541345 DOI: 10.1002/jbt.23279] [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: 06/25/2021] [Revised: 04/28/2022] [Accepted: 12/08/2022] [Indexed: 12/24/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is relatively associated with comorbidities in obesity and metabolic inflammation. Low-grade inflammation following the high-fat diet (HFD)-induced NAFLD can promote the development of nonalcoholic steatohepatitis (NASH) through particularly liver-resident immune cell recruitment and hepatic nuclear factor kappa B (NF-κB) pathway. Therefore, inflammatory intervention may contribute to NASH reduction. Pelargonic acid vanillylamide (PAVA) or nonivamide is one of the pungent capsaicinoids of Capsicum species and has been found in chili peppers. Our previous study demonstrated that PAVA improved hepatic function, decreased oxidative stress and reduced apoptotic cell death but the insight role of PAVA on NAFLD is still unclear. Thus, this study aimed to investigate the underlying anti-inflammatory mechanism of PAVA in an NAFLD-rat model. Male Sprague Dawley rats were fed with normal diet or HFD for 16 weeks. Then high-fat rats were given vehicle or PAVA (1 mg/kg/day) for another 4 weeks. We found that PAVA alleviated hepatic inflammation associated with the reducing toll-like receptor 4/NF-κB pathway, showing significantly lower recruitment of cluster of differentiation 44. PAVA also maintained activity of insulin signaling pathway, and attenuated NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome formation. NAFLD progresses to NASH through transforming growth factor (TGF-β1), and also recovery to simple stage followed by PAVA suppresses pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1β, interleukin-6, and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway. Therefore, our findings suggest that PAVA provides a novel therapeutic approach for NAFLD and slows the progression to NASH.
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Affiliation(s)
- Naruemon Wikan
- Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Jiraporn Tocharus
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Chio Oka
- Functional Genomics and Medicine, Division of Biological Science, Nara Institute of Science and Technology, Ikoma, Nara, Japan
| | | | - Waraluck Chaichompoo
- Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand
| | - Apichart Suksamrarn
- Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand
| | - Chainarong Tocharus
- Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Center for Research and Development of Natural Products for Health, Chiang Mai University, Chiang Mai, Thailand
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Zhang C, Deng Y, Zhang Y, Ba T, Niu S, Chen Y, Gao Y, Dai H. CXCR3 Inhibition Blocks the NF-κB Signaling Pathway by Elevating Autophagy to Ameliorate Lipopolysaccharide-Induced Intestinal Dysfunction in Mice. Cells 2023; 12:cells12010182. [PMID: 36611975 PMCID: PMC9818741 DOI: 10.3390/cells12010182] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 12/16/2022] [Accepted: 12/28/2022] [Indexed: 01/03/2023] Open
Abstract
Autophagy is a cellular catabolic process in the evolutionarily conservative turnover of intracellular substances in eukaryotes, which is involved in both immune homeostasis and injury repairment. CXCR3 is an interferon-induced chemokine receptor that participates in immune regulation and inflammatory responses. However, CXCR3 regulating intestine injury via autophagy along with the precise underlying mechanism have yet to be elucidated. In the current study, we employed an LPS-induced inflammatory mouse model and confirmed that CXCR3 knockout significantly attenuates intestinal mucosal structural damage and increases tight junction protein expression. CXCR3 knockout alleviated the LPS-induced increase in the expression of inflammatory factors including TNF-α, IL-6, p-65, and JNK-1 and enhanced autophagy by elevating LC3II, ATG12, and PINK1/Parkin expression. Mechanistically, the function of CXCR3 regarding autophagy and immunity was investigated in IPEC-J2 cells. CXCR3 inhibition by AMG487 enhanced autophagy and reduced the inflammatory response, as well as blocked the NF-κB signaling pathway and elevated the expression of the tight junction protein marker Claudin-1. Correspondingly, these effects were abolished by autophagy inhibition with the selective blocker, 3-MA. Moreover, the immunofluorescence assay results further demonstrated that CXCR3 inhibition-mediated autophagy blocked p65 nuclear translocation, and the majority of Claudin-1 was located at the tight junctions. In conclusion, CXCR3 inhibition reversed LPS-induced intestinal barrier damage and alleviated the NF-κB signaling pathway via enhancing autophagy. These data provided a theoretical basis for elucidating the immunoregulatory mechanism by targeting CXCR3 to prevent intestinal dysfunction.
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30
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Zou G, Park JI. Wnt signaling in liver regeneration, disease, and cancer. Clin Mol Hepatol 2023; 29:33-50. [PMID: 35785913 PMCID: PMC9845677 DOI: 10.3350/cmh.2022.0058] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 06/30/2022] [Indexed: 02/02/2023] Open
Abstract
The liver exhibits the highest recovery rate from acute injuries. However, in chronic liver disease, the long-term loss of hepatocytes often leads to adverse consequences such as fibrosis, cirrhosis, and liver cancer. The Wnt signaling plays a pivotal role in both liver regeneration and tumorigenesis. Therefore, manipulating the Wnt signaling has become an attractive approach to treating liver disease, including cancer. Nonetheless, given the crucial roles of Wnt signaling in physiological processes, blocking Wnt signaling can also cause several adverse effects. Recent studies have identified cancer-specific regulators of Wnt signaling, which would overcome the limitation of Wnt signaling target approaches. In this review, we discussed the role of Wnt signaling in liver regeneration, precancerous lesion, and liver cancer. Furthermore, we summarized the basic and clinical approaches of Wnt signaling blockade and proposed the therapeutic prospects of cancer-specific Wnt signaling blockade for liver cancer treatment.
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Affiliation(s)
- Gengyi Zou
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA,Corresponding author : Gengyi Zou Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Blvd Unit 1054, Houston, TX 77030, USA Tel: +1-713-792-3659, Fax: +1-713-794-5369, E-mail:
| | - Jae-Il Park
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA,Genetics and Epigenetics Program, The University of Texas MD Anderson Cancer Center Graduate School of Biomedical Sciences, Houston, TX, USA,Jae-Il Park Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Blvd. Unit 1052, Houston, TX 77030, USA Tel: +1-713-792-3659, Fax: +1-713-794-5369, E-mail:
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31
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Zhou Y, Tian N, Li P, He Y, Tong L, Xie W. The correlation between neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio with nonalcoholic fatty liver disease: a cross-sectional study. Eur J Gastroenterol Hepatol 2022; 34:1158-1164. [PMID: 36166298 PMCID: PMC9521580 DOI: 10.1097/meg.0000000000002439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 07/27/2022] [Indexed: 12/13/2022]
Abstract
OBJECTIVE The aim of this study is to investigate the correlation between neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) with nonalcoholic fatty liver disease (NAFLD). METHODS All subjects underwent medical check-ups, which included the measurement of basic clinical, biochemical tests and imaging tests. Univariate and multivariate logistic regression models and piece-wise linear regression were used to assess the relationship between NLR and PLR with NAFLD. RESULTS All participants were divided into two groups: the Non-NAFLD group and the NAFLD group. Univariate analysis model indicated PLR was negatively correlated with NAFLD (P < 0.001) and NLR was not significantly associated with NAFLD (P > 0.05). Multiple logistic regression showed that no correlation between NLR and PLR with NAFLD after adjusting all covariates (P > 0.05). Interestingly, a nonlinear association was detected between NLR and PLR with NAFLD by piece-wise linear regression adjusting for all confounding factors. The inflection points of NLR and PLR were 1.23 and 42.29, respectively. On the left side of the inflection point (NLR < 1.23), a positive correlation was detected between NLR and NAFLD (β = 2.35, 95% CI: 1.20~4.61, P = 0.013). And PLR was found to be negatively associated with NAFLD on the right side of the inflection point (β = 0.99, 95% CI: 0.98~0.99, P < 0.001). CONCLUSION This study demonstrated that the relationship between NLR and PLR with NAFLD was nonlinear after adjusting for potential confounding factors. The result suggested that PLR ≥ 42.29 might be a protective factor of NAFLD, while NLR < 1.23 might be a risk factor of NAFLD.
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Affiliation(s)
- Yuge Zhou
- Affiliated Guangdong Hospital of Integrated Traditional Chinese and Western Medicine of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Foshan City, Guangdong Province, People’s Republic of China
| | - Ning Tian
- Preventive Healthcare Center, Guangdong Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Foshan City, Guangdong Province, People’s Republic of China
| | - Peiling Li
- Affiliated Guangdong Hospital of Integrated Traditional Chinese and Western Medicine of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Foshan City, Guangdong Province, People’s Republic of China
| | - Yanting He
- Affiliated Guangdong Hospital of Integrated Traditional Chinese and Western Medicine of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Foshan City, Guangdong Province, People’s Republic of China
| | - Lijun Tong
- Preventive Healthcare Center, Guangdong Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Foshan City, Guangdong Province, People’s Republic of China
| | - Weining Xie
- Department of Scientific Research, Guangdong Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Foshan City, Guangdong Province, People’s Republic of China
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou City, Guangdong Province, People’s Republic of China
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Kroon T, Hagstedt T, Alexandersson I, Ferm A, Petersson M, Maurer S, Zarrouki B, Wallenius K, Oakes ND, Boucher J. Chronotherapy with a glucokinase activator profoundly improves metabolism in obese Zucker rats. Sci Transl Med 2022; 14:eabh1316. [DOI: 10.1126/scitranslmed.abh1316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Circadian rhythms play a critical role in regulating metabolism, including daily cycles of feeding/fasting. Glucokinase (GCK) is central for whole-body glucose homeostasis and oscillates according to a circadian clock. GCK activators (GKAs) effectively reduce hyperglycemia, but their use is also associated with hypoglycemia, hyperlipidemia, and hepatic steatosis. Given the circadian rhythmicity and natural postprandial activation of GCK, we hypothesized that GKA treatment would benefit from being timed specifically during feeding periods. Acute treatment of obese Zucker rats with the GKA AZD1656 robustly increased flux into all major metabolic pathways of glucose disposal, enhancing glucose elimination. Four weeks of continuous AZD1656 treatment of obese Zucker rats improved glycemic control; however, hepatic steatosis and inflammation manifested. In contrast, timing AZD1656 to feeding periods robustly reduced hepatic steatosis and inflammation in addition to improving glycemia, whereas treatment timed to fasting periods caused overall detrimental metabolic effects. Mechanistically, timing AZD1656 to feeding periods diverted newly synthesized lipid toward direct VLDL secretion rather than intrahepatic storage. In line with increased hepatic insulin signaling, timing AZD1656 to feeding resulted in robust activation of AKT, mTOR, and SREBP-1C after glucose loading, pathways known to regulate VLDL secretion and hepatic de novo lipogenesis. In conclusion, intermittent AZD1656 treatment timed to feeding periods promotes glucose disposal when needed the most, restores metabolic flexibility and hepatic insulin sensitivity, and thereby avoids hepatic steatosis. Thus, chronotherapeutic approaches may benefit the development of GKAs and other drugs acting on metabolic targets.
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Affiliation(s)
- Tobias Kroon
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 43183, Sweden
- Lundberg Laboratory for Diabetes Research, University of Gothenburg, Gothernburg 41345, Sweden
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothernburg 40530 Sweden
| | - Therese Hagstedt
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 43183, Sweden
| | - Ida Alexandersson
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 43183, Sweden
| | - Annett Ferm
- Animal Sciences and Technologies, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg 43183, Sweden
| | - Marie Petersson
- Animal Sciences and Technologies, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg 43183, Sweden
| | - Stefanie Maurer
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 43183, Sweden
| | - Bader Zarrouki
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 43183, Sweden
| | - Kristina Wallenius
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 43183, Sweden
| | - Nicholas D. Oakes
- Functional and Mechanistic Safety, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg 43183, Sweden
| | - Jeremie Boucher
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 43183, Sweden
- Lundberg Laboratory for Diabetes Research, University of Gothenburg, Gothernburg 41345, Sweden
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothernburg 40530 Sweden
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Hepatocyte phosphatase DUSP22 mitigates NASH-HCC progression by targeting FAK. Nat Commun 2022; 13:5945. [PMID: 36209205 PMCID: PMC9547917 DOI: 10.1038/s41467-022-33493-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 09/21/2022] [Indexed: 11/08/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH), a common clinical disease, is becoming a leading cause of hepatocellular carcinoma (HCC). Dual specificity phosphatase 22 (DUSP22, also known as JKAP or JSP-1) expressed in numerous tissues plays essential biological functions in immune responses and tumor growth. However, the effects of DUSP22 on NASH still remain unknown. Here, we find a significant decrease of DUSP22 expression in human and murine fatty liver, which is mediated by reactive oxygen species (ROS) generation. Hepatic-specific DUSP22 deletion particularly exacerbates lipid deposition, inflammatory response and fibrosis in liver, facilitating NASH and non-alcoholic fatty liver disease (NAFLD)-associated HCC progression. In contrast, transgenic over-expression, lentivirus or adeno-associated virus (AAV)-mediated DUSP22 gene therapy substantially inhibit NASH-related phenotypes and HCC development in mice. We provide mechanistic evidence that DUSP22 directly interacts with focal adhesion kinase (FAK) and restrains its phosphorylation at Tyr397 (Y397) and Y576 + Y577 residues, subsequently prohibiting downstream activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor-κB (NF-κB) cascades. The binding of DUSP22 to FAK and the dephosphorylation of FAK are indispensable for DUSP22-meliorated NASH progression. Collectively, our findings identify DUSP22 as a key suppressor of NASH-HCC, and underscore the DUSP22-FAK axis as a promising therapeutic target for treatment of the disease.
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Sitthirach C, Charoensuk L, Pairojkul C, Chaidee A, Intuyod K, Pongking T, Thongpon P, Jantawong C, Hongsrichan N, Waraasawapati S, Yingklang M, Pinlaor S. Curcumin-loaded nanocomplexes ameliorate the severity of nonalcoholic steatohepatitis in hamsters infected with Opisthorchis viverrini. PLoS One 2022; 17:e0275273. [PMID: 36166461 PMCID: PMC9514634 DOI: 10.1371/journal.pone.0275273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 09/13/2022] [Indexed: 11/18/2022] Open
Abstract
Background
Comorbidity of Opisthorchis viverrini (OV) infection and nonalcoholic fatty-liver disease (NAFLD) enhances NAFLD progression to nonalcoholic steatohepatitis (NASH) by promoting severe liver inflammation and fibrosis. Here, we investigated the effect of supplementation with curcumin-loaded nanocomplexes (CNCs) on the severity of NASH in hamsters.
Methodology
Hamsters were placed in experimental groups as follows: fed standard chow diet (normal control, NC); fed only high-fat and high-fructose (HFF) diet; O. viverrini-infected and fed HFF diet (HFFOV); group fed with blank nanocomplexes (HFFOV+BNCs); groups fed different doses of CNCs (25, 50 and 100 mg/kg body weight: HFFOV+CNCs25; HFFOV+CNCs50; HFFOV+CNCs100, respectively) and a group given native curcumin (HFFOV+CUR). All treatment were for three months.
Results
The HFF group revealed NAFLD as evidenced by hepatic fat accumulation, ballooning, mild inflammation and little or no fibrosis. These changes were more obvious in the HFFOV group, indicating development of NASH. In contrast, in the HFFOV+CNCs50 group, histopathological features indicated that hepatic fat accumulation, cell ballooning, cell inflammation and fibrosis were lower than in other treatment groups. Relevantly, the expression of lipid-uptake genes, including fatty-acid uptake (cluster of differentiation 36), was reduced, which was associated with the lowering of alanine aminotransferase, total cholesterol and triglyceride (TG) levels. Reduced expression of an inflammation marker (high-mobility group box protein 1) and a fibrosis marker (alpha smooth-muscle actin) were also observed in the HFFOV+CNCs50 group.
Conclusion
CNCs treatment attenuates the severity of NASH by decreasing hepatic steatosis, inflammation, and fibrosis as well as TG synthesis. CNCs mitigate the severity of NASH in this preclinical study, which indicates promise for future use in patients.
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Affiliation(s)
- Chutima Sitthirach
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Lakhanawan Charoensuk
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Clinical Pathology, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, Bangkok, Thailand
| | - Chawalit Pairojkul
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Apisit Chaidee
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Kitti Intuyod
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Thatsanapong Pongking
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Biomedical Science Program, Graduate School, Khon Kaen University, Khon Kaen, Thailand
| | - Phonpilas Thongpon
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Chanakan Jantawong
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Medical Technology, Faculty of Allied Health Science, Nakhonratchasima College, Nakhon Ratchasima, Thailand
| | - Nuttanan Hongsrichan
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Sakda Waraasawapati
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Manachai Yingklang
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Fundamentals of Public Health, Faculty of Public Health, Burapha University, Chonburi, Thailand
| | - Somchai Pinlaor
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- * E-mail:
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Seidel F, Kleemann R, van Duyvenvoorde W, van Trigt N, Keijzer N, van der Kooij S, van Kooten C, Verschuren L, Menke A, Kiliaan AJ, Winter J, Hughes TR, Morgan BP, Baas F, Fluiter K, Morrison MC. Therapeutic Intervention with Anti-Complement Component 5 Antibody Does Not Reduce NASH but Does Attenuate Atherosclerosis and MIF Concentrations in Ldlr-/-.Leiden Mice. Int J Mol Sci 2022; 23:ijms231810736. [PMID: 36142647 PMCID: PMC9506266 DOI: 10.3390/ijms231810736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/07/2022] [Accepted: 09/10/2022] [Indexed: 11/30/2022] Open
Abstract
Background: Chronic inflammation is an important driver in the progression of non-alcoholic steatohepatitis (NASH) and atherosclerosis. The complement system, one of the first lines of defense in innate immunity, has been implicated in both diseases. However, the potential therapeutic value of complement inhibition in the ongoing disease remains unclear. Methods: After 20 weeks of high-fat diet (HFD) feeding, obese Ldlr-/-.Leiden mice were treated twice a week with an established anti-C5 antibody (BB5.1) or vehicle control. A separate group of mice was kept on a chow diet as a healthy reference. After 12 weeks of treatment, NASH was analyzed histopathologically, and genome-wide hepatic gene expression was analyzed by next-generation sequencing and pathway analysis. Atherosclerotic lesion area and severity were quantified histopathologically in the aortic roots. Results: Anti-C5 treatment considerably reduced complement system activity in plasma and MAC deposition in the liver but did not affect NASH. Anti-C5 did, however, reduce the development of atherosclerosis, limiting the total lesion size and severity independently of an effect on plasma cholesterol but with reductions in oxidized LDL (oxLDL) and macrophage migration inhibitory factor (MIF). Conclusion: We show, for the first time, that treatment with an anti-C5 antibody in advanced stages of NASH is not sufficient to reduce the disease, while therapeutic intervention against established atherosclerosis is beneficial to limit further progression.
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Affiliation(s)
- Florine Seidel
- Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands
- Department Medical Imaging, Anatomy, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, 6525 EZ Nijmegen, The Netherlands
- Correspondence:
| | - Robert Kleemann
- Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands
| | - Wim van Duyvenvoorde
- Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands
| | - Nikki van Trigt
- Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands
| | - Nanda Keijzer
- Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands
| | - Sandra van der Kooij
- Department of Internal Medicine (Nephrology) and Transplant Center, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Cees van Kooten
- Department of Internal Medicine (Nephrology) and Transplant Center, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Lars Verschuren
- Department of Microbiology and Systems Biology, Netherlands Organisation for Applied Scientific Research (TNO), 3704 HE Zeist, The Netherlands
| | - Aswin Menke
- Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands
| | - Amanda J. Kiliaan
- Department Medical Imaging, Anatomy, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, 6525 EZ Nijmegen, The Netherlands
| | - Johnathan Winter
- Complement Biology Group, Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
- UK Dementia Research Institute Cardiff, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK
| | - Timothy R. Hughes
- Complement Biology Group, Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
- UK Dementia Research Institute Cardiff, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK
| | - B. Paul Morgan
- Complement Biology Group, Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
- UK Dementia Research Institute Cardiff, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK
| | - Frank Baas
- Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Kees Fluiter
- Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Martine C. Morrison
- Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands
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Shavakhi M, Nourigheimasi S, Dioso E, Goutnik M, Lucke-Wold B, Khanzadeh S, Heidari F. Prognostic Role of Neutrophil to Lymphocyte Ratio in Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. Can J Gastroenterol Hepatol 2022; 2022:1554079. [PMID: 37601979 PMCID: PMC10432763 DOI: 10.1155/2022/1554079] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/19/2022] [Accepted: 08/29/2022] [Indexed: 08/22/2023] Open
Abstract
Introduction Nonalcoholic steatohepatitis (NASH) and liver fibrosis are the most common complications of nonalcoholic fatty liver disease (NAFLD). In this systematic review and meta-analysis, we aim to analyze the current literature to evaluate the association of neutrophil to lymphocyte ratio (NLR) with NASH and fibrosis in patients with NAFLD. Methods PubMed, Web of Science, and Scopus were used to conduct a systematic search for relevant publications published before May 24, 2022. The Newcastle-Ottawa scale was used for quality assessment. Results Thirteen studies were included in our study. The pooled results showed that NAFLD patients with significant NASH had elevated levels of NLR compared to those with nonsignificant or without NASH (SMD = 0.97, 95% CI = 0.59-1.39, p < 0.001). The pooled sensitivity and specificity of NLR were 78.16% (95% CI = 73.70%-82.04%), and 76.93% (95% CI = 70.22%-82.50%), respectively. In addition, NAFLD patients with significant liver fibrosis had elevated levels of NLR compared to those with nonsignificant or without fibrosis (SMD = 1.59, 95% CI = 0.76-2.43, p < 0.001). The pooled sensitivity and specificity of NLR were 82.62% (95% CI = 70.235%-90.55%) and 81.22% (95% CI = 75.62%-85.78%), respectively. Conclusion Our findings support NLR to be a promising biomarker that can be readily integrated into clinical settings to aid in the prediction and prevention of NASH and fibrosis among patients with NAFLD.
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Affiliation(s)
- Mitra Shavakhi
- Department of Pathology, School of Medicine, Isfahan University of Medical Sciences, Iran
| | | | - Emma Dioso
- Department of Neurosurgery, University of Utah, Salt Lake City, USA
| | - Michael Goutnik
- Department of Neurosurgery, University of Florida, Gainesville, USA
| | | | - Shokoufeh Khanzadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fariba Heidari
- Department of Community and Family Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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Choi SE, Hwang Y, Lee SJ, Jung H, Shin TH, Son Y, Park S, Han SJ, Kim HJ, Lee KW, Lee G, Kemper JK, Song HK, Kang Y. Mitochondrial protease ClpP supplementation ameliorates diet-induced NASH in mice. J Hepatol 2022; 77:735-747. [PMID: 35421426 DOI: 10.1016/j.jhep.2022.03.034] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 02/18/2022] [Accepted: 03/21/2022] [Indexed: 01/04/2023]
Abstract
BACKGROUND & AIMS Mitochondrial dysfunction is considered a pathogenic linker in the development of non-alcoholic steatohepatitis (NASH). Inappropriate mitochondrial protein-quality control, possibly induced by insufficiency of the mitochondrial matrix caseinolytic protease P (ClpP), can potentially cause mitochondrial dysfunction. Herein, we aimed to investigate hepatic ClpP levels in a diet-induced model of NASH and determine whether supplementation of ClpP can ameliorate diet-induced NASH. METHODS NASH was induced by a high-fat/high-fructose (HF/HFr) diet in C57BL/6J mice. Stress/inflammatory signals were induced in mouse primary hepatocytes (MPHs) by treatment with palmitate/oleate (PA/OA). ClpP levels in hepatocytes were reduced using the RNAi-mediated gene knockdown technique but increased through the viral transduction of ClpP. ClpP activation was induced by administering a chemical activator of ClpP. RESULTS Hepatic ClpP protein levels in C57BL/6J mice fed a HF/HFr diet were lower than the levels in those fed a normal chow diet. PA/OA treatment also decreased the ClpP protein levels in MPHs. Overexpression or activation of ClpP reversed PA/OA-induced mitochondrial dysfunction and stress/inflammatory signal activation in MPHs, whereas ClpP knockdown induced mitochondrial dysfunction and stress/inflammatory signals in these cells. On the other hand, ClpP overexpression or activation improved HF/HFr-induced NASH characteristics such as hepatic steatosis, inflammation, fibrosis, and injury in the C57BL/6J mice, whereas ClpP knockdown further augmented steatohepatitis in mice fed a HF/HFr diet. CONCLUSIONS Reduced ClpP expression and subsequent mitochondrial dysfunction are key to the development of diet-induced NASH. ClpP supplementation through viral transduction or chemical activation represents a potential therapeutic strategy to prevent diet-induced NASH. LAY SUMMARY Western diets, containing high fat and high fructose, often induce non-alcoholic steatohepatitis (NASH). Mitochondrial dysfunction is considered pathogenically linked to diet-induced NASH. We observed that the mitochondrial protease ClpP decreased in the livers of mice fed a western diet and supplementation of ClpP ameliorated western diet-induced NASH.
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Affiliation(s)
- Sung-E Choi
- Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, Republic of Korea 443-749
| | - Yoonjung Hwang
- Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, Republic of Korea 443-749
| | - Soo-Jin Lee
- Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, Republic of Korea 443-749
| | - Hyunkyung Jung
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA 61801
| | - Tae Hwan Shin
- Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, Republic of Korea 443-749
| | - Youngho Son
- Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, Republic of Korea 443-749; Department of Biomedical Science, The Graduate School, Ajou University, Suwon, Gyunggi-do, Republic of Korea 443-749
| | - Seokho Park
- Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, Republic of Korea 443-749; Department of Biomedical Science, The Graduate School, Ajou University, Suwon, Gyunggi-do, Republic of Korea 443-749
| | - Seung Jin Han
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Gyunggi-do, Republic of Korea 443-749
| | - Hae Jin Kim
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Gyunggi-do, Republic of Korea 443-749
| | - Kwan Woo Lee
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Gyunggi-do, Republic of Korea 443-749
| | - Gwang Lee
- Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, Republic of Korea 443-749
| | - Jongsook Kim Kemper
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA 61801
| | - Hyun Kyu Song
- School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea 136-701
| | - Yup Kang
- Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, Republic of Korea 443-749.
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Min RWM, Aung FWM, Liu B, Arya A, Win S. Mechanism and Therapeutic Targets of c-Jun-N-Terminal Kinases Activation in Nonalcoholic Fatty Liver Disease. Biomedicines 2022; 10:biomedicines10082035. [PMID: 36009582 PMCID: PMC9406172 DOI: 10.3390/biomedicines10082035] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/15/2022] [Accepted: 08/18/2022] [Indexed: 11/16/2022] Open
Abstract
Non-alcoholic fatty liver (NAFL) is the most common chronic liver disease. Activation of mitogen-activated kinases (MAPK) cascade, which leads to c-Jun N-terminal kinase (JNK) activation occurs in the liver in response to the nutritional and metabolic stress. The aberrant activation of MAPKs, especially c-Jun-N-terminal kinases (JNKs), leads to unwanted genetic and epi-genetic modifications in addition to the metabolic stress adaptation in hepatocytes. A mechanism of sustained P-JNK activation was identified in acute and chronic liver diseases, suggesting an important role of aberrant JNK activation in NASH. Therefore, modulation of JNK activation, rather than targeting JNK protein levels, is a plausible therapeutic application for the treatment of chronic liver disease.
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Affiliation(s)
| | | | - Bryant Liu
- Division of Gastrointestinal and Liver Disease, Department of Medicine, Keck School of Medicine, University of Southern California, 2011 Zonal Ave., HMR 612, Los Angeles, CA 90089, USA
| | - Aliza Arya
- Division of Gastrointestinal and Liver Disease, Department of Medicine, Keck School of Medicine, University of Southern California, 2011 Zonal Ave., HMR 612, Los Angeles, CA 90089, USA
| | - Sanda Win
- Division of Gastrointestinal and Liver Disease, Department of Medicine, Keck School of Medicine, University of Southern California, 2011 Zonal Ave., HMR 612, Los Angeles, CA 90089, USA
- Correspondence:
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mTOR: A Potential New Target in Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2022; 23:ijms23169196. [PMID: 36012464 PMCID: PMC9409235 DOI: 10.3390/ijms23169196] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/10/2022] [Accepted: 08/11/2022] [Indexed: 11/17/2022] Open
Abstract
The global prevalence of nonalcoholic fatty liver disease (NAFLD) continues to rise, yet effective treatments are lacking due to the complex pathogenesis of this disease. Although recent research has provided evidence for the “multiple strikes” theory, the classic “two strikes” theory has not been overturned. Therefore, there is a crucial need to identify multiple targets in NAFLD pathogenesis for the development of diagnostic markers and targeted therapeutics. Since its discovery, the mechanistic target of rapamycin (mTOR) has been recognized as the central node of a network that regulates cell growth and development and is closely related to liver lipid metabolism and other processes. This paper will explore the mechanisms by which mTOR regulates lipid metabolism (SREBPs), insulin resistance (Foxo1, Lipin1), oxidative stress (PIG3, p53, JNK), intestinal microbiota (TLRs), autophagy, inflammation, genetic polymorphisms, and epigenetics in NAFLD. The specific influence of mTOR on NAFLD was hypothesized to be divided into micro regulation (the mechanism of mTOR’s influence on NAFLD factors) and macro mediation (the relationship between various influencing factors) to summarize the influence of mTOR on the developmental process of NAFLD, and prove the importance of mTOR as an influencing factor of NAFLD regarding multiple aspects. The effects of crosstalk between mTOR and its upstream regulators, Notch, Hedgehog, and Hippo, on the occurrence and development of NAFLD-associated hepatocellular carcinoma are also summarized. This analysis will hopefully support the development of diagnostic markers and new therapeutic targets in NAFLD.
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Carvalho-Gontijo R, Han C, Zhang L, Zhang V, Hosseini M, Mekeel K, Schnabl B, Loomba R, Karin M, Brenner DA, Kisseleva T. Metabolic Injury of Hepatocytes Promotes Progression of NAFLD and AALD. Semin Liver Dis 2022; 42:233-249. [PMID: 36001995 PMCID: PMC9662188 DOI: 10.1055/s-0042-1755316] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Nonalcoholic liver disease is a component of metabolic syndrome associated with obesity, insulin resistance, and hyperlipidemia. Excessive alcohol consumption may accelerate the progression of steatosis, steatohepatitis, and fibrosis. While simple steatosis is considered a benign condition, nonalcoholic steatohepatitis with inflammation and fibrosis may progress to cirrhosis, liver failure, and hepatocellular cancer. Studies in rodent experimental models and primary cell cultures have demonstrated several common cellular and molecular mechanisms in the pathogenesis and regression of liver fibrosis. Chronic injury and death of hepatocytes cause the recruitment of myeloid cells, secretion of inflammatory and fibrogenic cytokines, and activation of myofibroblasts, resulting in liver fibrosis. In this review, we discuss the role of metabolically injured hepatocytes in the pathogenesis of nonalcoholic steatohepatitis and alcohol-associated liver disease. Specifically, the role of chemokine production and de novo lipogenesis in the development of steatotic hepatocytes and the pathways of steatosis regulation are discussed.
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Affiliation(s)
- Raquel Carvalho-Gontijo
- Department of Medicine, University of California, San Diego School of Medicine, La Jolla
- Department of Surgery, University of California, San Diego School of Medicine, La Jolla
| | - Cuijuan Han
- Department of Medicine, University of California, San Diego School of Medicine, La Jolla
- Department of Surgery, University of California, San Diego School of Medicine, La Jolla
| | - Lei Zhang
- Department of Medicine, University of California, San Diego School of Medicine, La Jolla
- Department of Surgery, University of California, San Diego School of Medicine, La Jolla
| | - Vivian Zhang
- Department of Medicine, University of California, San Diego School of Medicine, La Jolla
- Department of Surgery, University of California, San Diego School of Medicine, La Jolla
| | - Mojgan Hosseini
- Department of Pathology, University of California, San Diego School of Medicine, La Jolla
| | - Kristin Mekeel
- Department of Surgery, University of California, San Diego School of Medicine, La Jolla
| | - Bernd Schnabl
- Department of Medicine, University of California, San Diego School of Medicine, La Jolla
| | - Rohit Loomba
- Department of Medicine, University of California, San Diego School of Medicine, La Jolla
| | - Michael Karin
- Department of Pharmacology, University of California, San Diego School of Medicine, La Jolla
| | - David A. Brenner
- Department of Medicine, University of California, San Diego School of Medicine, La Jolla
| | - Tatiana Kisseleva
- Department of Surgery, University of California, San Diego School of Medicine, La Jolla
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IκBζ regulates the development of nonalcoholic fatty liver disease through the attenuation of hepatic steatosis in mice. Sci Rep 2022; 12:11634. [PMID: 35804007 PMCID: PMC9270369 DOI: 10.1038/s41598-022-15840-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 06/30/2022] [Indexed: 11/24/2022] Open
Abstract
IκBζ is a transcriptional regulator that augments inflammatory responses from the Toll-like receptor or interleukin signaling. These innate immune responses contribute to the progression of nonalcoholic fatty liver disease (NAFLD); however, the role of IκBζ in the pathogenesis of NAFLD remains elusive. We investigated whether IκBζ was involved in the progression of NAFLD in mice. We generated hepatocyte-specific IκBζ-deficient mice (Alb-Cre; Nfkbizfl/fl) by crossing Nfkbizfl/fl mice with Alb-Cre transgenic mice. NAFLD was induced by feeding the mice a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). CDAHFD-induced IκBζ expression in the liver was observed in Nfkbizfl/fl mice, but not in Alb-Cre; Nfkbizfl/fl mice. Contrary to our initial expectation, IκBζ deletion in hepatocytes accelerated the progression of NAFLD after CDAHFD treatment. Although the increased expression of inflammatory cytokines and apoptosis-related proteins by CDAHFD remained unchanged between Nfkbizfl/fl and Alb-Cre; Nfkbizfl/fl mice, early-stage steatosis of the liver was significantly augmented in Alb-Cre; Nfkbizfl/fl mice. Overexpression of IκBζ in hepatocytes via the adeno-associated virus vector attenuated liver steatosis caused by the CDAHFD in wild-type C57BL/6 mice. This preventive effect of IκBζ overexpression on steatosis was not observed without transcriptional activity. Microarray analysis revealed a correlation between IκBζ expression and the changes of factors related to triglyceride biosynthesis and lipoprotein uptake. Our data suggest that hepatic IκBζ attenuates the progression of NAFLD possibly through the regulation of the factors related to triglyceride metabolism.
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Liu M, He H, Chen L. Protective Potential of Maresins in Cardiovascular Diseases. Front Cardiovasc Med 2022; 9:923413. [PMID: 35859590 PMCID: PMC9289265 DOI: 10.3389/fcvm.2022.923413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 06/02/2022] [Indexed: 11/16/2022] Open
Abstract
Cardiovascular diseases are the leading causes of global mortality. Growing evidence suggests that unresolved inflammation contributes to the chronicity, progression and morbidity of many cardiovascular diseases, thus emphasizing the urgent need to illuminate the mechanisms controlling inflammation and its resolution, for the sake of new effective therapeutic options. Macrophage mediators in resolving inflammation (Maresins) are a family of specialized pro-resolving lipid mediators (SPMs) derived from the ω-3 fatty acid docosahexaenoic acid (DHA). Studies have indicated that Maresins play critical role in initiating the pro-resolving functions of phagocytes, decreasing the magnitude of the overall inflammatory response, and thereby protecting against inflammation-related disorders. In this review, we summarize the detailed actions and the therapeutic potential of Maresins, with a particular emphasis on Maresin-1 (MaR1), in cardiovascular diseases. We hope this review will lead to new avenues to Maresins-based therapies for inflammation-associated cardiovascular diseases.
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Fiorucci S, Zampella A, Ricci P, Distrutti E, Biagioli M. Immunomodulatory functions of FXR. Mol Cell Endocrinol 2022; 551:111650. [PMID: 35472625 DOI: 10.1016/j.mce.2022.111650] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 03/31/2022] [Accepted: 04/04/2022] [Indexed: 02/08/2023]
Abstract
The Farnesoid-x-receptor (FXR) is a bile acids sensor activated in humans by primary bile acids. FXR is mostly expressed in liver, intestine and adrenal glands but also by cells of innate immunity, including macrophages, liver resident macrophages, the Kupffer cells, natural killer cells and dendritic cells. In normal physiology and clinical disorders, cells of innate immunity mediate communications between liver, intestine and adipose tissues. In addition to FXR, the G protein coupled receptor (GPBAR1), that is mainly activated by secondary bile acids, whose expression largely overlaps FXR, modulates chemical communications from the intestinal microbiota and the host's immune system, integrating epithelial cells and immune cells in the entero-hepatic system, providing a mechanism for development of a tolerogenic state toward the intestinal microbiota. Disruption of FXR results in generalized inflammation and disrupted bile acids metabolism. While FXR agonism in preclinical models provides counter-regulatory signals that attenuate inflammation-driven immune dysfunction in a variety of liver and intestinal disease models, the clinical relevance of these mechanisms in the setting of FXR-related disorders remain poorly defined.
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Affiliation(s)
- Stefano Fiorucci
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy. http://www.gastroenterologia.unipg.it
| | - Angela Zampella
- University of Naples Federico II, Department of Pharmacy, Naples, Italy
| | - Patrizia Ricci
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
| | - Eleonora Distrutti
- SC di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, Perugia, Italy
| | - Michele Biagioli
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
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Terayama Y, Nakamura SI, Mekada K, Matsuura T, Ozaki K. High-fat diet-induced nonalcoholic steatohepatitis is accelerated by low carnitine and impaired glucose tolerance in novel murine models. J Transl Med 2022; 102:621-630. [PMID: 35039610 DOI: 10.1038/s41374-022-00732-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 12/29/2021] [Accepted: 01/03/2022] [Indexed: 11/09/2022] Open
Abstract
Carnitine deficiency and impaired glucose tolerance (IGT) exacerbate liver steatosis. Given the current lack of ideal murine nonalcoholic steatohepatitis (NASH) models, we investigated new NASH models using jvs/+ mice with low carnitine and wild-type mice with low-dose alloxan-induced IGT. The jvs/+ and wild-type mice were divided into jvs/+ mice fed a high-fat diet (HFD) from 3 weeks of age (HF hetero group), wild-type mice with low-dose alloxan treatment fed HFD (AL + HF wild group), wild-type mice fed HFD (HF wild group), and two types of mice fed a normal diet-jvs/+ and wild-type (intact group). All mice were sacrificed at 20 or 40 weeks of age. All male HFD-fed mice showed obesity, IGT, high blood insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR), high liver enzyme levels, and high cholesterol levels. The degree of IGT was the worst in the AL + HF wild group, and blood insulin levels and HOMA-IR score were remarkably increased from 20 to 40 weeks of age. Almost all HFD-fed mice showed steatosis, fibrosis, and lobular inflammation in the centrilobular zone. These changes were accompanied by hepatocyte ballooning and were enhanced at 40 weeks of age. Furthermore, the incidence rate of nodular hyperplasia and adenoma in both the HF hetero and AL + HF wild groups was nearly 30%. We successfully established two novel murine models of NASH using male jvs/+ mice with low carnitine and male wild-type mice with IGT that eventually developed obesity, fatty liver, insulin resistance, liver fibrosis, and tumorigenesis. These results suggest that low carnitine levels and early-stage induction of IGT are important factors in the progression of NASH to tumorigenesis, similar to human NASH.
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Affiliation(s)
- Yui Terayama
- Laboratory of Pathology, Faculty of Pharmaceutical Science, Setsunan University, 45-1 Nagaotohge-cho, Hirakata, Osaka, 573-0101, Japan
| | - Shin-Ichi Nakamura
- Laboratory of Pathology, Faculty of Pharmaceutical Science, Setsunan University, 45-1 Nagaotohge-cho, Hirakata, Osaka, 573-0101, Japan.,Kyoto Institute of Nutrition & Pathology Inc, 7-2 Furuiketani, Tachikawa, Ujitawara, Tsuzuki-gun, Kyoto, 610-0231, Japan
| | - Kazuyuki Mekada
- Department of Zoology, Okayama University of Science, 1-1 Ridai-cho, Kita-ku, Okayama City, Okayama, 700-0005, Japan
| | - Tetsuro Matsuura
- Laboratory of Pathology, Faculty of Pharmaceutical Science, Setsunan University, 45-1 Nagaotohge-cho, Hirakata, Osaka, 573-0101, Japan
| | - Kiyokazu Ozaki
- Laboratory of Pathology, Faculty of Pharmaceutical Science, Setsunan University, 45-1 Nagaotohge-cho, Hirakata, Osaka, 573-0101, Japan.
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Mega-Dose Vitamin C Ameliorates Nonalcoholic Fatty Liver Disease in a Mouse Fast-Food Diet Model. Nutrients 2022; 14:nu14112195. [PMID: 35683997 PMCID: PMC9182669 DOI: 10.3390/nu14112195] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 05/16/2022] [Accepted: 05/23/2022] [Indexed: 12/15/2022] Open
Abstract
In previous studies, the increasing clinical importance of nonalcoholic fatty liver disease (NAFLD) has been recognized. However, the specific therapeutic strategies or drugs have not been discovered. Vitamin C is a water-soluble antioxidant and is a cofactor in many important biosynthesis pathways. Recently, many researchers have reported that the mega-dose vitamin C treatment had positive effects on various diseases. However, the precise relationship between mega-dose vitamin C and NAFLD has not been completely elucidated. This study has been designed to discover the effects of mega-dose vitamin C on the progression of NAFLD. Twelve-week-old wild-type C57BL6 mice were fed chow diets and high-fat and high-fructose diet (fast-food diet) ad libitum for 11 weeks with or without of vitamin C treatment. Vitamin C was administered in the drinking water (1.5 g/L). In this study, 11 weeks of the mega-dose vitamin C treatment significantly suppressed the development of nonalcoholic steatohepatitis (NASH) independently of the catabolic process. Vitamin C supplements in fast-food diet fed mice significantly decreased diet ingestion and increased water intake. Histopathological analysis revealed that the mice fed a fast-food diet with vitamin C water had a mild renal injury suggesting osmotic nephrosis due to fructose-mediated purine derivatives. These data suggest that the mega-dose vitamin C treatment suppresses high-fructose-diet-mediated NAFLD progression by decreasing diet ingestion and increasing water intake.
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Nozu T, Okumura T. Pathophysiological Commonality Between Irritable Bowel Syndrome and Metabolic Syndrome: Role of Corticotropin-releasing Factor-Toll-like Receptor 4-Proinflammatory Cytokine Signaling. J Neurogastroenterol Motil 2022; 28:173-184. [PMID: 35189599 PMCID: PMC8978123 DOI: 10.5056/jnm21002] [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: 01/04/2021] [Revised: 08/26/2021] [Accepted: 10/11/2021] [Indexed: 11/20/2022] Open
Abstract
Irritable bowel syndrome (IBS) displays chronic abdominal pain with altered defecation. Most of the patients develop visceral hypersensitivity possibly resulting from impaired gut barrier and altered gut microbiota. We previously demonstrated that colonic hyperpermeability with visceral hypersensitivity in animal IBS models, which is mediated via corticotropin-releasing factor (CRF)-Toll-like receptor 4 (TLR4)-proinflammatory cytokine signaling. CRF impairs gut barrier via TLR4. Leaky gut induces bacterial translocation resulting in dysbiosis, and increases lipopolysaccharide (LPS). Activation of TLR4 by LPS increases the production of proinflammatory cytokines, which activate visceral sensory neurons to induce visceral hypersensitivity. LPS also activates CRF receptors to further increase gut permeability. Metabolic syndrome (MS) is a cluster of cardiovascular risk factors, including insulin resistance, obesity, dyslipidemia, and hypertension, and recently several researchers suggest the possibility that impaired gut barrier and dysbiosis with low-grade systemic inflammation are involved in MS. Moreover, TLR4-proinflammatory cytokine contributes to the development of insulin resistance and obesity. Thus, the existence of pathophysiological commonality between IBS and MS is expected. This review discusses the potential mechanisms of IBS and MS with reference to gut barrier and microbiota, and explores the possibility of existence of pathophysiological link between these diseases with a focus on CRF, TLR4, and proinflammatory cytokine signaling. We also review epidemiological data supporting this possibility, and discuss the potential of therapeutic application of the drugs used for MS to IBS treatment. This notion may pave the way for exploring novel therapeutic approaches for these disorders.
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Affiliation(s)
- Tsukasa Nozu
- Department of Regional Medicine and Education, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.,Center for Medical Education, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Toshikatsu Okumura
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.,Department of General Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
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Abstract
Metabolic (dysfunction) associated fatty liver disease (MAFLD), previously known as non-alcoholic fatty liver disease, is the most common cause of chronic liver disease worldwide. Many risk factors contribute to the pathogenesis of MAFLD with metabolic dysregulation being the final arbiter of its development and progression. MAFLD poses a substantial economic burden to societies, which based on current trends is expected to increase over time. Numerous studies have addressed various aspects of MAFLD from its risk associations to its economic and social burden and clinical diagnosis and management, as well as the molecular mechanisms linking MAFLD to end-stage liver disease and hepatocellular carcinoma. This review summarizes current understanding of the pathogenesis of MAFLD and related diseases, particularly liver cancer. Potential therapeutic agents for MAFLD and diagnostic biomarkers are discussed.
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Marri UK, Madhusudhan KS. Dual-Energy Computed Tomography in Diffuse Liver Diseases. JOURNAL OF GASTROINTESTINAL AND ABDOMINAL RADIOLOGY 2022. [DOI: 10.1055/s-0042-1742432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
AbstractDual-energy computed tomography (DECT) is an advancement in the field of CT, where images are acquired at two energies. Materials are identified and quantified based on their attenuation pattern at two different energy beams using various material decomposition algorithms. With its ability to identify and quantify materials such as fat, calcium, iron, and iodine, DECT adds great value to conventional CT and has innumerable applications in body imaging. Continuous technological advances in CT scanner hardware, material decomposition algorithms, and image reconstruction software have led to considerable growth of these applications. Among all organs, the liver is the most widely investigated by DECT, and DECT has shown promising results in most liver applications. In this article, we aim to provide an overview of the role of DECT in the assessment of diffuse liver diseases, mainly the deposition of fat, fibrosis, and iron and review the most relevant literature.
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Affiliation(s)
- Uday Kumar Marri
- Department of Radiodiagnosis and Interventional Radiology, All India Institute of Medical Sciences, New Delhi, India
| | - Kumble Seetharama Madhusudhan
- Department of Radiodiagnosis and Interventional Radiology, All India Institute of Medical Sciences, New Delhi, India
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Arora M, Kutinová Canová N, Farghali H. mTOR as an eligible molecular target for possible pharmacological treatment of nonalcoholic steatohepatitis. Eur J Pharmacol 2022; 921:174857. [PMID: 35219732 DOI: 10.1016/j.ejphar.2022.174857] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 02/07/2022] [Accepted: 02/22/2022] [Indexed: 12/14/2022]
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50
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Lee N, Heo YJ, Choi SE, Jeon JY, Han SJ, Kim DJ, Kang Y, Lee KW, Kim HJ. Hepatoprotective effects of gemigliptin and empagliflozin in a murine model of diet-induced non-alcoholic fatty liver disease. Biochem Biophys Res Commun 2022; 588:154-160. [PMID: 34971904 DOI: 10.1016/j.bbrc.2021.12.065] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 12/14/2021] [Accepted: 12/18/2021] [Indexed: 12/19/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) includes a broad spectrum of liver diseases characterized by steatosis, inflammation, and fibrosis. This study aimed to investigate the potential of dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter 2 inhibitors in alleviating the progression of NAFLD. The NAFLD model was generated by feeding male C57BL/6J mice a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for 7 weeks. After 2 weeks of CDAHFD feeding, the NAFLD model mice were assigned to four groups, namely (ⅰ) VEHICLE, (ⅱ) gemigliptin (GEMI), (ⅲ) empagliflozin (EMPA), and (ⅳ) GEMI + EMPA. For the next 5 weeks, mice received the vehicle or the drug based upon the group to which they belonged. Thereafter, the triglyceride concentration, extent of fibrosis, and the expression of genes encoding inflammatory cytokines, chemokines, and antioxidant enzymes were analyzed in the livers of mice. The NAFLD activity score and hepatic fibrosis grade were assessed via hematoxylin and eosin and Sirius Red staining of the liver tissue samples. All mice belonging to the GEMI, EMPA, and GEMI + EMPA groups showed improvements in the accumulation of liver triglycerides and the expression of inflammatory cytokines and chemokines. Additionally, the oxidative stress was reduced due to inhibition of the c-Jun N-terminal kinase pathway and upregulation of the antioxidant enzymes. Furthermore, in these three groups, the galectin-3 and interleukin 33-induced activity of tumor necrosis factor-α was inhibited, thereby preventing the progression of liver fibrosis. These findings suggest that the GEMI, EMPA, and GEMI + EMPA treatments ameliorate hepatic steatosis, inflammation, oxidative stress, and fibrosis in CDAHFD-induced NAFLD mouse models.
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Affiliation(s)
- Nami Lee
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 164 Worldcup-ro, Yeoungtong-gu, Suwon, 16499, Republic of Korea
| | - Yu Jung Heo
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 164 Worldcup-ro, Yeoungtong-gu, Suwon, 16499, Republic of Korea
| | - Sung-E Choi
- Department of Physiology, Ajou University School of Medicine, 164 Worldcup-ro, Yeoungtong-gu, Suwon, 16499, Republic of Korea
| | - Ja Young Jeon
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 164 Worldcup-ro, Yeoungtong-gu, Suwon, 16499, Republic of Korea
| | - Seung Jin Han
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 164 Worldcup-ro, Yeoungtong-gu, Suwon, 16499, Republic of Korea
| | - Dae Jung Kim
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 164 Worldcup-ro, Yeoungtong-gu, Suwon, 16499, Republic of Korea
| | - Yup Kang
- Department of Physiology, Ajou University School of Medicine, 164 Worldcup-ro, Yeoungtong-gu, Suwon, 16499, Republic of Korea
| | - Kwan Woo Lee
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 164 Worldcup-ro, Yeoungtong-gu, Suwon, 16499, Republic of Korea
| | - Hae Jin Kim
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 164 Worldcup-ro, Yeoungtong-gu, Suwon, 16499, Republic of Korea.
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