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Ponsuksili S, Li S, Siengdee P, Hadlich F, Trakooljul N, Oster M, Reyer H, Wimmers K. DNA methylation in adipocyte differentiation of porcine mesenchymal stem cells and the impact of the donor metabolic type. Genomics 2025; 117:111050. [PMID: 40306557 DOI: 10.1016/j.ygeno.2025.111050] [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: 02/12/2024] [Revised: 07/26/2024] [Accepted: 04/22/2025] [Indexed: 05/02/2025]
Abstract
The impact of metabolic donor mesenchymal stem cells (MSCs) on DNA methylation, a critical epigenetic mechanism, significantly regulates adipogenesis. In this study, we investigated epigenetic changes during differentiation of synovial MSCs (SMSCs) from two pig breeds differing in metabolic performance (German Landrace (DL) and Angeln Saddleback (AS)). Stimulation of SMSCs to differentiate into adipocytes in vitro revealed several differentially methylated loci and regions, particularly on gene promoter regions, at day 7 and 14. AS breeds, known for higher fat deposition, exhibited more hypermethylation compared to DL. Furthermore, we utilized differentially methylated regions associated with the adipogenic process and breed, especially those in promoter regions, for predicting transcription factor motifs. This study provides insights into the DNA methylation landscape during adipogenesis in pigs of different metabolic types, revealing its role in regulating cell fate and donor memory retention in culture.
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Affiliation(s)
- Siriluck Ponsuksili
- Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany.
| | - Shuaichen Li
- Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany
| | - Puntita Siengdee
- Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany; Chulabhorn Graduate Institute, Program in Applied Biological Sciences, Chulabhorn Royal Academy, Kamphaeng Phet 6 Road, Laksi, Bangkok 10210, Thailand
| | - Frieder Hadlich
- Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany
| | - Nares Trakooljul
- Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany
| | - Michael Oster
- Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany
| | - Henry Reyer
- Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany
| | - Klaus Wimmers
- Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany; Faculty of Agricultural and Environmental Sciences, University of Rostock, Justus-von-Liebig-Weg 6b, 18059 Rostock, Germany
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Chen S, Huang J, Huang Y, Zhou C, Wang N, Zhang L, Zhang Z, Li B, He X, Wang K, Zhi Y, Lv G, Shen S. Metabolomics analyses reveal the liver-protective mechanism of Wang's metabolic formula on metabolic-associated fatty liver disease. Heliyon 2024; 10:e33418. [PMID: 39040343 PMCID: PMC11261804 DOI: 10.1016/j.heliyon.2024.e33418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 06/20/2024] [Accepted: 06/20/2024] [Indexed: 07/24/2024] Open
Abstract
Wang's metabolic formula (WMF) is a traditional Chinese medicine formula developed under the guidance of Professor Kungen Wang. WMF has been clinically utilized for several years. However, the therapeutic mechanism of WMF in treating metabolic-associated fatty liver disease (MAFLD) remains unclear. In this study, we performed phytochemical analysis on WMF using LC-MS. To study the role of WMF in MAFLD, we orally administered WMF (20.6 g/kg) to male MAFLD mice induced by a high-cholesterol high-fat diet (HCHFD). Then pathological, biochemical, and metabolomic analyses were performed. The main components of WMF are chlorogenic acid, geniposide, albiflorin, paeoniflorin, and calycosin-7-O-glucoside. MAFLD mice treated with WMF exhibited significant improvements in obesity, abnormal lipid metabolism, inflammation, and liver pathology. WMF decreased aspartate aminotransferase (AST), alanine aminotransferase (ALT), and triglyceride (TG) levels in the serum of MAFLD mice while increasing high-density lipoprotein cholesterol (HDL-c) levels. WMF lowered liver TG levels and inflammatory factors (IL-1β, IL-6, TNF-α, and NF-κB). Metabolomic analysis of the liver annotated 78 differentially regulated metabolites enriched in four pathways: glycerophospholipid metabolism, retinol metabolism, PPAR signaling pathway, and choline metabolism. Western blot experiments showed that WMF increased the expression of PPAR-α, PPAR-β, and RXR in the liver while decreasing the expression of RAR. The study demonstrates that WMF has a solid preventive and therapeutic effect on MAFLD. The anti-inflammatory and regulation of abnormal liver metabolism activities of WMF involve retinol metabolism and the PPAR signaling pathway.
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Affiliation(s)
- Suhong Chen
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
- Zhejiang Provincial Key Laboratory of TCM for Innovative R&D and Digital Intelligent Manufacturing of TCM Great Health Products, Huzhou, Zhejiang 313200, China
| | - Jiahui Huang
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China
- Zhejiang Provincial Key Laboratory of TCM for Innovative R&D and Digital Intelligent Manufacturing of TCM Great Health Products, Huzhou, Zhejiang 313200, China
| | - Yuzhen Huang
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China
- Zhejiang Provincial Key Laboratory of TCM for Innovative R&D and Digital Intelligent Manufacturing of TCM Great Health Products, Huzhou, Zhejiang 313200, China
| | - Chengliang Zhou
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China
- Zhejiang Provincial Key Laboratory of TCM for Innovative R&D and Digital Intelligent Manufacturing of TCM Great Health Products, Huzhou, Zhejiang 313200, China
| | - Ning Wang
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China
- Zhejiang Provincial Key Laboratory of TCM for Innovative R&D and Digital Intelligent Manufacturing of TCM Great Health Products, Huzhou, Zhejiang 313200, China
| | - Linnan Zhang
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China
- Zhejiang Provincial Key Laboratory of TCM for Innovative R&D and Digital Intelligent Manufacturing of TCM Great Health Products, Huzhou, Zhejiang 313200, China
| | - Zehua Zhang
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China
- Zhejiang Provincial Key Laboratory of TCM for Innovative R&D and Digital Intelligent Manufacturing of TCM Great Health Products, Huzhou, Zhejiang 313200, China
| | - Bo Li
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China
- Zhejiang Provincial Key Laboratory of TCM for Innovative R&D and Digital Intelligent Manufacturing of TCM Great Health Products, Huzhou, Zhejiang 313200, China
| | - Xinglishang He
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China
- Zhejiang Provincial Key Laboratory of TCM for Innovative R&D and Digital Intelligent Manufacturing of TCM Great Health Products, Huzhou, Zhejiang 313200, China
| | - Kungen Wang
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310006, China
- Kungen Wang National Famous Chinese Medicine Doctor Studio, Hangzhou, Zhejiang, 310006, China
| | - Yihui Zhi
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310006, China
- Kungen Wang National Famous Chinese Medicine Doctor Studio, Hangzhou, Zhejiang, 310006, China
| | - Guiyuan Lv
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
| | - Shuhua Shen
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310006, China
- Kungen Wang National Famous Chinese Medicine Doctor Studio, Hangzhou, Zhejiang, 310006, China
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Zou Y, Zhang Y, Li M, Cao K, Song C, Zhang Z, Cai K, Geng D, Chen S, Wu Y, Zhang N, Sun G, Wang J, Zhang Y, Sun Y. Regulation of lipid metabolism by E3 ubiquitin ligases in lipid-associated metabolic diseases. Int J Biol Macromol 2024; 265:130961. [PMID: 38508558 DOI: 10.1016/j.ijbiomac.2024.130961] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 03/10/2024] [Accepted: 03/15/2024] [Indexed: 03/22/2024]
Abstract
Previous studies have progressively elucidated the involvement of E3 ubiquitin (Ub) ligases in regulating lipid metabolism. Ubiquitination, facilitated by E3 Ub ligases, modifies critical enzymes in lipid metabolism, enabling them to respond to specific signals. In this review, we aim to present a comprehensive analysis of the role of E3 Ub ligases in lipid metabolism, which includes lipid synthesis and lipolysis, and their influence on cellular lipid homeostasis through the modulation of lipid uptake and efflux. Furthermore, it explores how the ubiquitination process governs the degradation or activation of pivotal enzymes, thereby regulating lipid metabolism at the transcriptional level. Perturbations in lipid metabolism have been implicated in various diseases, including hepatic lipid metabolism disorders, atherosclerosis, diabetes, and cancer. Therefore, this review focuses on the association between E3 Ub ligases and lipid metabolism in lipid-related diseases, highlighting enzymes critically involved in lipid synthesis and catabolism, transcriptional regulators, lipid uptake translocators, and transporters. Overall, this review aims to identify gaps in current knowledge, highlight areas requiring further research, offer potential targeted therapeutic approaches, and provide a comprehensive outlook on clinical conditions associated with lipid metabolic diseases.
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Affiliation(s)
- Yuanming Zou
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Ying Zhang
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China; Institute of Health Sciences, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, 110001, Liaoning Province, People's Republic of China.
| | - Mohan Li
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Kexin Cao
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Chunyu Song
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Zhaobo Zhang
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Kexin Cai
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Danxi Geng
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Shuxian Chen
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Yanjiao Wu
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Naijin Zhang
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China; Institute of Health Sciences, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, 110001, Liaoning Province, People's Republic of China; Key Laboratory of Reproductive and Genetic Medicine (China Medical University), National Health Commission, 77 Puhe Road, Shenbei New District, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Guozhe Sun
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China.
| | - Jing Wang
- Department of Hematology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China.
| | - Yixiao Zhang
- Department of Urology Surgery, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning Province, People's Republic of China.
| | - Yingxian Sun
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China; Institute of Health Sciences, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, 110001, Liaoning Province, People's Republic of China; Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, 110001, Liaoning Province, People's Republic of China.
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Pan Z, Li X, Wu D, Chen X, Zhang C, Jin S, Geng Z. The Duck RXRA Gene Promotes Adipogenesis and Correlates with Feed Efficiency. Animals (Basel) 2023; 13:ani13040680. [PMID: 36830469 PMCID: PMC9952354 DOI: 10.3390/ani13040680] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 02/06/2023] [Accepted: 02/07/2023] [Indexed: 02/18/2023] Open
Abstract
BACKGROUND The accumulation of fat in ducks is the main cause of low feed efficiency and metabolic diseases in ducks. Retinoic acid X receptor alpha (RXRA) is a member of the nuclear receptor superfamily involved in lipid, glucose, energy, and hormone metabolism. The effect of the RXRA gene on lipid metabolism in duck preadipocytes (DPACs) and the relationship between SNPs and the feed efficiency traits of ducks are unclear. METHODS qRT-PCR and Western blotting analyses were used to detect changes in mRNA and protein in cells. Intracellular triglycerides (TGs) were detected using an ELISA kit. A general linear model analysis was used to determine the association between RXRA SNPs and feed efficiency. RESULTS The duck RXRA gene was highly expressed on the fourth day of DPAC differentiation. The RXRA gene increased the content of fat and TG in DPACs and promoted the expression of cell differentiation genes; g.5,952,667 correlated with average daily feed intake (ADFI), residual feed intake (RFI), and feed conversion ratio (FCR). CONCLUSIONS Duck RXRA can accelerate fat accumulation, and the polymorphism of the RXRA gene is closely related to feed efficiency, which provides basic data for breeding high feed efficiency ducks.
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A Novel in Duck Myoblasts: The Transcription Factor Retinoid X Receptor Alpha (RXRA) Inhibits Lipid Accumulation by Promoting CD36 Expression. Int J Mol Sci 2023; 24:ijms24021180. [PMID: 36674699 PMCID: PMC9864336 DOI: 10.3390/ijms24021180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 12/14/2022] [Accepted: 12/23/2022] [Indexed: 01/11/2023] Open
Abstract
Retinoid X receptor alpha (RXRA) is a well-characterized factor that regulates lipid metabolism; however, the regulatory mechanism in muscle cells of poultry is still unknown. The overexpression and the knockdown of RXRA in myoblasts (CS2 cells), RT-PCR, and western blotting were used to detect the expression levels of genes and proteins related to PPAR-signaling pathways. Intracellular triglycerides (TGs), cholesterol (CHOL), and nonesterified free fatty acids (NEFAs) were detected by the Elisa kit. Fat droplets were stained with Oil Red O. The double-fluorescein reporter gene and chromatin immunoprecipitation (CHIP) were used to verify the relationship between RXRA and candidate target genes. The RXRA gene was highly expressed in duck breast muscle, and its mRNA and its protein were reduced during the differentiation of CS2 cells. The CS2 cells, with the overexpression of RXRA, showed reduced content in TGs, CHOL, NEFAs, and lipid droplets and upregulated the mRNA expression of CD36, ACSL1, and PPARG genes and the protein expression of CD36 and PPARG. The knockdown of RXRA expression in CS2 cells enhanced the content of TGs, CHOL, NEFAs, and lipid droplets and downregulated the mRNA and protein expression of CD36, ACLS1, ELOVL6, and PPARG. The overexpression of the RXRA gene, the activity of the double-luciferase reporter gene of the wild-type CD36 promoter was higher than that of the mutant type. RXRA bound to -860/-852 nt, -688/-680 nt, and -165/-157 nt at the promoter region of CD36. Moreover, the overexpression of CD36 in CS2 cells could suppress the content of TGs, CHOL, NEFAs, and lipid droplets, while the knockdown expression of CD36 increased the content of TGs, CHOL, NEFAs, and lipid droplets. In this study, the transcription factor, RXRA, inhibited the accumulation of TGs, CHOL, NEFAs, and fat droplets in CS2 cells by promoting CD36 expression.
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Jobe M, Agbla SC, Todorcevic M, Darboe B, Danso E, de Barros JPP, Lagrost L, Karpe F, Prentice AM. Possible mediators of metabolic endotoxemia in women with obesity and women with obesity-diabetes in The Gambia. Int J Obes (Lond) 2022; 46:1892-1900. [PMID: 35933445 PMCID: PMC9492538 DOI: 10.1038/s41366-022-01193-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 07/06/2022] [Accepted: 07/11/2022] [Indexed: 11/09/2022]
Abstract
AIMS/HYPOTHESIS Translocation of bacterial debris from the gut causes metabolic endotoxemia (ME) that results in insulin resistance, and may be on the causal pathway to obesity-related type 2 diabetes. To guide interventions against ME we tested two hypothesised mechanisms for lipopolysaccharide (LPS) ingress: a leaky gut and chylomicron-associated transfer following a high-fat meal. METHODS In lean women (n = 48; fat mass index (FMI) 9.6 kg/m2), women with obesity (n = 62; FMI 23.6 kg/m2) and women with obesity-diabetes (n = 38; FMI 24.9 kg/m2) we used the lactulose-mannitol dual-sugar permeability test (LM ratio) to assess gut integrity. Markers of ME (LPS, EndoCAb IgG and IgM, IL-6, CD14 and lipoprotein binding protein) were assessed at baseline, 2 h and 5 h after a standardised 49 g fat-containing mixed meal. mRNA expression of markers of inflammation, macrophage activation and lipid metabolism were measured in peri-umbilical adipose tissue (AT) biopsies. RESULTS The LM ratio did not differ between groups. LPS levels were 57% higher in the obesity-diabetes group (P < 0.001), but, contrary to the chylomicron transfer hypothesis, levels significantly declined following the high-fat challenge. EndoCAb IgM was markedly lower in women with obesity and women with obesity-diabetes. mRNA levels of inflammatory markers in adipose tissue were consistent with the prior concept that fat soluble LPS in AT attracts and activates macrophages. CONCLUSIONS/INTERPRETATION Raised levels of LPS and IL-6 in women with obesity-diabetes and evidence of macrophage activation in adipose tissue support the concept of metabolic endotoxemia-mediated inflammation, but we found no evidence for abnormal gut permeability or chylomicron-associated post-prandial translocation of LPS. Instead, the markedly lower EndoCAb IgM levels indicate a failure in sequestration and detoxification.
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Affiliation(s)
- Modou Jobe
- Medical Research Council Unit The Gambia at London School of Hygiene & Tropical Medicine, Banjul, The Gambia.
| | - Schadrac C Agbla
- Department of Health Data Sciences, University of Liverpool, Liverpool, UK
- Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK
| | | | - Bakary Darboe
- Medical Research Council Unit The Gambia at London School of Hygiene & Tropical Medicine, Banjul, The Gambia
| | - Ebrima Danso
- Medical Research Council Unit The Gambia at London School of Hygiene & Tropical Medicine, Banjul, The Gambia
| | | | - Laurent Lagrost
- Plateforme de Lipidomique-uBourgogne, INSERM UMR1231/LabEx LipSTIC, Dijon, France
- University Hospital of Dijon, Dijon, France
| | - Fredrik Karpe
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford, UK
- NIHR Oxford Biomedical Research Centre, OUH Foundation Trust, Oxford, UK
| | - Andrew M Prentice
- Medical Research Council Unit The Gambia at London School of Hygiene & Tropical Medicine, Banjul, The Gambia
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Corrales P, Vidal-Puig A, Medina-Gómez G. Obesity and pregnancy, the perfect metabolic storm. Eur J Clin Nutr 2021; 75:1723-1734. [PMID: 33911209 DOI: 10.1038/s41430-021-00914-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 03/15/2021] [Accepted: 03/29/2021] [Indexed: 02/02/2023]
Abstract
Pregnancy is a physiological stress that requires dynamic, regulated changes affecting maternal and fetal adiposity. Excessive accumulation of dysfunctional adipose tissue defined by metabolic and molecular alterations cause severe health consequences for mother and fetus. When subjected to sustained overnutrition, the cellular and lipid composition of the adipose tissue changes predisposing to insulin resistance, diabetes, and other metabolic disorders compromising the outcome of the pregnancy. Moreover, excessive maternal weight gain, usually in the context of obesity, predisposes to an increased flux of nutrients from mother to fetus throughout the placenta. The fetus of an obese mother will accumulate more adiposity and may increase the risk of future metabolic disorder later in life. Thus, further understanding of the interaction between maternal metabolism, epigenetic regulation of the adipose tissue, and their transgenerational transfer are required to mitigate the adverse health outcomes for the mother and the fetus associated with maternal obesity.
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Affiliation(s)
- Patricia Corrales
- Área de Bioquímica y Biología Molecular, Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Madrid, Spain.
| | - Antonio Vidal-Puig
- Metabolic Research Laboratories, Wellcome Trust MRC Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
- Wellcome Trust Sanger Institute, Hinxton, UK
- Cambridge University Nanjing Centre of Technology and Innovation, Nanjing, PR China
| | - Gema Medina-Gómez
- Área de Bioquímica y Biología Molecular, Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Madrid, Spain.
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8
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PPARs in liver physiology. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166097. [PMID: 33524529 DOI: 10.1016/j.bbadis.2021.166097] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 01/18/2021] [Accepted: 01/20/2021] [Indexed: 02/07/2023]
Abstract
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors and transcriptional modulators with crucial functions in hepatic and whole-body energy homeostasis. Besides their well-documented roles in lipid and glucose metabolism, emerging evidence also implicate PPARs in the control of other processes such as inflammatory responses. Recent technological advances, such as single-cell RNA sequencing, have allowed to unravel an unexpected complexity in the regulation of PPAR expression, activity and downstream signaling. Here we provide an overview of the latest advances in the study of PPARs in liver physiology, with a specific focus on formerly neglected aspects of PPAR regulation, such as tissular zonation, cellular heterogeneity, circadian rhythms, sexual dimorphism and species-specific features.
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Shang C, Sun W, Wang C, Wang X, Zhu H, Wang L, Yang H, Wang X, Gong F, Pan H. Comparative Proteomic Analysis of Visceral Adipose Tissue in Morbidly Obese and Normal Weight Chinese Women. Int J Endocrinol 2019; 2019:2302753. [PMID: 31929791 PMCID: PMC6935805 DOI: 10.1155/2019/2302753] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 08/26/2019] [Accepted: 10/01/2019] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE Visceral adipose tissue (VAT) plays a central role in the balance of energy metabolism. The objective of this study was to investigate the differentially expressed proteins in VAT between morbidly obese (BMI >35 kg/m2) and normal weight Chinese women. METHOD Nine morbidly obese women and 8 normal weight women as controls were enrolled. Abdominal VAT was excised and analyzed by label-free one-dimensional liquid chromatography tandem mass spectrometry (1D-LC-MS/MS). Differentially expressed VAT proteins were further analyzed with Gene Ontology (GO) analysis and Ingenuity Pathway Analysis (IPA). Masson's trichrome staining and CD68 immunohistochemical staining of VAT were conducted in all subjects. RESULT A total of 124 differentially expressed proteins were found with a ≥2-fold difference. Forty-one proteins were upregulated, and 83 proteins were downregulated in obese individuals. These altered VAT proteins were involved in the attenuation of the liver X receptor/retinoid X receptor (LXR/RXR) signaling pathway and the activation of the acute-phase response process. Three proteins (ACSL1, HADH, and UCHL1) were validated by western blotting using the same set of VAT samples from 6 morbidly obese and 7 normal weight patients, and the results indicated that the magnitude and direction of the protein changes were in accordance with the proteomic analysis. Masson's trichrome staining and CD68 immunohistochemical staining demonstrated that there was much more collagen fiber deposition and CD68-positive macrophages in the VAT of morbidly obese patients, suggesting extensive fiber deposition and macrophage infiltration. CONCLUSION A number of differentially expressed proteins were identified in VAT between morbidly obese and normal weight Chinese females. These differential proteins could be potential candidates in addressing the role of VAT in the development of obesity.
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Affiliation(s)
- Chen Shang
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, Beijing 100730, China
| | - Wei Sun
- Core Facility of Instrument, Institute of Basic Medicine, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Chunlin Wang
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, Beijing 100730, China
| | - Xiangqing Wang
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, Beijing 100730, China
| | - Huijuan Zhu
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, Beijing 100730, China
| | - Linjie Wang
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, Beijing 100730, China
| | - Hongbo Yang
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, Beijing 100730, China
| | - Xue Wang
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, Beijing 100730, China
| | - Fengying Gong
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, Beijing 100730, China
| | - Hui Pan
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, Beijing 100730, China
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Li S, Lan Y, Wu W, Duan X, Kong Z, Wu W, Zeng G. Peroxisome proliferator‐activated receptor γ modulates renal crystal retention associated with high oxalate concentration by regulating tubular epithelial cellular transdifferentiation. J Cell Physiol 2018; 234:2837-2850. [PMID: 30317563 DOI: 10.1002/jcp.27102] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 06/29/2018] [Indexed: 12/17/2022]
Affiliation(s)
- Shujue Li
- Department of UrologyMinimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou China
- Guangdong Key Laboratory of UrologyGuangzhou Institute of UrologyGuangzhou China
| | - Yu Lan
- Department of UrologyMinimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou China
- Guangdong Key Laboratory of UrologyGuangzhou Institute of UrologyGuangzhou China
| | - Wenzheng Wu
- Department of UrologyThe Second Affiliated Hospital of Guangzhou Medical UniversityGuangzhou China
| | - Xiaolu Duan
- Department of UrologyMinimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou China
- Guangdong Key Laboratory of UrologyGuangzhou Institute of UrologyGuangzhou China
| | - Zhenzhen Kong
- Department of UrologyMinimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou China
- Guangdong Key Laboratory of UrologyGuangzhou Institute of UrologyGuangzhou China
| | - Wenqi Wu
- Department of UrologyMinimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou China
- Guangdong Key Laboratory of UrologyGuangzhou Institute of UrologyGuangzhou China
| | - Guohua Zeng
- Department of UrologyMinimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou China
- Guangdong Key Laboratory of UrologyGuangzhou Institute of UrologyGuangzhou China
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11
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Fan P, Abderrahman B, Chai TS, Yerrum S, Jordan VC. Targeting Peroxisome Proliferator-Activated Receptor γ to Increase Estrogen-Induced Apoptosis in Estrogen-Deprived Breast Cancer Cells. Mol Cancer Ther 2018; 17:2732-2745. [PMID: 30224430 DOI: 10.1158/1535-7163.mct-18-0088] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 06/07/2018] [Accepted: 09/10/2018] [Indexed: 12/25/2022]
Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) is an important transcription factor that modulates lipid metabolism and inflammation. However, it remains unclear whether PPARγ is involved in modulation of estrogen (E2)-induced inflammation, thus affecting apoptosis of E2-deprived breast cancer cells, MCF-7:5C and MCF-7:2A. Here, we demonstrated that E2 treatment suppressed the function of PPARγ in both cell lines, although the suppressive effect in MCF-7:2A cells was delayed owing to high PPARγ expression. Activation of PPARγ by a specific agonist, pioglitazone, selectively blocked the induction of TNFα expression by E2, but did not affect other adipose inflammatory genes, such as fatty acid desaturase 1 and IL6. This suppression of TNFα expression by pioglitazone was mainly mediated by transrepression of nuclear factor-κB (NF-κB) DNA-binding activity. A novel finding was that NF-κB functions as an oxidative stress inducer in MCF-7:5C cells but an antioxidant in MCF-7:2A cells. Therefore, the NF-κB inhibitor JSH-23 displayed effects equivalent to those of pioglitazone, with complete inhibition of apoptosis in MCF-7:5C cells, but it increased E2-induced apoptosis in MCF-7:2A cells. Depletion of PPARγ by siRNA or the PPARγ antagonist T0070907 accelerated E2-induced apoptosis, with activation of NF-κB-dependent TNFα and oxidative stress. For the first time, we demonstrated that PPARγ is a growth signal and has potential to modulate NF-κB activity and oxidative stress in E2-deprived breast cancer cell lines. All of these findings suggest that anti-PPARγ therapy is a novel strategy to improve the therapeutic effects of E2-induced apoptosis in E2-deprived breast cancer.
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Affiliation(s)
- Ping Fan
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Balkees Abderrahman
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Tina S Chai
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.,University of Virginia, Charlottesville, Virginia
| | - Smitha Yerrum
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - V Craig Jordan
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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12
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Chauderlier A, Gilles M, Spolcova A, Caillierez R, Chwastyniak M, Kress M, Drobecq H, Bonnefoy E, Pinet F, Weil D, Buée L, Galas MC, Lefebvre B. Tau/DDX6 interaction increases microRNA activity. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2018; 1861:762-772. [DOI: 10.1016/j.bbagrm.2018.06.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Revised: 06/27/2018] [Accepted: 06/27/2018] [Indexed: 12/17/2022]
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13
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Corrales P, Vidal-Puig A, Medina-Gómez G. PPARs and Metabolic Disorders Associated with Challenged Adipose Tissue Plasticity. Int J Mol Sci 2018; 19:ijms19072124. [PMID: 30037087 PMCID: PMC6073677 DOI: 10.3390/ijms19072124] [Citation(s) in RCA: 113] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Revised: 07/13/2018] [Accepted: 07/18/2018] [Indexed: 02/07/2023] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are members of a family of nuclear hormone receptors that exert their transcriptional control on genes harboring PPAR-responsive regulatory elements (PPRE) in partnership with retinoid X receptors (RXR). The activation of PPARs coordinated by specific coactivators/repressors regulate networks of genes controlling diverse homeostatic processes involving inflammation, adipogenesis, lipid metabolism, glucose homeostasis, and insulin resistance. Defects in PPARs have been linked to lipodystrophy, obesity, and insulin resistance as a result of the impairment of adipose tissue expandability and functionality. PPARs can act as lipid sensors, and when optimally activated, can rewire many of the metabolic pathways typically disrupted in obesity leading to an improvement of metabolic homeostasis. PPARs also contribute to the homeostasis of adipose tissue under challenging physiological circumstances, such as pregnancy and aging. Given their potential pathogenic role and their therapeutic potential, the benefits of PPARs activation should not only be considered relevant in the context of energy balance-associated pathologies and insulin resistance but also as potential relevant targets in the context of diabetic pregnancy and changes in body composition and metabolic stress associated with aging. Here, we review the rationale for the optimization of PPAR activation under these conditions.
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Affiliation(s)
- Patricia Corrales
- Área de Bioquímica y Biología Molecular, Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Avda. de Atenas s/n. Alcorcón, 28922 Madrid, Spain.
| | - Antonio Vidal-Puig
- Metabolic Research Laboratories, Wellcome Trust MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, UK.
- Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
| | - Gema Medina-Gómez
- Área de Bioquímica y Biología Molecular, Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Avda. de Atenas s/n. Alcorcón, 28922 Madrid, Spain.
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14
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Firmin FF, Oger F, Gheeraert C, Dubois-Chevalier J, Vercoutter-Edouart AS, Alzaid F, Mazuy C, Dehondt H, Alexandre J, Derudas B, Dhalluin Q, Ploton M, Berthier A, Woitrain E, Lefebvre T, Venteclef N, Pattou F, Staels B, Eeckhoute J, Lefebvre P. The RBM14/CoAA-interacting, long intergenic non-coding RNA Paral1 regulates adipogenesis and coactivates the nuclear receptor PPARγ. Sci Rep 2017; 7:14087. [PMID: 29075020 PMCID: PMC5658386 DOI: 10.1038/s41598-017-14570-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Accepted: 10/12/2017] [Indexed: 02/03/2023] Open
Abstract
Adipocyte differentiation and function relies on a network of transcription factors, which is disrupted in obesity-associated low grade, chronic inflammation leading to adipose tissue dysfunction. In this context, there is a need for a thorough understanding of the transcriptional regulatory network involved in adipose tissue pathophysiology. Recent advances in the functional annotation of the genome has highlighted the role of non-coding RNAs in cellular differentiation processes in coordination with transcription factors. Using an unbiased genome-wide approach, we identified and characterized a novel long intergenic non-coding RNA (lincRNA) strongly induced during adipocyte differentiation. This lincRNA favors adipocyte differentiation and coactivates the master adipogenic regulator peroxisome proliferator-activated receptor gamma (PPARγ) through interaction with the paraspeckle component and hnRNP-like RNA binding protein 14 (RBM14/NCoAA), and was therefore called PPARγ-activator RBM14-associated lncRNA (Paral1). Paral1 expression is restricted to adipocytes and decreased in humans with increasing body mass index. A decreased expression was also observed in diet-induced or genetic mouse models of obesity and this down-regulation was mimicked in vitro by TNF treatment. In conclusion, we have identified a novel component of the adipogenic transcriptional regulatory network defining the lincRNA Paral1 as an obesity-sensitive regulator of adipocyte differentiation and function.
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Affiliation(s)
- François F Firmin
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France
| | - Frederik Oger
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France
| | - Céline Gheeraert
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France
| | - Julie Dubois-Chevalier
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France
| | - Anne-Sophie Vercoutter-Edouart
- CNRS, UMR 8576, UGSF, Unité de Glycobiologie Structurale et Fonctionnelle, FRABio FR 3688, Univ, Lille, Villeneuve d'Ascq, F-59650, France
| | - Fawaz Alzaid
- INSERM UMRS 1138, Sorbonne Universités, UPMC Université Paris 06; Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot; and Centre de Recherche des Cordeliers, Paris, F-75006, France
| | - Claire Mazuy
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France
| | - Hélène Dehondt
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France
| | - Jeremy Alexandre
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France
| | - Bruno Derudas
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France
| | - Quentin Dhalluin
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France
| | - Maheul Ploton
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France
| | - Alexandre Berthier
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France
| | - Eloise Woitrain
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France
| | - Tony Lefebvre
- CNRS, UMR 8576, UGSF, Unité de Glycobiologie Structurale et Fonctionnelle, FRABio FR 3688, Univ, Lille, Villeneuve d'Ascq, F-59650, France
| | - Nicolas Venteclef
- INSERM UMRS 1138, Sorbonne Universités, UPMC Université Paris 06; Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot; and Centre de Recherche des Cordeliers, Paris, F-75006, France
| | - François Pattou
- Univ. Lille, Inserm, CHU Lille, U1190- EGID, F-59000, Lille, France
| | - Bart Staels
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France
| | - Jérôme Eeckhoute
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France
| | - Philippe Lefebvre
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France.
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15
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Liu H, Zhou T, Wang B, Li L, Ye D, Yu S. Identification and functional analysis of a potential key lncRNA involved in fat loss of cancer cachexia. J Cell Biochem 2017; 119:1679-1688. [PMID: 28782835 DOI: 10.1002/jcb.26328] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 08/03/2017] [Indexed: 01/31/2023]
Abstract
Cancer cachexia is a devastating, multifactorial, and irreversible syndrome characterized by skeletal muscle reduction with or without fat loss. Although much attention has been focused on muscle wasting, fat loss may occur earlier and accelerate muscle wasting in cachexia. The cause of 20% of cancer related death makes it urgent to discover molecular mechanisms behind cancer cachexia. Here we applied weighted gene co-expression network analysis (WGCNA) to identify cachexia related gene modules using differentially expressed 3289 genes and 59 long non-coding RNAs based on microarray data of cachectic and non-cachectic subcutaneous adipose tissue. Subsequently, 16 independent modules were acquired and GSAASeqSP Toolset confirmed that black module was significantly associated with fat loss in cancer cachexia. Top 50 hub-genes in black module contained only one lncRNA, VLDLR antisense RNA 1 (VLDLR-AS1). We then explored the function of black module from the view of VLDLR-AS1-connected genes in the network. GO enrichment and KEGG pathways analysis revealed LDLR-AS1-connected genes were involved in Wnt signaling pathway, small GTPase mediated signal transduction, epithelial-mesenchymal transition and so on. Through construction of competing endogenous RNAs (ceRNAs) regulation network, we showed that VLDLR-AS1 may function with hsa-miR-600 to regulate gene GOLGA3, DUSP14, and UCHL1, or interact with hsa-miR-1224-3p to modulate the expression of gene GOLGA3, ZNF219, RNF141, and CALU. After literature validation, we predicted that VLDLR-AS1 most likely interacted with miR-600 to regulate UCH-L1 through Wnt/β-catenin signaling pathway. However, further experiments are still required to validate mechanisms of VLDLR-AS1 in fat reduction of cancer cachexia.
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Affiliation(s)
- Huiquan Liu
- Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ting Zhou
- Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bangyan Wang
- Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lu Li
- Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dawei Ye
- Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shiying Yu
- Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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16
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Abstract
Obesity is a worldwide epidemic that predisposes individuals to cardiometabolic complications, such as type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD), which are all related to inappropriate ectopic lipid deposition. Identification of the pathogenic molecular mechanisms and effective therapeutic approaches are highly needed. The peroxisome proliferator-activated receptors (PPARs) modulate several biological processes that are perturbed in obesity, including inflammation, lipid and glucose metabolism and overall energy homeostasis. Here, we review how PPARs regulate the functions of adipose tissues, such as adipogenesis, lipid storage and adaptive thermogenesis, under healthy and pathological conditions. We also discuss the clinical use and mechanism of PPAR agonists in the treatment of obesity comorbidities such as dyslipidaemia, T2DM and NAFLD. First generation PPAR agonists, primarily those acting on PPARγ, are associated with adverse effects that outweigh their clinical benefits, which led to the discontinuation of their development. An improved understanding of the physiological roles of PPARs might, therefore, enable the development of safe, new PPAR agonists with improved therapeutic potential.
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Affiliation(s)
- Barbara Gross
- Université de Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Michal Pawlak
- International Institute of Molecular and Cell Biology, 4 Ks. Trojdena Street, 02-109 Warsaw, Poland
| | - Philippe Lefebvre
- Université de Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Bart Staels
- Université de Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
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17
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Wehmeier K, Onstead-Haas LM, Wong NCW, Mooradian AD, Haas MJ. Pro-inflammatory signaling by 24,25-dihydroxyvitamin D3 in HepG2 cells. J Mol Endocrinol 2016; 57:87-96. [PMID: 27234962 DOI: 10.1530/jme-16-0009] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Accepted: 05/27/2016] [Indexed: 12/31/2022]
Abstract
The vitamin D metabolite 24,25-dihydroxyvitamin D3 (24, 25[OH]2D3) was shown to induce nongenomic signaling pathways in resting zone chondrocytes and other cells involved in bone remodeling. Recently, our laboratory demonstrated that 24,25-[OH]2D3 but not 25-hydroxyvitamin D3, suppresses apolipoprotein A-I (apo A-I) gene expression and high-density lipoprotein (HDL) secretion in hepatocytes. Since 24,25-[OH]2D3 has low affinity for the vitamin D receptor (VDR) and little is known with regard to how 24,25-[OH]2D3 modulates nongenomic signaling in hepatocytes, we investigated the capacity of 24,25-[OH]2D3 to activate various signaling pathways relevant to apo A-I synthesis in HepG2 cells. Treatment with 24,25-[OH]2D3 resulted in decreased peroxisome proliferator-activated receptor alpha (PPARα) expression and retinoid-X-receptor alpha (RXRα) expression. Similarly, treatment of hepatocytes with 50 nM 24,25-[OH]2D3 for 1-3 h induced PKCα activation as well as c-jun-N-terminal kinase 1 (JNK1) activity and extracellular-regulated kinase 1/2 (ERK1/2) activity. These changes in kinase activity correlated with changes in c-jun phosphorylation, an increase in AP-1-dependent transcriptional activity, as well as repression of apo A-I promoter activity. Furthermore, treatment with 24,25-[OH]2D3 increased IL-1β, IL-6, and IL-8 expression by HepG2 cells. These observations suggest that 24,25-[OH]2D3 elicits several novel rapid nongenomic-mediated pro-inflammatory protein kinases targeting AP1 activity, increasing pro-inflammatory cytokine expression, potentially impacting lipid metabolism and hepatic function.
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Affiliation(s)
- Kent Wehmeier
- Division of EndocrinologyDiabetes, and Metabolism, Department of Medicine, University of Florida Jacksonville College of Medicine, Jacksonville, Florida, USA
| | - Luisa M Onstead-Haas
- Division of EndocrinologyDiabetes, and Metabolism, Department of Medicine, University of Florida Jacksonville College of Medicine, Jacksonville, Florida, USA
| | - Norman C W Wong
- Department of MedicineBiochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
| | - Arshag D Mooradian
- Division of EndocrinologyDiabetes, and Metabolism, Department of Medicine, University of Florida Jacksonville College of Medicine, Jacksonville, Florida, USA
| | - Michael J Haas
- Division of EndocrinologyDiabetes, and Metabolism, Department of Medicine, University of Florida Jacksonville College of Medicine, Jacksonville, Florida, USA
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18
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Polvani S, Tarocchi M, Tempesti S, Bencini L, Galli A. Peroxisome proliferator activated receptors at the crossroad of obesity, diabetes, and pancreatic cancer. World J Gastroenterol 2016; 22:2441-2459. [PMID: 26937133 PMCID: PMC4768191 DOI: 10.3748/wjg.v22.i8.2441] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Revised: 12/17/2015] [Accepted: 01/09/2016] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth cause of cancer death with an overall survival of 5% at five years. The development of PDAC is characteristically associated to the accumulation of distinctive genetic mutations and is preceded by the exposure to several risk factors. Epidemiology has demonstrated that PDAC risk factors may be non-modifiable risks (sex, age, presence of genetic mutations, ethnicity) and modifiable and co-morbidity factors related to the specific habits and lifestyle. Recently it has become evident that obesity and diabetes are two important modifiable risk factors for PDAC. Obesity and diabetes are complex systemic and intertwined diseases and, over the years, experimental evidence indicate that insulin-resistance, alteration of adipokines, especially leptin and adiponectin, oxidative stress and inflammation may play a role in PDAC. Peroxisome proliferator activated receptor-γ (PPARγ) is a nuclear receptor transcription factor that is implicated in the regulation of metabolism, differentiation and inflammation. PPARγ is a key regulator of adipocytes differentiation, regulates insulin and adipokines production and secretion, may modulate inflammation, and it is implicated in PDAC. PPARγ agonists are used in the treatment of diabetes and oxidative stress-associated diseases and have been evaluated for the treatment of PDAC. PPARγ is at the cross-road of diabetes, obesity, and PDAC and it is an interesting target to pharmacologically prevent PDAC in obese and diabetic patients.
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19
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Wang X, Hai C. Redox modulation of adipocyte differentiation: hypothesis of "Redox Chain" and novel insights into intervention of adipogenesis and obesity. Free Radic Biol Med 2015; 89:99-125. [PMID: 26187871 DOI: 10.1016/j.freeradbiomed.2015.07.012] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 06/19/2015] [Accepted: 07/08/2015] [Indexed: 02/08/2023]
Abstract
In view of the global prevalence of obesity and obesity-associated disorders, it is important to clearly understand how adipose tissue forms. Accumulating data from various laboratories implicate that redox status is closely associated with energy metabolism. Thus, biochemical regulation of the redox system may be an attractive alternative for the treatment of obesity-related disorders. In this work, we will review the current data detailing the role of the redox system in adipocyte differentiation, as well as identifying areas for further research. The redox system affects adipogenic differentiation in an extensive way. We propose that there is a complex and interactive "redox chain," consisting of a "ROS-generating enzyme chain," "combined antioxidant chain," and "transcription factor chain," which contributes to fine-tune the regulation of ROS level and subsequent biological consequences. The roles of the redox system in adipocyte differentiation are paradoxical. The redox system exerts a "tridimensional" mechanism in the regulation of adipocyte differentiation, including transcriptional, epigenetic, and posttranslational modulations. We suggest that redoxomic techniques should be extensively applied to understand the biological effects of redox alterations in a more integrated way. A stable and standardized "redox index" is urgently needed for the evaluation of the general redox status. Therefore, more effort should be made to establish and maintain a general redox balance rather than to conduct simple prooxidant or antioxidant interventions, which have comprehensive implications.
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Affiliation(s)
- Xin Wang
- Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, 710032, China.
| | - Chunxu Hai
- Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, 710032, China.
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20
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Murakami S, Motohashi H. Roles of Nrf2 in cell proliferation and differentiation. Free Radic Biol Med 2015; 88:168-178. [PMID: 26119783 DOI: 10.1016/j.freeradbiomed.2015.06.030] [Citation(s) in RCA: 183] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Revised: 06/18/2015] [Accepted: 06/22/2015] [Indexed: 02/07/2023]
Abstract
The Keap1-Nrf2 system plays pivotal roles in defense mechanisms by regulating cellular redox homeostasis. Nrf2 is an inducible transcription factor that activates a battery of genes encoding antioxidant proteins and phase II enzymes in response to oxidative stress and electrophilic xenobiotics. The activity of Nrf2 is regulated by Keap1, which promotes the ubiquitination and subsequent degradation of Nrf2 under normal conditions and releases the inhibited Nrf2 activity upon exposure to the stresses. Though an impressive contribution of the Keap1-Nrf2 system to the protection from exogenous and endogenous electrophilic insults has been well established, a line of evidence has suggested that the Keap1-Nrf2 system has various novel functions, particularly in cell proliferation and differentiation. Because the proliferation and differentiation of diverse cell types are often influenced and modulated by the cellular redox balance, Nrf2 has been considered to control these cellular processes by regulating the cellular levels of reactive oxygen species (ROS). In addition, analyses of the genome-wide distribution of Nrf2 have identified new sets of Nrf2 target genes whose products are involved in cell proliferation and differentiation but not necessarily in the regulation of oxidative stress. Considering the most characteristic features of Nrf2 as an inducible transcription factor, a newly emerged concept proposes that the Keap1-Nrf2 system translates environmental stresses into regulatory network signals in cell fate determination. In this review, we introduce the contribution of Nrf2 to lineage-specific differentiation, maintenance and differentiation of stem cells, and proliferation of normal and cancer cells, and we discuss how the response to fluctuating environments modulates cell behavior through the Keap1-Nrf2 system.
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Affiliation(s)
- Shohei Murakami
- Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
| | - Hozumi Motohashi
- Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
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21
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Francque S, Verrijken A, Caron S, Prawitt J, Paumelle R, Derudas B, Lefebvre P, Taskinen MR, Van Hul W, Mertens I, Hubens G, Van Marck E, Michielsen P, Van Gaal L, Staels B. PPARα gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis. J Hepatol 2015; 63:164-73. [PMID: 25703085 DOI: 10.1016/j.jhep.2015.02.019] [Citation(s) in RCA: 277] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Revised: 02/08/2015] [Accepted: 02/10/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Peroxisome proliferator-activated receptors (PPARs) have been implicated in non-alcoholic steatohepatitis (NASH) pathogenesis, mainly based on animal data. Gene expression data in NASH patients are scarce. We studied liver PPARα, β/δ, and γ expression in a large cohort of obese patients assessed for presence of NAFLD at baseline and 1 year follow-up. METHODS Patients presented to the obesity clinic underwent a hepatic work-up. If NAFLD was suspected, liver biopsy was performed. Gene expression was studied by mRNA quantification. Patients were reassessed after 1 year. RESULTS 125 patients were consecutively included in the study, of which 85 patients had paired liver biopsy taken at 1 year of follow-up. Liver PPARα expression negatively correlated with the presence of NASH (p=0.001) and with severity of steatosis (p=0.003), ballooning (p=0.001), NASH activity score (p=0.008) and fibrosis (p=0.003). PPARα expression was positively correlated to adiponectin (R(2)=0.345, p=0.010) and inversely correlated to visceral fat (R(2)=-0.343, p<0.001), HOMA IR (R(2)=-0.411, p<0.001) and CK18 (R(2)=-0.233, p=0.012). Liver PPARβ/δ and PPARγ expression did not correlate with any histological feature nor with glucose metabolism or serum lipids. At 1 year, correlation of PPARα expression with liver histology was confirmed. In longitudinal analysis, an increase in expression of PPARα and its target genes was significantly associated with histological improvement (p=0.008). CONCLUSION Human liver PPARα gene expression negatively correlates with NASH severity, visceral adiposity and insulin resistance and positively with adiponectin. Histological improvement is associated with an increase in expression of PPARα and its target genes. These data might suggest that PPARα is a potential therapeutic target in NASH.
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Affiliation(s)
- Sven Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium; Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
| | - An Verrijken
- Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; Department of Endocrinology, Diabetes and Metabolism, Antwerp University Hospital, Antwerp, Belgium
| | - Sandrine Caron
- Université Lille 2, INSERM U1011, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille, France
| | - Janne Prawitt
- Université Lille 2, INSERM U1011, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille, France
| | - Réjane Paumelle
- Université Lille 2, INSERM U1011, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille, France
| | - Bruno Derudas
- Université Lille 2, INSERM U1011, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille, France
| | - Philippe Lefebvre
- Université Lille 2, INSERM U1011, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille, France
| | - Marja-Riitta Taskinen
- Division of Cardiology, Department of Medicine, Helsinki University Central Hospital and Biomedicum, Finland
| | - Wim Van Hul
- Department of Medical Genetics, University of Antwerp, Belgium
| | - Ilse Mertens
- Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; Department of Endocrinology, Diabetes and Metabolism, Antwerp University Hospital, Antwerp, Belgium
| | - Guy Hubens
- Department of Abdominal Surgery, Antwerp University Hospital, Antwerp, Belgium
| | - Eric Van Marck
- Department of Pathology, Antwerp University Hospital, Antwerp, Belgium
| | - Peter Michielsen
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium; Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Luc Van Gaal
- Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; Department of Endocrinology, Diabetes and Metabolism, Antwerp University Hospital, Antwerp, Belgium
| | - Bart Staels
- Université Lille 2, INSERM U1011, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille, France
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22
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Lee JH, Yoo JY, You YA, Kwon WS, Lee SM, Pang MG, Kim YJ. Proteomic analysis of fetal programming-related obesity markers. Proteomics 2015; 15:2669-77. [PMID: 25886259 DOI: 10.1002/pmic.201400359] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Revised: 02/16/2015] [Accepted: 04/14/2015] [Indexed: 12/14/2022]
Abstract
The objectives of this study were to analyze fetal programming in rat brain using proteomic analysis and to identify fetal programming-related obesity markers. Sprague-Dawley rats were divided into four feeding groups: (i) the Ad Libitum (AdLib)/AdLib group was given a normal diet during pregnancy and the lactation period; (ii) the AdLib/maternal food restriction group (FR) was subjected to 50% FR during the lactation period; (iii) the FR/AdLib group was subjected to 50% FR during pregnancy; and (iv) the FR/FR group was subjected to 50% FR during pregnancy and the lactation period. Offspring from each group were sacrificed at 3 weeks of age and whole brains were dissected. To obtain a maximum number of protein markers related to obesity, 2DE and Pathway Studio bioinformatics analysis were performed. The identities of the markers among the selected and candidate proteins were confirmed by Western blotting and immunohistochemistry. Proteomic and bioinformatics analyses revealed that expression of ubiquitin carboxy-terminal hydrolase L1 (UCHL1) and Secernin 1 (SCRN1) were significantly different in the FR/AdLib group compared with the AdLib/AdLib group for both male and female offspring. These findings suggest that UCHL1 and SCRN1 may be used as fetal programming-related obesity markers.
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Affiliation(s)
- Ji Hye Lee
- Department of Obstetrics and Gynecology, Ewha Womans University, Seoul, South Korea
| | - Jae Young Yoo
- Department of Obstetrics and Gynecology, Ewha Womans University, Seoul, South Korea
| | - Young-Ah You
- Department of Obstetrics and Gynecology, Ewha Womans University, Seoul, South Korea
| | - Woo-Sung Kwon
- Department of Animal Science and Technology, Chung-Ang University, Anseong, Gyeonggi-Do 456-756, South Korea
| | - Sang Mi Lee
- Department of Obstetrics and Gynecology, Ewha Womans University, Seoul, South Korea
| | - Myung-Geol Pang
- Department of Animal Science and Technology, Chung-Ang University, Anseong, Gyeonggi-Do 456-756, South Korea
| | - Young Ju Kim
- Department of Obstetrics and Gynecology, Ewha Womans University, Seoul, South Korea
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23
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Pawlak M, Baugé E, Bourguet W, De Bosscher K, Lalloyer F, Tailleux A, Lebherz C, Lefebvre P, Staels B. The transrepressive activity of peroxisome proliferator-activated receptor alpha is necessary and sufficient to prevent liver fibrosis in mice. Hepatology 2014; 60:1593-606. [PMID: 24995693 DOI: 10.1002/hep.27297] [Citation(s) in RCA: 111] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2013] [Accepted: 07/01/2014] [Indexed: 12/16/2022]
Abstract
UNLABELLED Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and strongly associated with central obesity, dyslipidemia, and insulin resistance. According to the multiple-hit model of NAFLD pathogenesis, lipid accumulation drives nonalcoholic steatohepatitis (NASH) initiation by triggering oxidative stress, lipotoxicity, and subsequent activation of hepatic inflammatory responses that may progress, in predisposed individuals, to fibrosis and cirrhosis. While there is an unmet therapeutical need for NASH and fibrosis, recent preclinical studies showed that peroxisome proliferator-activated receptor (PPAR)-α agonism can efficiently oppose these symptoms. To dissect the relative contribution of antisteatotic versus anti-inflammatory PPAR-α activities in counteracting dietary-induced liver fibrosis, we used a PPAR-α mutant lacking its DNA-binding-dependent activity on fatty acid metabolism. Liver-specific expression of wild-type or a DNA-binding-deficient PPAR-α in acute and chronic models of inflammation were used to study PPAR-α's anti-inflammatory versus metabolic activities in NASH and fibrosis. Pharmacologically activated PPAR-α inhibited hepatic inflammatory responses and the transition from steatosis toward NASH and fibrosis through a direct, anti-inflammatory mechanism independent of its lipid handling properties. CONCLUSION The transrepression activity of PPAR-α on chronic liver inflammation is sufficient to prevent progression of NASH to liver fibrosis. Dissociated PPAR-α agonists, selectively modulating PPAR-α transrepression activity, could thus be an option to prevent NASH and fibrosis progression.
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Affiliation(s)
- Michal Pawlak
- European Genomic Institute for Diabetes, Lille, France; INSERM UMR1011, F-59000, Lille, France; University Lille 2, Lille, France; Institut Pasteur de Lille, Lille, France
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24
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Dubois-Chevalier J, Oger F, Dehondt H, Firmin FF, Gheeraert C, Staels B, Lefebvre P, Eeckhoute J. A dynamic CTCF chromatin binding landscape promotes DNA hydroxymethylation and transcriptional induction of adipocyte differentiation. Nucleic Acids Res 2014; 42:10943-59. [PMID: 25183525 PMCID: PMC4176165 DOI: 10.1093/nar/gku780] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
CCCTC-binding factor (CTCF) is a ubiquitously expressed multifunctional transcription factor characterized by chromatin binding patterns often described as largely invariant. In this context, how CTCF chromatin recruitment and functionalities are used to promote cell type-specific gene expression remains poorly defined. Here, we show that, in addition to constitutively bound CTCF binding sites (CTS), the CTCF cistrome comprises a large proportion of sites showing highly dynamic binding patterns during the course of adipogenesis. Interestingly, dynamic CTCF chromatin binding is positively linked with changes in expression of genes involved in biological functions defining the different stages of adipogenesis. Importantly, a subset of these dynamic CTS are gained at cell type-specific regulatory regions, in line with a requirement for CTCF in transcriptional induction of adipocyte differentiation. This relates to, at least in part, CTCF requirement for transcriptional activation of both the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARG) and its target genes. Functionally, we show that CTCF interacts with TET methylcytosine dioxygenase (TET) enzymes and promotes adipogenic transcriptional enhancer DNA hydroxymethylation. Our study reveals a dynamic CTCF chromatin binding landscape required for epigenomic remodeling of enhancers and transcriptional activation driving cell differentiation.
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Affiliation(s)
- Julie Dubois-Chevalier
- Inserm UMR U1011, F-59000 Lille, France Université Lille 2, F-59000 Lille, France Institut Pasteur de Lille, F-59019 Lille, France European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France
| | - Frédérik Oger
- Inserm UMR U1011, F-59000 Lille, France Université Lille 2, F-59000 Lille, France Institut Pasteur de Lille, F-59019 Lille, France European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France
| | - Hélène Dehondt
- Inserm UMR U1011, F-59000 Lille, France Université Lille 2, F-59000 Lille, France Institut Pasteur de Lille, F-59019 Lille, France European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France
| | - François F Firmin
- Inserm UMR U1011, F-59000 Lille, France Université Lille 2, F-59000 Lille, France Institut Pasteur de Lille, F-59019 Lille, France European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France
| | - Céline Gheeraert
- Inserm UMR U1011, F-59000 Lille, France Université Lille 2, F-59000 Lille, France Institut Pasteur de Lille, F-59019 Lille, France European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France
| | - Bart Staels
- Inserm UMR U1011, F-59000 Lille, France Université Lille 2, F-59000 Lille, France Institut Pasteur de Lille, F-59019 Lille, France European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France
| | - Philippe Lefebvre
- Inserm UMR U1011, F-59000 Lille, France Université Lille 2, F-59000 Lille, France Institut Pasteur de Lille, F-59019 Lille, France European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France
| | - Jérôme Eeckhoute
- Inserm UMR U1011, F-59000 Lille, France Université Lille 2, F-59000 Lille, France Institut Pasteur de Lille, F-59019 Lille, France European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France
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25
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Rodrigues RMM, de-Carvalho J, Ferreira GNM. Kinetic characterization of the retinoic X receptor binding to specific and unspecific DNA oligoduplexes with a quartz crystal microbalance. Analyst 2014; 139:3434-40. [PMID: 24824382 DOI: 10.1039/c4an00286e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Quartz Crystal Microbalance (QCM) biosensor technology was used to study the interaction of the DNA-binding domain (DBD) of the transcription factor RXRα with immobilized specific (DR1) and unspecific (DR1neg) DNA oligoduplexes. We identify the QCM sensor frequency at the susceptance minimum (fBmin) as a better measuring parameter, and we show that fBmin is proportional to the mass adsorbed at the sensor surface and is not influenced by interferences coming from viscoelastic variations of the adsorbed layers or buffers. This parameter was used to study the binding of RXRα to DNA and to calculate the association and dissociation kinetic constants of RXRαDBD-DR1 interaction. We show that RXRαDBD binds to DNA both as a monomer and as a homodimer, and that the mechanism of binding is salt dependent and occurs in two steps. The QCM biosensor data reveal that a high ionic strength buffer prevents the unspecific interactions and at a lower ionic strength the dissociation of RXRαDBD-DR1 occurs in two phases.
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Affiliation(s)
- Rogério M M Rodrigues
- IBB-Institute for Biotechnology and Bioengineering, Centro de Biomedicina Molecular e Estrutural, Universidade do Algarve, 8005-139 Faro, Portugal.
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26
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Lien F, Berthier A, Bouchaert E, Gheeraert C, Alexandre J, Porez G, Prawitt J, Dehondt H, Ploton M, Colin S, Lucas A, Patrice A, Pattou F, Diemer H, Van Dorsselaer A, Rachez C, Kamilic J, Groen AK, Staels B, Lefebvre P. Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk. J Clin Invest 2014; 124:1037-51. [PMID: 24531544 DOI: 10.1172/jci68815] [Citation(s) in RCA: 115] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Accepted: 12/05/2013] [Indexed: 12/24/2022] Open
Abstract
The nuclear bile acid receptor farnesoid X receptor (FXR) is an important transcriptional regulator of bile acid, lipid, and glucose metabolism. FXR is highly expressed in the liver and intestine and controls the synthesis and enterohepatic circulation of bile acids. However, little is known about FXR-associated proteins that contribute to metabolic regulation. Here, we performed a mass spectrometry-based search for FXR-interacting proteins in human hepatoma cells and identified AMPK as a coregulator of FXR. FXR interacted with the nutrient-sensitive kinase AMPK in the cytoplasm of target cells and was phosphorylated in its hinge domain. In cultured human and murine hepatocytes and enterocytes, pharmacological activation of AMPK inhibited FXR transcriptional activity and prevented FXR coactivator recruitment to promoters of FXR-regulated genes. Furthermore, treatment with AMPK activators, including the antidiabetic biguanide metformin, inhibited FXR agonist induction of FXR target genes in mouse liver and intestine. In a mouse model of intrahepatic cholestasis, metformin treatment induced FXR phosphorylation, perturbed bile acid homeostasis, and worsened liver injury. Together, our data indicate that AMPK directly phosphorylates and regulates FXR transcriptional activity to precipitate liver injury under conditions favoring cholestasis.
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27
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Abstract
Retinoid X Receptors (RXR) were initially identified as nuclear receptors binding with stereo-selectivity the vitamin A derivative 9-cis retinoic acid, although the relevance of this molecule as endogenous activator of RXRs is still elusive. Importantly, within the nuclear receptor superfamily, RXRs occupy a peculiar place, as they are obligatory partners for a number of other nuclear receptors, thus integrating the corresponding signaling pathways. In this chapter, we describe the structural features allowing RXR to form homo- and heterodimers, and the functional consequences of this unique ability. Furthermore, we discuss the importance of studying RXR activity at a genome-wide level in order to comprehensively address the biological implications of their action that is fundamental to understand to what extent RXRs could be exploited as new therapeutic targets.
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Affiliation(s)
- Federica Gilardi
- Center for Integrative Genomics, University of Lausanne, Genopode Building, 1015, Lausanne, Switzerland,
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28
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Nutrigenomics of high fat diet induced obesity in mice suggests relationships between susceptibility to fatty liver disease and the proteasome. PLoS One 2013; 8:e82825. [PMID: 24324835 PMCID: PMC3855786 DOI: 10.1371/journal.pone.0082825] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2013] [Accepted: 10/28/2013] [Indexed: 01/22/2023] Open
Abstract
Nutritional factors play important roles in the etiology of obesity, type 2 diabetes mellitus and their complications through genotype x environment interactions. We have characterised molecular adaptation to high fat diet (HFD) feeding in inbred mouse strains widely used in genetic and physiological studies. We carried out physiological tests, plasma lipid assays, obesity measures, liver histology, hepatic lipid measurements and liver genome-wide gene transcription profiling in C57BL/6J and BALB/c mice fed either a control or a high fat diet. The two strains showed marked susceptibility (C57BL/6J) and relative resistance (BALB/c) to HFD-induced insulin resistance and non alcoholic fatty liver disease (NAFLD). Global gene set enrichment analysis (GSEA) of transcriptome data identified consistent patterns of expression of key genes (Srebf1, Stard4, Pnpla2, Ccnd1) and molecular pathways in the two strains, which may underlie homeostatic adaptations to dietary fat. Differential regulation of pathways, including the proteasome, the ubiquitin mediated proteolysis and PPAR signalling in fat fed C57BL/6J and BALB/c suggests that altered expression of underlying diet-responsive genes may be involved in contrasting nutrigenomic predisposition and resistance to insulin resistance and NAFLD in these models. Collectively, these data, which further demonstrate the impact of gene x environment interactions on gene expression regulations, contribute to improved knowledge of natural and pathogenic adaptive genomic regulations and molecular mechanisms associated with genetically determined susceptibility and resistance to metabolic diseases.
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Oger F, Dubois-Chevalier J, Gheeraert C, Avner S, Durand E, Froguel P, Salbert G, Staels B, Lefebvre P, Eeckhoute J. Peroxisome proliferator-activated receptor γ regulates genes involved in insulin/insulin-like growth factor signaling and lipid metabolism during adipogenesis through functionally distinct enhancer classes. J Biol Chem 2013; 289:708-22. [PMID: 24288131 DOI: 10.1074/jbc.m113.526996] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The nuclear receptor peroxisome proliferator-activated receptor (PPAR) is a transcription factor whose expression is induced during adipogenesis and that is required for the acquisition and control of mature adipocyte functions. Indeed, PPAR induces the expression of genes involved in lipid synthesis and storage through enhancers activated during adipocyte differentiation. Here, we show that PPAR also binds to enhancers already active in preadipocytes as evidenced by an active chromatin state including lower DNA methylation levels despite higher CpG content. These constitutive enhancers are linked to genes involved in the insulin/insulin-like growth factor signaling pathway that are transcriptionally induced during adipogenesis but to a lower extent than lipid metabolism genes, because of stronger basal expression levels in preadipocytes. This is consistent with the sequential involvement of hormonal sensitivity and lipid handling during adipocyte maturation and correlates with the chromatin structure dynamics at constitutive and activated enhancers. Interestingly, constitutive enhancers are evolutionary conserved and can be activated in other tissues, in contrast to enhancers controlling lipid handling genes whose activation is more restricted to adipocytes. Thus, PPAR utilizes both broadly active and cell type-specific enhancers to modulate the dynamic range of activation of genes involved in the adipogenic process.
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30
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Porez G, Gross B, Prawitt J, Gheeraert C, Berrabah W, Alexandre J, Staels B, Lefebvre P. The hepatic orosomucoid/α1-acid glycoprotein gene cluster is regulated by the nuclear bile acid receptor FXR. Endocrinology 2013; 154:3690-701. [PMID: 23861371 DOI: 10.1210/en.2013-1263] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The α-1-acid glycoprotein/orosomucoids (ORMs) are members of the lipocalin protein family. Encoded by 3 polymorphic genes in mouse (2 in man, 1 in rat), ORMs are expressed in hepatocytes and function as acute-phase proteins secreted in plasma under stressful conditions. In addition to their role of nanocarrier, ORMs are involved in several pathophysiological processes such as immunosuppression, cardioprotection, and inflammatory bowel disease. The nuclear bile acid receptor farnesoid X receptor (FXR) regulates bile acid homeostasis and lipid and glucose metabolism and is an important modulator of enterohepatic functions. Here we report that hepatic FXR deletion in mice affects the expression of several members of the lipocalin family, among which ORMs are identified as direct FXR target genes. Indeed, a FXR response element upstream of the mouse Orm1 promoter was identified to which hepatic, but not ileal, FXR can bind and activate ORM expression in vitro and in vivo. However, ORMs are regulated in a species-specific manner because the ORM cluster is regulated by FXR neither in human nor rat cell lines. Consistent with these data, chromatin immunoprecipitation sequencing analysis of the FXR genomic binding sites did not detect any FXR response element in the vicinity of the human or rat ORM gene cluster. Thus, bile acids and their cognate nuclear receptor, FXR, are regulators of ORM expression, with potential implications for the species-specific metabolic and inflammation control by FXR because the expression of the proinflammatory genes in epididymal white adipose tissue was dependent on liver FXR activation.
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Affiliation(s)
- Geoffrey Porez
- PhD, Director, Institut National de la Santé et de la Recherche Médicale, Atherosclerosis, Boulevard Du Pr Leclerc, Batiment J&K, Faclte De Medecine De Lille, Lille 59000, France.
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González-Muniesa P, Marrades MP, Martínez JA, Moreno-Aliaga MJ. Differential proinflammatory and oxidative stress response and vulnerability to metabolic syndrome in habitual high-fat young male consumers putatively predisposed by their genetic background. Int J Mol Sci 2013; 14:17238-55. [PMID: 23975165 PMCID: PMC3794726 DOI: 10.3390/ijms140917238] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2013] [Revised: 08/12/2013] [Accepted: 08/13/2013] [Indexed: 12/18/2022] Open
Abstract
The current nutritional habits and lifestyles of modern societies favor energy overloads and a diminished physical activity, which may produce serious clinical disturbances and excessive weight gain. In order to investigate the mechanisms by which the environmental factors interact with molecular mechanisms in obesity, a pathway analysis was performed to identify genes differentially expressed in subcutaneous abdominal adipose tissue (SCAAT) from obese compared to lean male (21–35 year-old) subjects living in similar obesogenic conditions: habitual high fat dietary intake and moderate physical activity. Genes involved in inflammation (ALCAM, CTSB, C1S, YKL-40, MIF, SAA2), extracellular matrix remodeling (MMP9, PALLD), angiogenesis (EGFL6, leptin) and oxidative stress (AKR1C3, UCHL1, HSPB7 and NQO1) were upregulated; whereas apoptosis, signal transcription (CITED 2 and NR3C1), cell control and cell cycle-related genes were downregulated. Interestingly, the expression of some of these genes (C1S, SAA2, ALCAM, CTSB, YKL-40 and tenomodulin) was found to be associated with some relevant metabolic syndrome features. The obese group showed a general upregulation in the expression of inflammatory, oxidative stress, extracellular remodeling and angiogenic genes compared to lean subjects, suggesting that a given genetic background in an obesogenic environment could underlie the resistance to gaining weight and obesity-associated manifestations.
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Affiliation(s)
- Pedro González-Muniesa
- Department of Nutrition, Food Sciences and Physiology, University of Navarra, 31008 Pamplona, Spain; E-Mails: (P.G.-M.); (M.P.M.); (J.A.M.)
- CIBERobn Physiopathology of Obesity and Nutrition, Centre of Biomedical Research Network, 29029 Madrid, Spain
| | - María Pilar Marrades
- Department of Nutrition, Food Sciences and Physiology, University of Navarra, 31008 Pamplona, Spain; E-Mails: (P.G.-M.); (M.P.M.); (J.A.M.)
| | - José Alfredo Martínez
- Department of Nutrition, Food Sciences and Physiology, University of Navarra, 31008 Pamplona, Spain; E-Mails: (P.G.-M.); (M.P.M.); (J.A.M.)
- CIBERobn Physiopathology of Obesity and Nutrition, Centre of Biomedical Research Network, 29029 Madrid, Spain
| | - María Jesús Moreno-Aliaga
- Department of Nutrition, Food Sciences and Physiology, University of Navarra, 31008 Pamplona, Spain; E-Mails: (P.G.-M.); (M.P.M.); (J.A.M.)
- CIBERobn Physiopathology of Obesity and Nutrition, Centre of Biomedical Research Network, 29029 Madrid, Spain
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +34-948-425-600 (ext. 806558); Fax: +34-948-425-740
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Flajollet S, Rachez C, Ploton M, Schulz C, Gallais R, Métivier R, Pawlak M, Leray A, Issulahi AA, Héliot L, Staels B, Salbert G, Lefebvre P. The elongation complex components BRD4 and MLLT3/AF9 are transcriptional coactivators of nuclear retinoid receptors. PLoS One 2013; 8:e64880. [PMID: 23762261 PMCID: PMC3677938 DOI: 10.1371/journal.pone.0064880] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2013] [Accepted: 04/18/2013] [Indexed: 12/20/2022] Open
Abstract
Nuclear all-trans retinoic acid receptors (RARs) initiate early transcriptional events which engage pluripotent cells to differentiate into specific lineages. RAR-controlled transactivation depends mostly on agonist-induced structural transitions in RAR C-terminus (AF-2), thus bridging coactivators or corepressors to chromatin, hence controlling preinitiation complex assembly. However, the contribution of other domains of RAR to its overall transcriptional activity remains poorly defined. A proteomic characterization of nuclear proteins interacting with RAR regions distinct from the AF-2 revealed unsuspected functional properties of the RAR N-terminus. Indeed, mass spectrometry fingerprinting identified the Bromodomain-containing protein 4 (BRD4) and ALL1-fused gene from chromosome 9 (AF9/MLLT3), known to associate with and regulates the activity of Positive Transcription Elongation Factor b (P-TEFb), as novel RAR coactivators. In addition to promoter sequences, RAR binds to genomic, transcribed regions of retinoid-regulated genes, in association with RNA polymerase II and as a function of P-TEFb activity. Knockdown of either AF9 or BRD4 expression affected differentially the neural differentiation of stem cell-like P19 cells. Clusters of retinoid-regulated genes were selectively dependent on BRD4 and/or AF9 expression, which correlated with RAR association to transcribed regions. Thus RAR establishes physical and functional links with components of the elongation complex, enabling the rapid retinoid-induced induction of genes required for neuronal differentiation. Our data thereby extends the previously known RAR interactome from classical transcriptional modulators to components of the elongation machinery, and unravel a functional role of RAR in transcriptional elongation.
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Affiliation(s)
- Sébastien Flajollet
- European Genomic Institute for Diabetes (EGID), FR 3508, Lille, France
- INSERM UMR1011, Lille, France
- Univ Lille 2, Lille, France
- Institut Pasteur de Lille, Lille, France
| | - Christophe Rachez
- Unité de Régulation Epigénétique, URA 2578 du CNRS, Département de Biologie du Développement, Institut Pasteur, Paris, France
| | - Maheul Ploton
- European Genomic Institute for Diabetes (EGID), FR 3508, Lille, France
- INSERM UMR1011, Lille, France
- Univ Lille 2, Lille, France
- Institut Pasteur de Lille, Lille, France
| | - Céline Schulz
- Interdisciplinary Research Institute, Univ Lille 1, USR 3078 CNRS, Biophotonique Cellulaire Fonctionnelle, Villeneuve d’Ascq, France
| | - Rozenn Gallais
- Equipe SPARTE, UMR CNRS 6026-Université Rennes 1, Rennes, France
| | - Raphaël Métivier
- Equipe SPARTE, UMR CNRS 6026-Université Rennes 1, Rennes, France
| | - Michal Pawlak
- European Genomic Institute for Diabetes (EGID), FR 3508, Lille, France
- INSERM UMR1011, Lille, France
- Univ Lille 2, Lille, France
- Institut Pasteur de Lille, Lille, France
| | - Aymeric Leray
- Interdisciplinary Research Institute, Univ Lille 1, USR 3078 CNRS, Biophotonique Cellulaire Fonctionnelle, Villeneuve d’Ascq, France
| | - Al Amine Issulahi
- Interdisciplinary Research Institute, Univ Lille 1, USR 3078 CNRS, Biophotonique Cellulaire Fonctionnelle, Villeneuve d’Ascq, France
| | - Laurent Héliot
- Interdisciplinary Research Institute, Univ Lille 1, USR 3078 CNRS, Biophotonique Cellulaire Fonctionnelle, Villeneuve d’Ascq, France
| | - Bart Staels
- European Genomic Institute for Diabetes (EGID), FR 3508, Lille, France
- INSERM UMR1011, Lille, France
- Univ Lille 2, Lille, France
- Institut Pasteur de Lille, Lille, France
| | - Gilles Salbert
- Equipe SPARTE, UMR CNRS 6026-Université Rennes 1, Rennes, France
| | - Philippe Lefebvre
- European Genomic Institute for Diabetes (EGID), FR 3508, Lille, France
- INSERM UMR1011, Lille, France
- Univ Lille 2, Lille, France
- Institut Pasteur de Lille, Lille, France
- * E-mail:
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Ahmadian M, Suh JM, Hah N, Liddle C, Atkins AR, Downes M, Evans RM. PPARγ signaling and metabolism: the good, the bad and the future. Nat Med 2013; 19:557-66. [PMID: 23652116 PMCID: PMC3870016 DOI: 10.1038/nm.3159] [Citation(s) in RCA: 1660] [Impact Index Per Article: 138.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2012] [Accepted: 03/06/2013] [Indexed: 11/09/2022]
Abstract
Thiazolidinediones (TZDs) are potent insulin sensitizers that act through the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) and are highly effective oral medications for type 2 diabetes. However, their unique benefits are shadowed by the risk for fluid retention, weight gain, bone loss and congestive heart failure. This raises the question as to whether it is possible to build a safer generation of PPARγ-specific drugs that evoke fewer side effects while preserving insulin-sensitizing potential. Recent studies that have supported the continuing physiologic and therapeutic relevance of the PPARγ pathway also provide opportunities to develop newer classes of molecules that reduce or eliminate adverse effects. This review highlights key advances in understanding PPARγ signaling in energy homeostasis and metabolic disease and also provides new explanations for adverse events linked to TZD-based therapy.
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Affiliation(s)
- Maryam Ahmadian
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA
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Perng W, Mora-Plazas M, Marín C, Rozek LS, Baylin A, Villamor E. A prospective study of LINE-1DNA methylation and development of adiposity in school-age children. PLoS One 2013; 8:e62587. [PMID: 23638120 PMCID: PMC3640064 DOI: 10.1371/journal.pone.0062587] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2012] [Accepted: 03/22/2013] [Indexed: 01/31/2023] Open
Abstract
Background Repetitive element DNA methylation is related to prominent obesity-related chronic diseases including cancer and cardiovascular disease; yet, little is known of its relation with weight status. We examined associations of LINE-1 DNA methylation with changes in adiposity and linear growth in a longitudinal study of school-age children from Bogotá, Colombia. Methods We quantified methylation of LINE-1 elements from peripheral leukocytes of 553 children aged 5–12 years at baseline using pyrosequencing technology. Anthropometric characteristics were measured periodically for a median of 30 months. We estimated mean change in three age-and sex-standardized indicators of adiposity: body mass index (BMI)-for-age Z-score, waist circumference Z-score, and subscapular-to-triceps skinfold thickness ratio Z-score according to quartiles of LINE-1 methylation using mixed effects regression models. We also examined associations with height-for-age Z-score. Results There were non-linear, inverse relations of LINE-1 methylation with BMI-for-age Z-score and the skinfold thickness ratio Z-score. After adjustment for baseline age and socioeconomic status, boys in the lowest quartile of LINE-1 methylation experienced annual gains in BMI-for-age Z-score and skinfold thickness ratio Z-score that were 0.06 Z/year (P = 0.04) and 0.07 Z/year (P = 0.03), respectively, higher than those in the upper three quartiles. The relation of LINE-1 methylation and annual change in waist circumference followed a decreasing monotonic trend across the four quartiles (P trend = 0.02). DNA methylation was not related to any of the adiposity indicators in girls. There were no associations between LINE-1 methylation and linear growth in either sex. Conclusions Lower LINE-1 DNA methylation is related to development of adiposity in boys.
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Affiliation(s)
- Wei Perng
- Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan, United States of America.
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Katano-Toki A, Satoh T, Tomaru T, Yoshino S, Ishizuka T, Ishii S, Ozawa A, Shibusawa N, Tsuchiya T, Saito T, Shimizu H, Hashimoto K, Okada S, Yamada M, Mori M. THRAP3 interacts with HELZ2 and plays a novel role in adipocyte differentiation. Mol Endocrinol 2013; 27:769-80. [PMID: 23525231 DOI: 10.1210/me.2012-1332] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Using yeast two-hybrid screen, we previously isolated HELZ2 (helicase with zinc finger 2, transcriptional coactivator) that functions as a coregulator of peroxisome proliferator-activated receptorγ (PPARγ). To further delineate its molecular function, we here identified thyroid hormone receptor-associated protein3 (THRAP3), a putative component of the Mediator complex, as a protein stably associating with HELZ2 using immunoprecipitation coupled with mass spectrometry analyses. In immunoprecipitation assays, Thrap3 could associate with endogenous Helz2 as well as Pparg in differentiated 3T3-L1 cells. HELZ2 interacts with the serine/arginine-rich domain and Bcl2 associated transcription factor1-homologous region in THRAP3, whereas THRAP3 directly binds 2 helicase motifs in HELZ2. HELZ2 and THRAP3 synergistically augment transcriptional activation mediated by PPARγ, whereas knockdown of endogenous THRAP3 abolished the enhancement by HELZ2 in reporter assays. Thrap3, similar to Helz2, is evenly expressed in the process of adipogenic differentiation in 3T3-L1 cells. Knockdown of Thrap3 in 3T3-L1 preadipocytes using short-interfering RNA did not influence the expression of Krox20, Klf5, Cebpb, or Cebpd during early stages of adipocyte differentiation, but significantly attenuated the expression of Pparg, Cebpa, and Fabp4/aP2 and accumulation of lipid droplets. Pharmacologic activation of Pparg by troglitazone could not fully restore the differentiation of Thrap3-knockdown adipocytes. In chromatin immunoprecipitation assays, endogenous Helz2 and Thrap3 could be co-recruited, in a ligand-dependent manner, to the PPARγ-response elements in Fabp4/aP2 and Adipoq gene enhancers in differentiated 3T3-L1 cells. These findings collectively suggest that Thrap3 could play indispensable roles in terminal differentiation of adipocytes by enhancing PPARγ-mediated gene activation cooperatively with Helz2.
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Affiliation(s)
- Akiko Katano-Toki
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan
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Gharib SA, Hayes AL, Rosen MJ, Patel SR. A pathway-based analysis on the effects of obstructive sleep apnea in modulating visceral fat transcriptome. Sleep 2013; 36:23-30. [PMID: 23288968 DOI: 10.5665/sleep.2294] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
RATIONALE Obstructive sleep apnea (OSA) has been associated with metabolic dysregulation and systemic inflammation. This may be due to pathophysiologic effects of OSA on visceral adipose tissue. We sought to assess the transcriptional consequences of OSA on adipocytes by utilizing pathway-focused analyses. METHODS Patients scheduled to undergo ventral hernia repair surgery were recruited to wear a portable home sleep monitor for 2 nights prior to surgery. Visceral fat biopsies were obtained intraoperatively. RNA was extracted and whole-genome expression profiling was performed. Gene Set Enrichment Analysis (GSEA) was used to identify curated gene sets that were differentially enriched in OSA subjects. Network analysis was applied to a select set of highly enriched pathways. RESULTS Ten patients with OSA and 8 control subjects were recruited. There were no differences in age, gender, or body mass index between the 2 groups, but the OSA subjects had a significantly higher respiratory disturbance index (19.2 vs. 0.6, P = 0.05) and worse hypoxemia (minimum oxygen saturation 79.7% vs. 87.8%, P < 0.001). GSEA identified a number of gene sets up-regulated in adipose tissue of OSA patients, including the pro-inflammatory NF-κB pathway and the proteolytic ubiquitin/proteasome module. A critical metabolic pathway, the peroxisome proliferator-activated receptor (PPAR), was down-regulated in subjects with OSA. Network analysis linked members of these modules together and identified regulatory hubs. CONCLUSIONS OSA is associated with alterations in visceral fat gene expression. Pathway-based network analysis highlighted perturbations in several key pathways whose coordinated interactions may contribute to the metabolic dysregulation observed in this complex disorder.
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Affiliation(s)
- Sina A Gharib
- Center for Lung Biology, Department of Medicine, University of Washington, Seattle, WA 98109, USA.
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Insenser M, Montes-Nieto R, Vilarrasa N, Lecube A, Simó R, Vendrell J, Escobar-Morreale HF. A nontargeted proteomic approach to the study of visceral and subcutaneous adipose tissue in human obesity. Mol Cell Endocrinol 2012; 363:10-9. [PMID: 22796336 DOI: 10.1016/j.mce.2012.07.001] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2012] [Revised: 06/08/2012] [Accepted: 07/06/2012] [Indexed: 11/28/2022]
Abstract
Subcutaneous (SAT) and visceral adipose tissue (VAT) differ in biochemical and metabolic properties, especially when obesity is present. We submitted paired SAT and VAT samples from six morbidly obese patients and six non-obese persons to two-dimensional differential gel electrophoresis and matrix-assisted laser desorption/ionization-time-of-flight/time-of-flight mass spectrometry. Compared with non-obese subjects, obese patients presented with increased carboxylesterase-1, zinc finger protein 324A, annexin A5, ubiquitin carboxyl-terminal hydrolase, α-crystallin B chain, osteoglycin, retinal dehydrogenase-1 and 14-3-3 protein γ, and decreased transferrin, complement C3, fibrinogen γ chain, albumin, α1-antitrypsin and peroxiredoxin-6, irrespective of the adipose tissue depot studied. SAT and VAT differed in protein species of fibrinogen and osteoglycin, whereas adipose tissue depot and obesity interacted on the protein abundance of actin, α-actinin 1, one protein species of carboxylesterase-1, retinal dehydrogenase-1 and 14-3-3 protein γ. Our nontargeted proteomic approach identified novel protein species that may be involved in the development of obesity in humans.
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Affiliation(s)
- María Insenser
- Diabetes, Obesity and Human Reproduction Group, Universidad de Alcalá & Hospital Universitario Ramón y Cajal & Instituto Ramón y Cajal de Investigación Sanitaria IRYCIS, Madrid, Spain
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Stravodimou A, Mazzoccoli G, Voutsadakis IA. Peroxisome proliferator-activated receptor gamma and regulations by the ubiquitin-proteasome system in pancreatic cancer. PPAR Res 2012; 2012:367450. [PMID: 23049538 PMCID: PMC3459232 DOI: 10.1155/2012/367450] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Accepted: 08/13/2012] [Indexed: 12/11/2022] Open
Abstract
Pancreatic cancer is one of the most lethal forms of human cancer. Although progress in oncology has improved outcomes in many forms of cancer, little progress has been made in pancreatic carcinoma and the prognosis of this malignancy remains grim. Several molecular abnormalities often present in pancreatic cancer have been defined and include mutations in K-ras, p53, p16, and DPC4 genes. Nuclear receptor Peroxisome Proliferator-Activated Receptor gamma (PPARγ) has a role in many carcinomas and has been found to be overexpressed in pancreatic cancer. It plays generally a tumor suppressor role antagonizing proteins promoting carcinogenesis such as NF-κB and TGFβ. Regulation of pathways involved in pancreatic carcinogenesis is effectuated by the Ubiquitin Proteasome System (UPS). This paper will examine PPARγ in pancreatic cancer, the regulation of this nuclear receptor by the UPS, and their relationship to other pathways important in pancreatic carcinogenesis.
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Affiliation(s)
- Athina Stravodimou
- Centre Pluridisciplinaire d'Oncologie, Centre Hospitalier Universitaire Vaudois, BH06, Bugnon 46, 1011 Lausanne, Switzerland
| | - Gianluigi Mazzoccoli
- Division of Internal Medicine and Chronobiology Unit, Department of Medical Sciences, IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, Italy
| | - Ioannis A. Voutsadakis
- Centre Pluridisciplinaire d'Oncologie, Centre Hospitalier Universitaire Vaudois, BH06, Bugnon 46, 1011 Lausanne, Switzerland
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Eeckhoute J, Oger F, Staels B, Lefebvre P. Coordinated Regulation of PPARγ Expression and Activity through Control of Chromatin Structure in Adipogenesis and Obesity. PPAR Res 2012; 2012:164140. [PMID: 22991504 PMCID: PMC3444001 DOI: 10.1155/2012/164140] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2012] [Accepted: 07/10/2012] [Indexed: 12/14/2022] Open
Abstract
The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is required for differentiation and function of mature adipocytes. Its expression is induced during adipogenesis where it plays a key role in establishing the transcriptome of terminally differentiated white fat cells. Here, we review findings indicating that PPARγ expression and activity are intricately regulated through control of chromatin structure. Hierarchical and combinatorial activation of transcription factors, noncoding RNAs, and chromatin remodelers allows for temporally controlled expression of PPARγ and its target genes through sequential chromatin remodelling. In obesity, these regulatory pathways may be altered and lead to modified PPARγ activity.
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Affiliation(s)
- Jérôme Eeckhoute
- Université Lille Nord de France, 59000 Lille, France
- Inserm, U1011, 59000 Lille, France
- UDSL, 59000 Lille, France
- Institut Pasteur de Lille, 59019 Lille, France
| | - Frédérik Oger
- Université Lille Nord de France, 59000 Lille, France
- Inserm, U1011, 59000 Lille, France
- UDSL, 59000 Lille, France
- Institut Pasteur de Lille, 59019 Lille, France
| | - Bart Staels
- Université Lille Nord de France, 59000 Lille, France
- Inserm, U1011, 59000 Lille, France
- UDSL, 59000 Lille, France
- Institut Pasteur de Lille, 59019 Lille, France
| | - Philippe Lefebvre
- Université Lille Nord de France, 59000 Lille, France
- Inserm, U1011, 59000 Lille, France
- UDSL, 59000 Lille, France
- Institut Pasteur de Lille, 59019 Lille, France
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Chorley BN, Campbell MR, Wang X, Karaca M, Sambandan D, Bangura F, Xue P, Pi J, Kleeberger SR, Bell DA. Identification of novel NRF2-regulated genes by ChIP-Seq: influence on retinoid X receptor alpha. Nucleic Acids Res 2012; 40:7416-29. [PMID: 22581777 PMCID: PMC3424561 DOI: 10.1093/nar/gks409] [Citation(s) in RCA: 455] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2011] [Revised: 04/18/2012] [Accepted: 04/19/2012] [Indexed: 12/14/2022] Open
Abstract
Cellular oxidative and electrophilic stress triggers a protective response in mammals regulated by NRF2 (nuclear factor (erythroid-derived) 2-like; NFE2L2) binding to deoxyribonucleic acid-regulatory sequences near stress-responsive genes. Studies using Nrf2-deficient mice suggest that hundreds of genes may be regulated by NRF2. To identify human NRF2-regulated genes, we conducted chromatin immunoprecipitation (ChIP)-sequencing experiments in lymphoid cells treated with the dietary isothiocyanate, sulforaphane (SFN) and carried out follow-up biological experiments on candidates. We found 242 high confidence, NRF2-bound genomic regions and 96% of these regions contained NRF2-regulatory sequence motifs. The majority of binding sites were near potential novel members of the NRF2 pathway. Validation of selected candidate genes using parallel ChIP techniques and in NRF2-silenced cell lines indicated that the expression of about two-thirds of the candidates are likely to be directly NRF2-dependent including retinoid X receptor alpha (RXRA). NRF2 regulation of RXRA has implications for response to retinoid treatments and adipogenesis. In mouse, 3T3-L1 cells' SFN treatment affected Rxra expression early in adipogenesis, and knockdown of Nrf2-delayed Rxra expression, both leading to impaired adipogenesis.
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Affiliation(s)
- Brian N. Chorley
- Environmental Genomics Section, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institutes of Health, The Hamner Institutes and Environmental Genetics Section, Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Michelle R. Campbell
- Environmental Genomics Section, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institutes of Health, The Hamner Institutes and Environmental Genetics Section, Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Xuting Wang
- Environmental Genomics Section, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institutes of Health, The Hamner Institutes and Environmental Genetics Section, Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Mehmet Karaca
- Environmental Genomics Section, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institutes of Health, The Hamner Institutes and Environmental Genetics Section, Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Deepa Sambandan
- Environmental Genomics Section, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institutes of Health, The Hamner Institutes and Environmental Genetics Section, Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Fatu Bangura
- Environmental Genomics Section, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institutes of Health, The Hamner Institutes and Environmental Genetics Section, Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Peng Xue
- Environmental Genomics Section, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institutes of Health, The Hamner Institutes and Environmental Genetics Section, Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Jingbo Pi
- Environmental Genomics Section, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institutes of Health, The Hamner Institutes and Environmental Genetics Section, Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Steven R. Kleeberger
- Environmental Genomics Section, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institutes of Health, The Hamner Institutes and Environmental Genetics Section, Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Douglas A. Bell
- Environmental Genomics Section, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institutes of Health, The Hamner Institutes and Environmental Genetics Section, Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
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Liu H, Yu S, Xu W, Xu J. Enhancement of 26S proteasome functionality connects oxidative stress and vascular endothelial inflammatory response in diabetes mellitus. Arterioscler Thromb Vasc Biol 2012; 32:2131-40. [PMID: 22772755 DOI: 10.1161/atvbaha.112.253385] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
OBJECTIVE Although the connection of oxidative stress and inflammation has been long recognized in diabetes mellitus, the underlying mechanisms are not fully elucidated. This study defined the role of 26S proteasomes in promoting vascular inflammatory response in early diabetes mellitus. METHODS AND RESULTS The 26S proteasome functionality, markers of autophagy, and unfolded protein response were assessed in (1) cultured 26S proteasome reporter cells and endothelial cells challenged with high glucose, (2) transgenic reporter (Ub(G76V)-green fluorescence protein) and wild-type (C57BL/6J) mice rendered diabetic, and (3) genetically diabetic (Akita and OVE26) mice. In glucose-challenged cells, and also in aortic, renal, and retinal tissues from diabetic mice, enhanced 26S proteasome functionality was observed, evidenced by augmentation of proteasome (chymotrypsin-like) activities and reduction in 26S proteasome reporter proteins, accompanied by increased nitrotyrosine-containing proteins. Also, whereas inhibitor of the nuclear factor κ-light-chain-enhancer of activated B cells α proteins were decreased, an increase was found in nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) nucleus translocation, which enhanced the NF-κB-mediated proinflammatory response, without affecting markers of autophagy or unfolded protein response. Importantly, the alterations were abolished by MG132 administration, small interfering RNA knockdown of PA700 (proteasome activator protein complex), or superoxide scavenging in vivo. CONCLUSIONS Early hyperglycemia enhances 26S proteasome functionality, not autophagy or unfolded protein response, through peroxynitrite/superoxide-mediated PA700-dependent proteasomal activation, which elevates NF- ĸB-mediated endothelial inflammatory response in early diabetes mellitus.
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Affiliation(s)
- Hongtao Liu
- Section of Endocrinology and Diabetes, Department of Medicine, University of Oklahoma Health Sciences Center, Harold Hamm Oklahoma Diabetes Center, Oklahoma City, OK 73104, USA
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Sérandour AA, Avner S, Oger F, Bizot M, Percevault F, Lucchetti-Miganeh C, Palierne G, Gheeraert C, Barloy-Hubler F, Péron CL, Madigou T, Durand E, Froguel P, Staels B, Lefebvre P, Métivier R, Eeckhoute J, Salbert G. Dynamic hydroxymethylation of deoxyribonucleic acid marks differentiation-associated enhancers. Nucleic Acids Res 2012; 40:8255-65. [PMID: 22730288 PMCID: PMC3458548 DOI: 10.1093/nar/gks595] [Citation(s) in RCA: 150] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Enhancers are developmentally controlled transcriptional regulatory regions whose activities are modulated through histone modifications or histone variant deposition. In this study, we show by genome-wide mapping that the newly discovered deoxyribonucleic acid (DNA) modification 5-hydroxymethylcytosine (5hmC) is dynamically associated with transcription factor binding to distal regulatory sites during neural differentiation of mouse P19 cells and during adipocyte differentiation of mouse 3T3-L1 cells. Functional annotation reveals that regions gaining 5hmC are associated with genes expressed either in neural tissues when P19 cells undergo neural differentiation or in adipose tissue when 3T3-L1 cells undergo adipocyte differentiation. Furthermore, distal regions gaining 5hmC together with H3K4me2 and H3K27ac in P19 cells behave as differentiation-dependent transcriptional enhancers. Identified regions are enriched in motifs for transcription factors regulating specific cell fates such as Meis1 in P19 cells and PPARγ in 3T3-L1 cells. Accordingly, a fraction of hydroxymethylated Meis1 sites were associated with a dynamic engagement of the 5-methylcytosine hydroxylase Tet1. In addition, kinetic studies of cytosine hydroxymethylation of selected enhancers indicated that DNA hydroxymethylation is an early event of enhancer activation. Hence, acquisition of 5hmC in cell-specific distal regulatory regions may represent a major event of enhancer progression toward an active state and participate in selective activation of tissue-specific genes.
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Affiliation(s)
- Aurélien A Sérandour
- Université de Rennes 1, CNRS UMR6290, Team SP@RTE, Campus de Beaulieu, Rennes F-35042, France
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Kilroy G, Kirk-Ballard H, Carter LE, Floyd ZE. The ubiquitin ligase Siah2 regulates PPARγ activity in adipocytes. Endocrinology 2012; 153:1206-18. [PMID: 22294748 PMCID: PMC3281538 DOI: 10.1210/en.2011-1725] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Moderate reductions in peroxisome proliferator-activated receptor (PPAR)γ levels control insulin sensitivity as effectively as activation of PPARγ in adipocytes by the thiazolidinediones. That observation suggests that PPARγ activity can be regulated by modulating the amount of PPARγ protein in adipocytes. Activation of PPARγ in adipocytes is linked to changes in PPARγ protein levels via increased degradation of PPARγ proteins by the ubiquitin proteasome system. Identification of the ubiquitin ligase or ligases that recognize ligand bound PPARγ is an essential step in determining the physiological significance of the relationship between activation and ubiquitin-dependent degradation of PPARγ. Using an RNA interference-based screen, we identified five RING (really interesting new gene)-type ubiquitin ligases that alter PPARγ protein levels in adipocytes. Here, we demonstrate that Drosophila seven-in-absentia homolog 2 (Siah2), a mammalian homolog of Drosophila seven-in-absentia, regulates PPARγ ubiquitylation and ligand-dependent activation of PPARγ in adipocytes. We also demonstrate that Siah2 expression is up-regulated during adipogenesis and that PPARγ interacts with Siah2 during adipogenesis. In addition, Siah2 is required for adipogenesis. These data suggest that modulation of PPARγ protein levels by the ubiquitin ligase Siah2 is essential in determining the physiological effects of PPARγ activation in adipocytes.
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Affiliation(s)
- Gail Kilroy
- Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, Louisiana 70808, USA
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Briand O, Helleboid-Chapman A, Ploton M, Hennuyer N, Carpentier R, Pattou F, Vandewalle B, Moerman E, Gmyr V, Kerr-Conte J, Eeckhoute J, Staels B, Lefebvre P. The nuclear orphan receptor Nur77 is a lipotoxicity sensor regulating glucose-induced insulin secretion in pancreatic β-cells. Mol Endocrinol 2012; 26:399-413. [PMID: 22301783 DOI: 10.1210/me.2011-1317] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The NR4A orphan nuclear receptors Nur77, Nurr1, and Nor1 exert multiple cellular and metabolic functions. These transcriptional regulators are activated in response to extracellular stresses, including lipotoxic fatty acids (FA) and proinflammatory cytokines. The contribution of NR4As to β-cell pathophysiology is, however, unknown. We have therefore examined the role of NR4As as downstream contributors to FA-induced β-cell dysfunctions. Human pancreatic islets and insulinoma β-cells were used to determine transcriptional programs elicited by NR4A, which were compared to those triggered by palmitate treatment. Functional studies evaluated the consequence of an increased NR4A expression on insulin biosynthesis and secretion and cell viability in insulinoma β-cells. FA and cytokine treatment increased NR4A expression in pancreatic β-cells, with Nur77 being most highly inducible in murine β-cells. Nur77, Nurr1, or Nor1 modulated common and distinct clusters of genes involved notably in cation homeostasis and insulin gene transcription. By altering zinc homeostasis, insulin gene transcription, and secretion, Nur77 was found to be a major transcriptional mediator of part of FA-induced β-cell dysfunctions. The repressive role of Nur77 in insulin gene regulation was tracked down to protein-protein interaction with FoxO1, a pivotal integrator of the insulin gene regulatory network. The present study identifies a member of the NR4A nuclear receptor subclass, Nur77/NR4A1, as a modulator of pancreatic β-cell biology. Together with its previously documented role in liver and muscle, its role in β-cells establishes Nur77 as an important integrator of glucose metabolism.
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Affiliation(s)
- Olivier Briand
- Institut Pasteur de Lille, Faculté de Médecine de Lille-Pôle Recherche; Institut National de la Santé et de la Recherche Médicale (INSERM) U1011-Bâtiment J&K; Boulevard du Pr Leclerc, Lille cedex, France
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Zhuang LN, Hu WX, Xin SM, Zhao J, Pei G. Beta-arrestin-1 protein represses adipogenesis and inflammatory responses through its interaction with peroxisome proliferator-activated receptor-gamma (PPARgamma). J Biol Chem 2011; 286:28403-13. [PMID: 21700709 DOI: 10.1074/jbc.m111.256099] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
One of the master regulators of adipogenesis and macrophage function is peroxisome proliferator-activated receptor-γ (PPARγ). Here, we report that a deficiency of β-arrestin-1 expression affects PPARγ-mediated expression of lipid metabolic genes and inflammatory genes. Further mechanistic studies revealed that β-arrestin-1 interacts with PPARγ. β-Arrestin-1 suppressed the formation of a complex between PPARγ and 9-cis-retinoic acid receptor-α through its direct interaction with PPARγ. The interaction of β-arrestin-1 with PPARγ repressed PPARγ/9-cis-retinoic acid receptor-α function but promoted PPARγ/nuclear receptor corepressor function in PPARγ-mediated adipogenesis and inflammatory gene expression. Consistent with these results, a deficiency of β-arrestin-1 binding to PPARγ abolished its suppression of PPARγ-dependent adipogenesis and inflammatory responses. These results indicate that the regulation of PPARγ by β-arrestin-1 is critical. Furthermore, in vivo expression of β-arrestin-1 (but not the binding-deficient mutant) significantly repressed adipogenesis, macrophage infiltration, and diet-induced obesity and improved glucose tolerance and systemic insulin sensitivity. Therefore, our findings not only reveal a molecular mechanism for the modulation of obesity by β-arrestin-1 but also suggest a potential tactical approach against obesity and its associated metabolic disorders.
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Affiliation(s)
- Le-nan Zhuang
- Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Tongji University, Shanghai 200092, China
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Zhou H, Saito S, Piao G, Liu ZP, Wang J, Horimoto K, Chen L. Network screening of Goto-Kakizaki rat liver microarray data during diabetic progression. BMC SYSTEMS BIOLOGY 2011; 5 Suppl 1:S16. [PMID: 21689475 PMCID: PMC3121116 DOI: 10.1186/1752-0509-5-s1-s16] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Background Type 2 diabetes mellitus (T2DM) is a complex systemic disease, with significant disorders of metabolism. The liver, a central energy metabolic organ, plays a critical role in the development of diabetes. Although gene expression levels are able to be measured via microarray since 1996, it is difficult to evaluate the contributions of one altered gene expression to a specific disease. One of the reasons is that a whole network picture responsible for a specific phase of diabetes is missing, while a single gene has to be put into a network picture to evaluate its importance. In the aim of identifying significant transcriptional regulatory networks in the liver contributing to diabetes, we have performed comprehensive active regulatory network survey by network screening in 4 weeks (w), 8-12 w, and 18-20 w Goto-Kakizaki (GK) rat liver microarray data. Results We identify active regulatory networks in GK rat by network screening in the following procedure. First, the regulatory networks are compiled by using the known binary relationships between the transcriptional factors and their regulated genes and the biological classification scheme, and second, the consistency of each regulatory network with the microarray data measured in GK rat is estimated to detect the active networks under the corresponding conditions. The comprehensive survey of the consistency between the networks and the measured data by the network screening approach in the case of non-insulin dependent diabetes in the GK rat reveals: 1. More pathways are active during inter-middle stage diabetes; 2. Inflammation, hypoxia, increased apoptosis, decreased proliferation, and altered metabolism are characteristics and display as early as 4weeks in GK strain; 3. Diabetes progression accompanies insults and compensations; 4. Nuclear receptors work in concert to maintain normal glycemic robustness system. Conclusion Notably this is the first comprehensive network screening study of non-insulin dependent diabetes in the GK rat based on high throughput data of the liver. Several important pathways have been revealed playing critical roles in the diabetes progression. Our findings also implicate that network screening is able to help us understand complex disease such as diabetes, and demonstrate the power of network systems biology approach to elucidate the essential mechanisms which would escape conventional single gene-based analysis.
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Affiliation(s)
- Huarong Zhou
- Key Laboratory of Systems Biology, SIBS-Novo Nordisk Translational Research Centre for PreDiabetes, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
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du Souich P, Fradette C. The effect and clinical consequences of hypoxia on cytochrome P450, membrane carrier proteins activity and expression. Expert Opin Drug Metab Toxicol 2011; 7:1083-100. [DOI: 10.1517/17425255.2011.586630] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Godfrey KM, Sheppard A, Gluckman PD, Lillycrop KA, Burdge GC, McLean C, Rodford J, Slater-Jefferies JL, Garratt E, Crozier SR, Emerald BS, Gale CR, Inskip HM, Cooper C, Hanson MA. Epigenetic gene promoter methylation at birth is associated with child's later adiposity. Diabetes 2011; 60:1528-34. [PMID: 21471513 PMCID: PMC3115550 DOI: 10.2337/db10-0979] [Citation(s) in RCA: 496] [Impact Index Per Article: 35.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2010] [Accepted: 02/27/2011] [Indexed: 01/03/2023]
Abstract
OBJECTIVE Fixed genomic variation explains only a small proportion of the risk of adiposity. In animal models, maternal diet alters offspring body composition, accompanied by epigenetic changes in metabolic control genes. Little is known about whether such processes operate in humans. RESEARCH DESIGN AND METHODS Using Sequenom MassARRAY we measured the methylation status of 68 CpGs 5' from five candidate genes in umbilical cord tissue DNA from healthy neonates. Methylation varied greatly at particular CpGs: for 31 CpGs with median methylation ≥5% and a 5-95% range ≥10%, we related methylation status to maternal pregnancy diet and to child's adiposity at age 9 years. Replication was sought in a second independent cohort. RESULTS In cohort 1, retinoid X receptor-α (RXRA) chr9:136355885+ and endothelial nitric oxide synthase (eNOS) chr7:150315553+ methylation had independent associations with sex-adjusted childhood fat mass (exponentiated regression coefficient [β] 17% per SD change in methylation [95% CI 4-31], P = 0.009, n = 64, and β = 20% [9-32], P < 0.001, n = 66, respectively) and %fat mass (β = 10% [1-19], P = 0.023, n = 64 and β =12% [4-20], P = 0.002, n = 66, respectively). Regression analyses including sex and neonatal epigenetic marks explained >25% of the variance in childhood adiposity. Higher methylation of RXRA chr9:136355885+, but not of eNOS chr7:150315553+, was associated with lower maternal carbohydrate intake in early pregnancy, previously linked with higher neonatal adiposity in this population. In cohort 2, cord eNOS chr7:150315553+ methylation showed no association with adiposity, but RXRA chr9:136355885+ methylation showed similar associations with fat mass and %fat mass (β = 6% [2-10] and β = 4% [1-7], respectively, both P = 0.002, n = 239). CONCLUSIONS Our findings suggest a substantial component of metabolic disease risk has a prenatal developmental basis. Perinatal epigenetic analysis may have utility in identifying individual vulnerability to later obesity and metabolic disease.
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Affiliation(s)
- Keith M Godfrey
- Institute of Developmental Sciences, University of Southampton, Southampton, UK.
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Lefebvre P, Benomar Y, Staels B. Retinoid X receptors: common heterodimerization partners with distinct functions. Trends Endocrinol Metab 2010; 21:676-83. [PMID: 20674387 DOI: 10.1016/j.tem.2010.06.009] [Citation(s) in RCA: 231] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2010] [Revised: 06/25/2010] [Accepted: 06/29/2010] [Indexed: 01/19/2023]
Abstract
Retinoid X receptors (RXRs) have been implicated in a diversity of cellular processes ranging from cellular proliferation to lipid metabolism. These pleiotropic effects stem not only from the ability of RXRs to dimerize with diverse nuclear receptors, which exert transcriptional control on specific aspects of cell biology, but also because binding of RXR ligands to heterodimers can stimulate transcriptional activation by RXR partner receptors. This signaling network is rendered more complex by the existence of different RXR isotypes (RXRα, RXRβ, RXRγ) with distinct properties that thereby modulate the transcriptional activity of RXR-containing heterodimers. This review discusses the emerging roles of RXR isotypes in the RXR signaling network and possible implications for our understanding of nuclear receptor biology and pharmacology.
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