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Xie X, Gao M, Zhao W, Li C, Zhang W, Yang J, Zhang Y, Chen E, Guo Y, Guo Z, Zhang M, Ngowi EE, Wang H, Wang X, Zhu Y, Wang Y, Li X, Yao H, Yan L, Fang F, Li M, Qiao A, Liu X. LncRNA Snhg3 aggravates hepatic steatosis via PPARγ signaling. eLife 2024; 13:RP96988. [PMID: 39436790 PMCID: PMC11495842 DOI: 10.7554/elife.96988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2024] Open
Abstract
LncRNAs are involved in modulating the individual risk and the severity of progression in metabolic dysfunction-associated fatty liver disease (MASLD), but their precise roles remain largely unknown. This study aimed to investigate the role of lncRNA Snhg3 in the development and progression of MASLD, along with the underlying mechanisms. The result showed that Snhg3 was significantly downregulated in the liver of high-fat diet-induced obesity (DIO) mice. Notably, palmitic acid promoted the expression of Snhg3 and overexpression of Snhg3 increased lipid accumulation in primary hepatocytes. Furthermore, hepatocyte-specific Snhg3 deficiency decreased body and liver weight, alleviated hepatic steatosis and promoted hepatic fatty acid metabolism in DIO mice, whereas overexpression induced the opposite effect. Mechanistically, Snhg3 promoted the expression, stability and nuclear localization of SND1 protein via interacting with SND1, thereby inducing K63-linked ubiquitination modification of SND1. Moreover, Snhg3 decreased the H3K27me3 level and induced SND1-mediated chromatin loose remodeling, thus reducing H3K27me3 enrichment at the Pparg promoter and enhancing PPARγ expression. The administration of PPARγ antagonist T0070907 improved Snhg3-aggravated hepatic steatosis. Our study revealed a new signaling pathway, Snhg3/SND1/H3K27me3/PPARγ, responsible for mice MASLD and indicates that lncRNA-mediated epigenetic modification has a crucial role in the pathology of MASLD.
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Affiliation(s)
- Xianghong Xie
- Department of Biochemistry & Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical CollegeBeijingChina
| | - Mingyue Gao
- Department of Biochemistry & Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical CollegeBeijingChina
| | - Wei Zhao
- Department of Biochemistry & Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical CollegeBeijingChina
| | - Chunmei Li
- Department of Biochemistry & Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical CollegeBeijingChina
| | - Weihong Zhang
- Department of Microbiology and Immunology, Shanxi Medical UniversityTaiyuanChina
| | - Jiahui Yang
- Department of Microbiology and Immunology, Shanxi Medical UniversityTaiyuanChina
| | - Yinliang Zhang
- Department of Biochemistry & Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical CollegeBeijingChina
| | - Enhui Chen
- Department of Pathophysiology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical CollegeBeijingChina
| | - Yanfang Guo
- Department of Biochemistry & Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical CollegeBeijingChina
| | - Zeyu Guo
- Department of Biochemistry & Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical CollegeBeijingChina
| | - Minglong Zhang
- Department of Pathophysiology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical CollegeBeijingChina
| | - Ebenezeri Erasto Ngowi
- Shanghai Institute of Materia Medica, Chinese Academy of SciencesShanghaiChina
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of SciencesZhongshanChina
| | - Heping Wang
- Department of Biochemistry & Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical CollegeBeijingChina
| | - Xiaoman Wang
- Department of Biochemistry & Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical CollegeBeijingChina
| | - Yinghan Zhu
- Department of Pathophysiology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical CollegeBeijingChina
| | - Yiting Wang
- Department of Biochemistry & Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical CollegeBeijingChina
| | - Xiaolu Li
- Department of Biochemistry & Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical CollegeBeijingChina
| | - Hong Yao
- Department of Microbiology and Immunology, Shanxi Medical UniversityTaiyuanChina
| | - Li Yan
- Department of Pathophysiology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical CollegeBeijingChina
| | - Fude Fang
- Department of Biochemistry & Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical CollegeBeijingChina
| | - Meixia Li
- State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of SciencesBeijingChina
| | - Aijun Qiao
- Shanghai Institute of Materia Medica, Chinese Academy of SciencesShanghaiChina
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of SciencesZhongshanChina
| | - Xiaojun Liu
- Department of Biochemistry & Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical CollegeBeijingChina
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Hozumi K, Sugawara K, Ishihara T, Ishihara N, Ogawa W. Effects of imeglimin on mitochondrial function, AMPK activity, and gene expression in hepatocytes. Sci Rep 2023; 13:746. [PMID: 36639407 PMCID: PMC9839736 DOI: 10.1038/s41598-023-27689-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 01/05/2023] [Indexed: 01/15/2023] Open
Abstract
Imeglimin is a recently launched antidiabetic drug structurally related to metformin. To provide insight into the pharmacological properties of imeglimin, we investigated its effects on hepatocytes and compared them with those of metformin. The effects of imeglimin on mitochondrial function in HepG2 cells or mouse primary hepatocytes were examined with an extracellular flux analyzer and on gene expression in HepG2 cells by comprehensive RNA-sequencing analysis. The effects of the drug on AMPK activity in HepG2 cells, mouse primary hepatocytes, and mouse liver were also examined. Treatment of HepG2 cells or mouse primary hepatocytes with imeglimin reduced the oxygen consumption rate coupled to ATP production. Imeglimin activated AMPK in these cells whereas the potency was smaller than metformin. Bolus administration of imeglimin in mice also activated AMPK in the liver. Whereas the effects of imeglimin and metformin on gene expression in HepG2 cells were similar overall, the expression of genes encoding proteins of mitochondrial respiratory complex III and complex I was upregulated by imeglimin but not by metformin. Our results suggest that imeglimin and metformin exert similar pharmacological effects on mitochondrial respiration, AMPK activity, and gene expression in cultured hepatocytes, whereas the two drugs differ in their effects on the expression of certain genes related to mitochondrial function.
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Affiliation(s)
- Kaori Hozumi
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Kenji Sugawara
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Takaya Ishihara
- Department of Biological Sciences, Graduate School of Science, Osaka University, Toyonaka, Japan
| | - Naotada Ishihara
- Department of Biological Sciences, Graduate School of Science, Osaka University, Toyonaka, Japan
| | - Wataru Ogawa
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
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Zheng M, Yang X, Wu Q, Gong Y, Pang N, Ge X, Nagaratnam N, Jiang P, Zhou M, Hu T, Hua H, Zheng K, Huang X, Yu Y. Butyrate Attenuates Hepatic Steatosis Induced by a High-Fat and Fiber-Deficient Diet via the Hepatic GPR41/43-CaMKII/HDAC1-CREB Pathway. Mol Nutr Food Res 2023; 67:e2200597. [PMID: 36382553 PMCID: PMC10078002 DOI: 10.1002/mnfr.202200597] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Indexed: 11/17/2022]
Abstract
SCOPE Hepatic steatosis is a major health issue that can be attenuated by a healthy diet. This study investigates the effects and molecular mechanisms of butyrate, a dietary fiber metabolite of gut microbiota, on lipid metabolism in hepatocytes. METHODS AND RESULTS This study examines the effects of butyrate (0-8 mM) on lipid metabolism in primary hepatocytes. The results show that butyrate (2 mM) consistently inhibits lipogenic genes and activates lipid oxidation-related gene expression in hepatocytes. Furthermore, butyrate modulates lipid metabolism genes, reduces fat droplet accumulation, and activates the calcium/calmodulin-dependent protein kinase II (CaMKII)/histone deacetylase 1 (HDAC1)-cyclic adenosine monophosphate response element binding protein (CREB) signaling pathway in the primary hepatocytes and liver of wild-type (WT) mice, but not in G-protein-coupled receptor 41 (GPR41) knockout and 43 (GPR43) knockout mice. This suggests that butyrate regulated hepatic lipid metabolism requires GPR41 and GPR43. Finally, the study finds that dietary butyrate supplementation (5%) ameliorates hepatic steatosis and abnormal lipid metabolism in the liver of mice fed a high-fat and fiber-deficient diet for 15 weeks. CONCLUSION This work reveals that butyrate improves hepatic lipid metabolism through the GPR41/43-CaMKII/HDAC1-CREB pathway, providing support for consideration of butyrate as a dietary supplement to prevent the progression of NAFLD induced by the Western-style diet.
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Affiliation(s)
- Mingxuan Zheng
- Jiangsu Key Laboratory of Immunity and MetabolismDepartment of Pathogen Biology and ImmunologyXuzhou Medical UniversityXuzhouJiangsu221004P. R. China
| | - Xiaoying Yang
- Jiangsu Key Laboratory of Immunity and MetabolismDepartment of Pathogen Biology and ImmunologyXuzhou Medical UniversityXuzhouJiangsu221004P. R. China
| | - Qingyuan Wu
- Jiangsu Key Laboratory of Immunity and MetabolismDepartment of Pathogen Biology and ImmunologyXuzhou Medical UniversityXuzhouJiangsu221004P. R. China
| | - Yuying Gong
- Jiangsu Key Laboratory of Immunity and MetabolismDepartment of Pathogen Biology and ImmunologyXuzhou Medical UniversityXuzhouJiangsu221004P. R. China
| | - Ning Pang
- Tianjin Third Central HospitalTianjin300170P. R. China
| | - Xing Ge
- Jiangsu Key Laboratory of Immunity and MetabolismDepartment of Pathogen Biology and ImmunologyXuzhou Medical UniversityXuzhouJiangsu221004P. R. China
| | - Nathan Nagaratnam
- Illawarra Health and Medical Research Institute(IHMRI) and School of MedicineUniversity of WollongongWollongongNSW2522Australia
| | - Pengfei Jiang
- Jiangsu Key Laboratory of Immunity and MetabolismDepartment of Pathogen Biology and ImmunologyXuzhou Medical UniversityXuzhouJiangsu221004P. R. China
| | - Menglu Zhou
- Jiangsu Key Laboratory of Immunity and MetabolismDepartment of Pathogen Biology and ImmunologyXuzhou Medical UniversityXuzhouJiangsu221004P. R. China
| | - Tao Hu
- Jiangsu Key Laboratory of Immunity and MetabolismDepartment of Pathogen Biology and ImmunologyXuzhou Medical UniversityXuzhouJiangsu221004P. R. China
| | - Hui Hua
- Jiangsu Key Laboratory of Immunity and MetabolismDepartment of Pathogen Biology and ImmunologyXuzhou Medical UniversityXuzhouJiangsu221004P. R. China
| | - Kuiyang Zheng
- Jiangsu Key Laboratory of Immunity and MetabolismDepartment of Pathogen Biology and ImmunologyXuzhou Medical UniversityXuzhouJiangsu221004P. R. China
- National Experimental Demonstration Center for Basic Medicine EducationXuzhou Medical UniversityXuzhouJiangsu221004P. R. China
| | - Xu‐Feng Huang
- Illawarra Health and Medical Research Institute(IHMRI) and School of MedicineUniversity of WollongongWollongongNSW2522Australia
| | - Yinghua Yu
- Jiangsu Key Laboratory of Immunity and MetabolismDepartment of Pathogen Biology and ImmunologyXuzhou Medical UniversityXuzhouJiangsu221004P. R. China
- Illawarra Health and Medical Research Institute(IHMRI) and School of MedicineUniversity of WollongongWollongongNSW2522Australia
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Popescu MS, Firu DM, Pădureanu V, Mărginean CM, Mitruț R, Arsene AL, Mărgăritescu DN, Calina D, Docea AO, Mitruț P. Effects of Achieving Sustained Virologic Response after Direct-Acting Antiviral Agents on Long-Term Liver Fibrosis in Diabetics vs. in Non-Diabetic Patients with Chronic Hepatitis C Infection. Biomedicines 2022; 10:2093. [PMID: 36140194 PMCID: PMC9495608 DOI: 10.3390/biomedicines10092093] [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: 08/04/2022] [Revised: 08/22/2022] [Accepted: 08/24/2022] [Indexed: 12/15/2022] Open
Abstract
Because of the prevalence of HCV worldwide as well as its undiagnosed population due to a lack of screening, HCV can be considered a modern pandemic disease. In 2016, the World Health Organization (WHO) set goals for HCV's elimination that included a 65 percent reduction in mortality and an 80 percent reduction in newly infected cases by 2030. This study is a follow-up evaluation of 80 patients who received interferon-free treatment with direct-acting agents (DAA) for chronic HCV infection between the second half of 2017 and the end of 2018. They were assessed using a FibroMax test prior to DAA administration. Two pills/day of Ombitasvir 12.5 mg/Paritaprevir 75 mg/Ritonavir 50 mg and two pills/day of Dasabuvir 250 mg were given to the patients for 8 weeks. After treatment, all 80 patients in this study achieved an SVR (sustained virologic response), and the FibroMax test was performed three years later. Our study found that successfully treating HCV infection can play a significant role in reducing fibrosis in T2DM patients. In comparison to those of ActiTest and SteatoTest, FibroMax scores showed a significantly greater reduction in T2DM patients than in treatment-naive patients.
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Affiliation(s)
- Marian-Sorin Popescu
- Department of Medical Semiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Dan-Mihai Firu
- Department of Medical Semiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Vlad Pădureanu
- Department of Medical Semiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Cristina Maria Mărginean
- Department of Medical Semiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Radu Mitruț
- Department of Cardiology, University and Emergency Hospital, 050098 Bucharest, Romania
| | - Andreea Letitia Arsene
- Department of Microbiology, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | | | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Anca Oana Docea
- Department of Toxicology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Paul Mitruț
- Department of Medical Semiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
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Banik SK, Baishya S, Das Talukdar A, Choudhury MD. Network analysis of atherosclerotic genes elucidates druggable targets. BMC Med Genomics 2022; 15:42. [PMID: 35241081 PMCID: PMC8893053 DOI: 10.1186/s12920-022-01195-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 08/18/2021] [Indexed: 11/22/2022] Open
Abstract
Background Atherosclerosis is one of the major causes of cardiovascular disease. It is characterized by the accumulation of atherosclerotic plaque in arteries under the influence of inflammatory responses, proliferation of smooth muscle cell, accumulation of modified low density lipoprotein. The pathophysiology of atherosclerosis involves the interplay of a number of genes and metabolic pathways. In traditional translation method, only a limited number of genes and pathways can be studied at once. However, the new paradigm of network medicine can be explored to study the interaction of a large array of genes and their functional partners and their connections with the concerned disease pathogenesis. Thus, in our study we employed a branch of network medicine, gene network analysis as a tool to identify the most crucial genes and the miRNAs that regulate these genes at the post transcriptional level responsible for pathogenesis of atherosclerosis. Result From NCBI database 988 atherosclerotic genes were retrieved. The protein–protein interaction using STRING database resulted in 22,693 PPI interactions among 872 nodes (genes) at different confidence score. The cluster analysis of the 872 genes using MCODE, a plug-in of Cytoscape software revealed a total of 18 clusters, the topological parameter and gene ontology analysis facilitated in the selection of four influential genes viz., AGT, LPL, ITGB2, IRS1 from cluster 3. Further, the miRNAs (miR-26, miR-27, and miR-29 families) targeting these genes were obtained by employing MIENTURNET webtool. Conclusion Gene network analysis assisted in filtering out the 4 probable influential genes and 3 miRNA families in the pathogenesis of atherosclerosis. These genes, miRNAs can be targeted to restrict the occurrence of atherosclerosis. Given the importance of atherosclerosis, any approach in the understanding the genes involved in its pathogenesis can substantially enhance the health care system. Supplementary Information The online version contains supplementary material available at 10.1186/s12920-022-01195-y.
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Affiliation(s)
- Sheuli Kangsa Banik
- Department of Life Science and Bioinformatics, Assam University, Silchar, India
| | - Somorita Baishya
- Department of Life Science and Bioinformatics, Assam University, Silchar, India
| | - Anupam Das Talukdar
- Department of Life Science and Bioinformatics, Assam University, Silchar, India
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Zhang X, Zhang Y, Zhou M, Xie Y, Dong X, Bai F, Zhang J. DPHC From Alpinia officinarum Ameliorates Oxidative Stress and Insulin Resistance via Activation of Nrf2/ARE Pathway in db/db Mice and High Glucose-Treated HepG2 Cells. Front Pharmacol 2022; 12:792977. [PMID: 35111058 PMCID: PMC8801804 DOI: 10.3389/fphar.2021.792977] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 11/23/2021] [Indexed: 12/17/2022] Open
Abstract
(R)-5-hydroxy-1,7-diphenyl-3-heptanone (DPHC) from the natural plant Alpinia officinarum has been reported to have antioxidation and antidiabetic effects. In this study, the therapeutic effect and molecular mechanism of DPHC on type 2 diabetes mellitus (T2DM) were investigated based on the regulation of oxidative stress and insulin resistance (IR) in vivo and in vitro. In vivo, the fasting blood glucose (FBG) level of db/db mice was significantly reduced with improved glucose tolerance and insulin sensitivity after 8 weeks of treatment with DPHC. In vitro, DPHC ameliorated IR because of its increasing glucose consumption and glucose uptake of IR-HepG2 cells induced by high glucose. In addition, in vitro and in vivo experiments showed that DPHC could regulate the antioxidant enzyme levels including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), thereby reducing the occurrence of oxidative stress and improving insulin resistance. Western blotting and polymerase chain reaction results showed that DPHC could promote the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), the heme oxygenase-1 (HO-1), protein kinase B (AKT), and glucose transporter type 4 (GLUT4), and reduced the phosphorylation levels of c-Jun N-terminal kinase (JNK) and insulin receptor substrate-1 (IRS-1) on Ser307 both in vivo and in vitro. These findings verified that DPHC has the potential to relieve oxidative stress and IR to cure T2DM by activating Nrf2/ARE signaling pathway in db/db mice and IR-HepG2 cells.
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Affiliation(s)
- Xuguang Zhang
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Provincial Key Laboratory for Research and Development of Tropical Herbs, Haikou Key Laboratory of Li Nationality Medicine, School of Pharmacy, Hainan Medical University, Haikou, China
| | - Yuxin Zhang
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Provincial Key Laboratory for Research and Development of Tropical Herbs, Haikou Key Laboratory of Li Nationality Medicine, School of Pharmacy, Hainan Medical University, Haikou, China
| | - Mingyan Zhou
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Provincial Key Laboratory for Research and Development of Tropical Herbs, Haikou Key Laboratory of Li Nationality Medicine, School of Pharmacy, Hainan Medical University, Haikou, China
| | - Yiqiang Xie
- Traditional Chinese Medicine (TCM) College, Hainan Medical University, Haikou, China
| | - Xiujuan Dong
- Traditional Chinese Medicine (TCM) College, Hainan Medical University, Haikou, China
| | - Feihu Bai
- The Gastroenterology Clinical Medical Center of Hainan Province, Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Junqing Zhang
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Provincial Key Laboratory for Research and Development of Tropical Herbs, Haikou Key Laboratory of Li Nationality Medicine, School of Pharmacy, Hainan Medical University, Haikou, China
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Lee CH, Chiang CF, Lin FH, Kuo FC, Su SC, Huang CL, Li PF, Liu JS, Lu CH, Hsieh CH, Hung YJ, Shieh YS. PDIA4, a new endoplasmic reticulum stress protein, modulates insulin resistance and inflammation in skeletal muscle. Front Endocrinol (Lausanne) 2022; 13:1053882. [PMID: 36619574 PMCID: PMC9816868 DOI: 10.3389/fendo.2022.1053882] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 12/09/2022] [Indexed: 12/24/2022] Open
Abstract
INTRODUCTION Endoplasmic reticulum (ER) stress has emerged as a key player in insulin resistance (IR) progression in skeletal muscle. Recent reports revealed that ER stress-induced the expression of protein disulfide isomerase family a member 4 (PDIA4), which may be involved in IR-related diseases. A previous study showed that metformin modulated ER stress-induced IR. However, it remained unclear whether metformin alleviated IR by regulating PDIA4 expression in skeletal muscle. METHODS Herein, we used palmitate-induced IR in C2C12 cells and a high-fat diet-induced IR mouse model to document the relations between metformin, IR, and PDIA4. RESULTS In C2C12 cells, palmitate-induced IR increased inflammatory cytokines and PDIA4 expression. Besides, knocking down PDIA4 decreased palmitate-induced IR and inflammation in C2C12 cells. Furthermore, metformin modulated PDIA4 expression and alleviated IR both in vitro and in vivo. In addition, serum PDIA4 concentrations are associated with IR and inflammatory cytokines levels in human subjects. DISCUSSION Thus, this study is the first to demonstrate that PDIA4 participates in the metformin-induced effects on skeletal muscle IR and indicates that PDIA4 is a potential novel therapeutic target for directly alleviating IR.
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Affiliation(s)
- Chien-Hsing Lee
- Division of Endocrinology and Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Department and Graduate Institute of Biochemistry, National Defense Medical Center, Taipei, Taiwan
- *Correspondence: Chien-Hsing Lee,
| | - Chi-Fu Chiang
- School of Dentistry, National Defense Medical Center, Taipei, Taiwan
| | - Fu-Huang Lin
- School of Public Health, National Defense Medical Center, Taipei, Taiwan
| | - Feng-Chih Kuo
- Division of Endocrinology and Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Sheng-Chiang Su
- Division of Endocrinology and Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chia-Luen Huang
- Division of Endocrinology and Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Peng-Fei Li
- Division of Endocrinology and Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Jhih-Syuan Liu
- Division of Endocrinology and Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chieh-Hua Lu
- Division of Endocrinology and Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chang-Hsun Hsieh
- Division of Endocrinology and Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Yi-Jen Hung
- Division of Endocrinology and Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Department and Graduate Institute of Biochemistry, National Defense Medical Center, Taipei, Taiwan
| | - Yi-Shing Shieh
- Division of Endocrinology and Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Department and Graduate Institute of Biochemistry, National Defense Medical Center, Taipei, Taiwan
- School of Dentistry, National Defense Medical Center, Taipei, Taiwan
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Zhang X, Chen G, Zhang J, Zhang B, Li L, Li X. Fermented noni (Morinda citrifolia L.) fruit juice improved oxidative stress and insulin resistance under the synergistic effect of Nrf2/ARE pathway and gut flora in db/db mice and HepG2 cells. Food Funct 2022; 13:8254-8273. [DOI: 10.1039/d2fo00595f] [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
Oxidative stress interferes with blood glucose homeostasis, leading to insulin resistance (IR) and hyperglycemia, which eventually induces type 2 diabetes (T2DM). Fermented noni (Morinda citrifolia L.) fruit juice (FNJ) is...
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Taxifolin and Sorghum Ethanol Extract Protect against Hepatic Insulin Resistance via the miR-195/IRS1/PI3K/AKT and AMPK Signalling Pathways. Antioxidants (Basel) 2021; 10:antiox10091331. [PMID: 34572963 PMCID: PMC8465682 DOI: 10.3390/antiox10091331] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 08/18/2021] [Accepted: 08/21/2021] [Indexed: 12/17/2022] Open
Abstract
This study aimed to evaluate the effects of taxifolin and sorghum ethanol extract on free fatty acid (FFA)-induced hepatic insulin resistance. FFA treatment decreased glucose uptake by 16.2% compared with that in the control, whereas taxifolin and sorghum ethanol extract increased the glucose uptake. Additionally, taxifolin and sorghum ethanol extract increased the expression of p-PI3K, p-IRS1, p-AKT, p-AMPK, and p-ACC in FFA-induced hepatocytes. Furthermore, FFA treatment increased the expression of miR-195. However, compared with the FFA treatment, treatment with taxifolin and sorghum ethanol extract decreased miR-195 expression in a dose-dependent manner. Taxifolin and sorghum ethanol extract enhanced p-IRS1, p-PI3K, p-AMPK, p-AKT, and p-ACC expression by suppressing miR-195 levels in miR-195 mimic- or inhibitor-transfected cells. These results indicate that taxifolin and sorghum ethanol extract attenuate insulin resistance by regulating miR-195 expression, which suggests that taxifolin and sorghum ethanol extract may be useful antidiabetic agents.
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Wu HY, Cheng Y, Jin LY, Zhou Y, Pang HY, Zhu H, Yan CC, Yan YS, Yu JE, Sheng JZ, Huang HF. Paternal obesity impairs hepatic gluconeogenesis of offspring by altering Igf2/H19 DNA methylation. Mol Cell Endocrinol 2021; 529:111264. [PMID: 33811969 DOI: 10.1016/j.mce.2021.111264] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 03/23/2021] [Accepted: 03/24/2021] [Indexed: 11/16/2022]
Abstract
Over the past four decades, the global prevalence of obesity has increased rapidly in all age ranges. Emerging evidence suggests that paternal lifestyle and environmental exposure have a crucial role in the health of offspring. Therefore, the current study investigated the impact of paternal obesity on the metabolic profile of offspring in a male mouse model of obesity. Female offspring of obese fathers fed a high-fat diet (HFD) (60% kcal fat) showed hyperglycemia because of enhanced gluconeogenesis and elevated expression of phosphoenolpyruvate carboxykinase (PEPCK), which is a key enzyme involved in the regulation of gluconeogenesis. Methylation of the Igf2/H19 imprinting control region (ICR) was dysregulated in the liver of offspring, and the sperm, of HFD fathers, suggesting that epigenetic changes in germ cells contribute to this father-offspring transmission. In addition, we explored whether H19 might regulate hepatic gluconeogenesis. Our results showed that overexpression of H19 in Hepa1-6 cells enhanced the expression of PEPCK and gluconeogenesis by promoting nuclear retention of forkhead box O1 (FOXO1), which is involved in the transcriptional regulation of Pepck. Thus, the current study suggests that paternal exposure to HFD impairs the gluconeogenesis of offspring via altered Igf2/H19 DNA methylation.
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Affiliation(s)
- Hai-Yan Wu
- The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yi Cheng
- The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Lu-Yang Jin
- The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yin Zhou
- Department of Reproductive Medicine, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Hai-Yan Pang
- The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Hong Zhu
- Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Cao-Chong Yan
- The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yi-Shang Yan
- The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jia-En Yu
- The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jian-Zhong Sheng
- The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - He-Feng Huang
- The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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11
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Yang Z, Yu Y, Sun N, Zhou L, Zhang D, Chen H, Miao W, Gao W, Zhang C, Liu C, Yang X, Wu X, Gao Y. Ginsenosides Rc, as a novel SIRT6 activator, protects mice against high fat diet induced NAFLD. J Ginseng Res 2020; 47:376-384. [DOI: 10.1016/j.jgr.2020.07.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 05/01/2020] [Accepted: 07/29/2020] [Indexed: 10/23/2022] Open
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12
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Hosooka T, Hosokawa Y, Matsugi K, Shinohara M, Senga Y, Tamori Y, Aoki C, Matsui S, Sasaki T, Kitamura T, Kuroda M, Sakaue H, Nomura K, Yoshino K, Nabatame Y, Itoh Y, Yamaguchi K, Hayashi Y, Nakae J, Accili D, Yokomizo T, Seino S, Kasuga M, Ogawa W. The PDK1-FoxO1 signaling in adipocytes controls systemic insulin sensitivity through the 5-lipoxygenase-leukotriene B 4 axis. Proc Natl Acad Sci U S A 2020; 117:11674-11684. [PMID: 32393635 PMCID: PMC7261087 DOI: 10.1073/pnas.1921015117] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Although adipocytes are major targets of insulin, the influence of impaired insulin action in adipocytes on metabolic homeostasis remains unclear. We here show that adipocyte-specific PDK1 (3'-phosphoinositide-dependent kinase 1)-deficient (A-PDK1KO) mice manifest impaired metabolic actions of insulin in adipose tissue and reduction of adipose tissue mass. A-PDK1KO mice developed insulin resistance, glucose intolerance, and hepatic steatosis, and this phenotype was suppressed by additional ablation of FoxO1 specifically in adipocytes (A-PDK1/FoxO1KO mice) without an effect on adipose tissue mass. Neither circulating levels of adiponectin and leptin nor inflammatory markers in adipose tissue differed between A-PDK1KO and A-PDK1/FoxO1KO mice. Lipidomics and microarray analyses revealed that leukotriene B4 (LTB4) levels in plasma and in adipose tissue as well as the expression of 5-lipoxygenase (5-LO) in adipose tissue were increased and restored in A-PDK1KO mice and A-PDK1/FoxO1KO mice, respectively. Genetic deletion of the LTB4 receptor BLT1 as well as pharmacological intervention to 5-LO or BLT1 ameliorated insulin resistance in A-PDK1KO mice. Furthermore, insulin was found to inhibit LTB4 production through down-regulation of 5-LO expression via the PDK1-FoxO1 pathway in isolated adipocytes. Our results indicate that insulin signaling in adipocytes negatively regulates the production of LTB4 via the PDK1-FoxO1 pathway and thereby maintains systemic insulin sensitivity.
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Affiliation(s)
- Tetsuya Hosooka
- Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, 650-0017 Kobe, Japan
| | - Yusei Hosokawa
- Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, 650-0017 Kobe, Japan
| | - Kaku Matsugi
- Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, 650-0017 Kobe, Japan
| | - Masakazu Shinohara
- Division of Epidemiology, Kobe University Graduate School of Medicine, 650-0017 Kobe, Japan
- The Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, 650-0017 Kobe, Japan
| | - Yoko Senga
- Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, 650-0017 Kobe, Japan
| | - Yoshikazu Tamori
- Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, 650-0017 Kobe, Japan
- Department of Internal Medicine, Chibune General Hospital, 555-0001 Osaka, Japan
| | - Chikako Aoki
- Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, 650-0017 Kobe, Japan
| | - Sho Matsui
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 371-8512 Maebashi, Japan
| | - Tsutomu Sasaki
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 371-8512 Maebashi, Japan
| | - Tadahiro Kitamura
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 371-8512 Maebashi, Japan
| | - Masashi Kuroda
- Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, 770-8503 Tokushima, Japan
| | - Hiroshi Sakaue
- Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, 770-8503 Tokushima, Japan
| | - Kazuhiro Nomura
- Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, 650-0017 Kobe, Japan
| | - Kei Yoshino
- Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, 650-0017 Kobe, Japan
| | - Yuko Nabatame
- Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, 650-0017 Kobe, Japan
| | - Yoshito Itoh
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, 602-8566 Kyoto, Japan
| | - Kanji Yamaguchi
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, 602-8566 Kyoto, Japan
| | - Yoshitake Hayashi
- Division of Molecular Medicine and Medical Genetics, Kobe University Graduate School of Medicine, 650-0017 Kobe, Japan
| | - Jun Nakae
- Department of Internal Medicine, Keio University School of Medicine, 160-8582 Tokyo, Japan
| | - Domenico Accili
- Department of Medicine and Naomi Berrie Diabetes Center, Columbia University, NY 10032
| | - Takehiko Yokomizo
- Department of Biochemistry, Juntendo University School of Medicine, 113-8421 Tokyo, Japan
| | - Susumu Seino
- Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, 650-0017 Kobe, Japan
| | - Masato Kasuga
- The Institute for Adult Diseases, Asahi Life Foundation, 103-0002 Tokyo, Japan
| | - Wataru Ogawa
- Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, 650-0017 Kobe, Japan;
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13
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Gao Z, Zhang J, Wei L, Yang X, Zhang Y, Cheng B, Yang Z, Gao W, Song C, Miao W, Williams K, Liu C, Xu Q, Chang Y, Gao Y. The Protective Effects of Imperatorin on Acetaminophen Overdose-Induced Acute Liver Injury. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:8026838. [PMID: 32454943 PMCID: PMC7243017 DOI: 10.1155/2020/8026838] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 12/23/2019] [Accepted: 12/28/2019] [Indexed: 12/11/2022]
Abstract
Acetaminophen (APAP) toxicity leads to severe acute liver injury (ALI) by inducing excessive oxidative stress, inflammatory response, and hepatocyte apoptosis. Imperatorin (IMP) is a furanocoumarin from Angelica dahurica, which has antioxidant and anti-inflammatory effects. However, its potential to ameliorate ALI is unknown. In this study, APAP-treated genetic knockout of Farnesoid X receptor (FXR) and Sirtuin 1 (SIRT1) mice were used for research. The results revealed that IMP could improve the severity of liver injury and inhibit the increase of proinflammatory cytokines, oxidative damage, and apoptosis induced by overdose APAP in an FXR-dependent manner. We also found that IMP enhanced the activation and translocation of FXR by increasing the expression of SIRT1 and the phosphorylation of AMPK. Besides, single administration of IMP at 4 h after APAP injection can also improve necrotic areas and serum transaminase, indicating that IMP have both preventive and therapeutic effects. Taken together, it is the first time to demonstrate that IMP exerts protective effects against APAP overdose-induced hepatotoxicity by stimulating the SIRT1-FXR pathway. These findings suggest that IMP is a potential therapeutic candidate for ALI, offering promise for the treatment of hepatotoxicity associated with APAP overdose.
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Affiliation(s)
- Zhao Gao
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Guangdong Institute of Sports Science, Guangzhou, China
| | - Jiecheng Zhang
- Department of Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Li Wei
- The Second Clinical Medical College, Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
| | - Xingping Yang
- The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Yuan Zhang
- Guangdong Institute of Sports Science, Guangzhou, China
| | - Bo Cheng
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zehong Yang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Weihang Gao
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chunhui Song
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wei Miao
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Kevin Williams
- Division of Hypothalamic Research, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Changhui Liu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qin Xu
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yongsheng Chang
- Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Immune Micro-Environment and Disease (Ministry of Education), Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Yong Gao
- The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
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14
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Cheng B, Gao W, Wu X, Zheng M, Yu Y, Song C, Miao W, Yang Z, He Y, Liu C, Yang W, Yang X, Li Y, Zhang F, Gao Y. Ginsenoside Rg2 Ameliorates High-Fat Diet-Induced Metabolic Disease through SIRT1. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:4215-4226. [PMID: 32181656 DOI: 10.1021/acs.jafc.0c00833] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Ginsenoside Rg2 has been previously reported to reduce glucose production and adipogenesis in adipose tissue. However, the effects of ginsenosides Rg2 on hepatic lipid metabolism remain vacant. In this study, we found that ginsenoside Rg2 treatment significantly attenuated oleic acid and palmitic acid (OA&PA)-induced intracellular lipid deposition and oxidative stress in mouse primary hepatocytes. C57BL/6J mice that are fed with a high-fat diet (HFD) and treated with ginsenosides Rg2 displayed decreased body weight, reversed hepatic steatosis, and improved glucose tolerance and insulin sensitivity. Ginsenoside Rg2 administration significantly ameliorated HFD-induced hepatic oxidative stress and apoptosis. Moreover, Ginsenoside Rg2 had a good affinity with Sirtuin1 (SIRT1) and regulated its expression in vivo and in vitro. Deficiency of SIRT1 eliminated the therapeutic effect of ginsenoside Rg2 on lipid accumulation and overproduction of reactive oxygen species (ROS) in OA&PA-induced mice primary hepatocytes. Ginsenoside Rg2 treatment failed to alter the lipid and glucose disorder in hepatic SIRT1 deficient mice feeding on HFD. SIRT1 deficiency dissolves the therapeutic effect of ginsenoside Rg2 on oxidative stress and hepatocyte apoptosis induced by HFD. In summary, ginsenoside Rg2 plays a therapeutic role in HFD-induced hepatosteatosis of mice by decreasing the lipogenesis process and improving antioxidant capacity in an SIRT1-dependent manner.
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Affiliation(s)
- Bo Cheng
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
- Division of Hypothalamic Research, University of Texas Southwestern Medical Center at Dallas, Dallas Texas, 75390-9077, United States
| | - Weihang Gao
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Xiaojie Wu
- Central Lab of Binzhou People's Hospital, Shandong 256610, China
| | - Mingxuan Zheng
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou 221004, China
| | - Yuanyuan Yu
- Institute of Science and Technology, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Chunhui Song
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Wei Miao
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Zehong Yang
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Yuqing He
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Changhui Liu
- School Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Wangyin Yang
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China
| | - Xiaoying Yang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou 221004, China
| | - Yanwu Li
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Fang Zhang
- Central Lab of Binzhou People's Hospital, Shandong 256610, China
| | - Yong Gao
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
- Division of Hypothalamic Research, University of Texas Southwestern Medical Center at Dallas, Dallas Texas, 75390-9077, United States
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15
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Wu X, Zheng H, Yang R, Luan X, Zhang L, Jin Q, Jin Y, Xue J. Mouse trefoil factor 3 ameliorated high-fat-diet-induced hepatic steatosis via increasing peroxisome proliferator-activated receptor-α-mediated fatty acid oxidation. Am J Physiol Endocrinol Metab 2019; 317:E436-E445. [PMID: 31211621 DOI: 10.1152/ajpendo.00454.2018] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Hepatic trefoil factor 3 (Tff3) was identified as a potential protein for the treatment of diabetes, yet the effect of Tff3 on nonalcoholic fatty liver disease (NAFLD) has never been explored. Here, we found that the expression of hepatic Tff3 was significantly decreased in NAFLD mice models, suggesting that Tff3 was a potential marker gene for NAFLD. Restoring the expression of Tff3 in the liver of NAFLD mice, including diabetic (db), obese (ob/ob), and diet-induced obese mice, with adenovirus-mediated Tff3 (Ad-Tff3) apparently attenuates the fatty liver phenotype. In contrast, adenovirus-mediated knockdown of Tff3 (Ad-shTff3) in C57BL/6J mice results in an obvious fatty liver phenotype. Furthermore, our molecular experiments indicated that hepatic Tff3 could alleviate hepatic steatosis via upregulating the expression of peroxisome proliferator-activated receptor-α (PPARα) directly, thereby enhancing the fatty acid oxidation process in the liver. Notably, we found that Tff3 attenuates the fatty liver phenotype independent of modulation of lipogenesis and improves the capacity of anti-inflammation. Overall, our results suggested that hepatic Tff3 could be effectively used as a potential therapy target for the treatment of NAFLD.
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Affiliation(s)
- Xiaojie Wu
- Department of Immunology, Binzhou Medical University, Yantai, China
- Central Laboratory, Binzhou People's Hospital, Binzhou, China
| | - Hongze Zheng
- Central Laboratory, Binzhou People's Hospital, Binzhou, China
| | - Rui Yang
- Department of Immunology, Binzhou Medical University, Yantai, China
| | - Xiying Luan
- Department of Immunology, Binzhou Medical University, Yantai, China
| | - Lingyun Zhang
- Department of Endocrinology, Yantai Affiliated Hospital, Binzhou Medical University, Yantai, China
| | - Qingsong Jin
- Department of Endocrinology, Yantai Affiliated Hospital, Binzhou Medical University, Yantai, China
| | - Yongjun Jin
- Department of Endocrinology, Yantai Affiliated Hospital, Binzhou Medical University, Yantai, China
| | - Jiangnan Xue
- Department of Immunology, Binzhou Medical University, Yantai, China
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16
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Hypoglycemic effects of esculeoside A are mediated via activation of AMPK and upregulation of IRS-1. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2019; 19:136. [PMID: 31215434 PMCID: PMC6582491 DOI: 10.1186/s12906-019-2543-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 06/03/2019] [Indexed: 02/06/2023]
Abstract
Background Tomato fruit (Lycopersicon esculentum Mill.) has been suggested to be useful for the prevention of diabetes. Esculeoside A is the main saponin compounds in tomatoes. This study investigated the hypoglycemic effects and the underlying mechanism of esculeoside A in C57BLKS/Leprdb (db/db) mice. Methods Wild-type C57BLKS (db/dm) mice were used in the db/dm mouse group and db/db mice were randomly divided into 2 groups: untreated and treated db/db mouse groups. Esculeoside A (100 mg/kg) was administered by gavage for 56 days to the treated db/db mouse group. Distilled water was administered to the db/dm mouse group and the untreated db/db mouse group. The blood and liver biochemical parameters and the expression of liver insulin signaling-related proteins were examined. Results The results showed that esculeoside A reduced the fasting blood glucose (FBG) levels and improved the glucose tolerance. Further investigation revealed that hepatic protein expressions of total AMP-activated protein kinase (T-AMPK), phosphorylated AMP-activated protein kinase (p-AMPK), insulin receptor substrate-1 (IRS-1), and glucokinase (GCK) were significantly upregulated after esculeoside A treatment. In contrast, the hepatic protein expression of phosphoenolpyruvate carboxykinase (PEPCK) was significantly downregulated by esculeoside A treatment. Conclusion These findings suggested that esculeoside A has a potential of alleviating the metabolic abnormalities in db/db mice via regulation of AMPK/IRS-1 pathway. Our findings supported a possible application of esculeoside A as a functional supplement for diabetes treatment.
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17
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Sato T, Muramatsu N, Ito Y, Yamamoto Y, Nagasawa T. L-Lysine Attenuates Hepatic Steatosis in Senescence-Accelerated Mouse Prone 8 Mice. J Nutr Sci Vitaminol (Tokyo) 2018; 64:192-199. [PMID: 29962430 DOI: 10.3177/jnsv.64.192] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Non-alcoholic hepatic steatosis is a phenotype of metabolic syndrome, and aging is a risk factor for this condition. Senescence-accelerated mouse prone 8 (SAMP8) is a murine model for studying aging-associated disorders. We here investigated the effect of dietary supplementation with L-lysine (Lys) on non-alcoholic hepatic steatosis in SAMP8 mice. Triglyceride (TG) and cholesterol (Chol) accumulated in the livers of SAMP8 mice fed a standard diet at 36 wk of age. However, intake of a Lys-rich diet for 2 mo prevented the accumulation of TG and Chol in the liver. Plasma alanine aminotransferase activity, an index of liver injury, was decreased by Lys. The mRNA expression levels of peroxisome proliferator-activated receptor gamma coactivator 1-α and carnitine palmitoyltransferase 1a, which regulate β-oxidation, were increased in the livers of SAMP8 mice fed the Lys-rich diet. Taken together, our study suggests dietary intake of Lys prevents hepatic steatosis by stimulating β-oxidation in SAMP8 mice.
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Affiliation(s)
- Tomonori Sato
- Department of Bioresources Science, The United Graduate School of Agricultural Sciences, Iwate University
| | - Nao Muramatsu
- Department of Biological Chemistry and Food Science, Graduate School of Agriculture, Iwate University
| | - Yoshiaki Ito
- Department of Bioresources Science, The United Graduate School of Agricultural Sciences, Iwate University.,Department of Biological Chemistry and Food Science, Graduate School of Agriculture, Iwate University
| | - Yoshio Yamamoto
- Laboratory of Veterinary Anatomy and Cell Biology, Faculty of Agriculture, Iwate University.,Department of Basic Veterinary Science, United Graduate School of Veterinary Science, Gifu University
| | - Takashi Nagasawa
- Department of Bioresources Science, The United Graduate School of Agricultural Sciences, Iwate University.,Department of Biological Chemistry and Food Science, Graduate School of Agriculture, Iwate University
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18
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Gao M, Zhao W, Li C, Xie X, Li M, Bi Y, Fang F, Du Y, Liu X. Spermidine ameliorates non-alcoholic fatty liver disease through regulating lipid metabolism via AMPK. Biochem Biophys Res Commun 2018; 505:93-98. [DOI: 10.1016/j.bbrc.2018.09.078] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Accepted: 09/12/2018] [Indexed: 12/12/2022]
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19
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PHD3 regulates glucose metabolism by suppressing stress-induced signalling and optimising gluconeogenesis and insulin signalling in hepatocytes. Sci Rep 2018; 8:14290. [PMID: 30250231 PMCID: PMC6155226 DOI: 10.1038/s41598-018-32575-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 09/11/2018] [Indexed: 02/06/2023] Open
Abstract
Glucagon-mediated gene transcription in the liver is critical for maintaining glucose homeostasis. Promoting the induction of gluconeogenic genes and blocking that of insulin receptor substrate (Irs)2 in hepatocytes contributes to the pathogenesis of type 2 diabetes. However, the molecular mechanism by which glucagon signalling regulates hepatocyte metabolism is not fully understood. We previously showed that a fasting-inducible signalling module consisting of general control non-repressed protein 5, co-regulator cAMP response element-binding protein binding protein/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2, and protein kinase A is required for glucagon-induced transcription of gluconeogenic genes. The present study aimed to identify the downstream effectors of this module in hepatocytes by examining glucagon-induced potential target genes. One of these genes was prolyl hydroxylase domain (PHD)3, which suppressed stress signalling through inhibition of the IκB kinase-nuclear factor-κB pathway in a proline hydroxylase-independent manner to maintain insulin signalling. PHD3 was also required for peroxisome proliferator-activated receptor γ coactivator 1α-induced gluconeogenesis, which was dependent on proline hydroxylase activity, suggesting that PHD3 regulates metabolism in response to glucagon as well as insulin. These findings demonstrate that glucagon-inducible PHD3 regulates glucose metabolism by suppressing stress signalling and optimising gluconeogenesis and insulin signalling in hepatocytes.
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20
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Honma M, Sawada S, Ueno Y, Murakami K, Yamada T, Gao J, Kodama S, Izumi T, Takahashi K, Tsukita S, Uno K, Imai J, Kakazu E, Kondo Y, Mizuno K, Kawagishi N, Shimosegawa T, Katagiri H. Selective insulin resistance with differential expressions of IRS-1 and IRS-2 in human NAFLD livers. Int J Obes (Lond) 2018; 42:1544-1555. [PMID: 29717275 PMCID: PMC6160396 DOI: 10.1038/s41366-018-0062-9] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 01/31/2018] [Accepted: 02/13/2018] [Indexed: 12/30/2022]
Abstract
BACKGROUND/OBJECTIVE Insulin signals, via the regulation of key enzyme expression, both suppress gluconeogenesis and enhance lipid synthesis in the liver. Animal studies have revealed insulin signaling favoring gluconeogenesis suppression to be selectively impaired in steatotic livers. However, whether, and if so how, such selective insulin resistance occurs in human steatotic livers remains unknown. Our aim was to investigate selective insulin resistance in human livers with non-alcoholic fatty liver disease (NAFLD). SUBJECTS/METHODS We examined mRNA expressions of key molecules for insulin signaling, gluconeogenesis and lipogenesis in human liver biopsy samples obtained from 51 non-diabetic subjects: 9 healthy controls and 42 NAFLD patients, and analyzed associations of these molecules with each other and with detailed pathological and clinical biochemistry data. RESULTS In NAFLD patients, insulin receptor substrate (IRS)-2 expression was decreased, while those of key enzymes for gluconeogenesis were increased. These alterations of IRS-2 and gluconeogenesis enzymes were induced both in simple steatosis (SS) and non-alcoholic steatohepatitis (NASH), while these expression levels did not differ between SS and NASH. Furthermore, alterations in the expressions of IRS-2 and gluconeogenesis enzymes showed strong negative correlations and were concurrently induced in the early histological stage of NAFLD. In contrast, fatty acid synthase (FAS) expression was not decreased in NAFLD, despite IRS-2 downregulation, but correlated strongly with IRS-1 expression. Furthermore, no histological scores were associated with these molecules. Thus, IRS-1 signaling, which is not impaired in NAFLD, appears to modulate FAS expression. CONCLUSION These analyses revealed that selective insulin resistance is present in human NAFLD livers and occurs in its early phases. The effect of insulin, during the IRS step, on gene expressions for lipogenesis and gluconeogenesis are apparently distinct and preferential downregulation of IRS-2 may contribute to selective resistance to the suppressive effects of insulin on gluconeogenesis.
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Affiliation(s)
- Midori Honma
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shojiro Sawada
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan.
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
- Japan Agency for Medical Research and Development, CREST, Tokyo, Japan
| | - Keigo Murakami
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tetsuya Yamada
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
- Center for Metabolic Diseases, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Junhong Gao
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shinjiro Kodama
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomohito Izumi
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kei Takahashi
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Sohei Tsukita
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | | | | | - Eiji Kakazu
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yasuteru Kondo
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kei Mizuno
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Naoki Kawagishi
- Division of Transplantation, Reconstruction and Endoscopic Surgery, Tohoku University Hospital, Sendai, Japan
| | - Tooru Shimosegawa
- Center for Metabolic Diseases, Tohoku University Graduate School of Medicine, Sendai, Japan
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hideki Katagiri
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan.
- Japan Agency for Medical Research and Development, CREST, Tokyo, Japan.
- Center for Metabolic Diseases, Tohoku University Graduate School of Medicine, Sendai, Japan.
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21
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Effects of Sleeve Gastrectomy on Nonalcoholic Fatty Liver Disease in an Obese Rat Model. Obes Surg 2017; 28:1532-1539. [PMID: 29280057 DOI: 10.1007/s11695-017-3052-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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22
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Chao HW, Doi M, Fustin JM, Chen H, Murase K, Maeda Y, Hayashi H, Tanaka R, Sugawa M, Mizukuchi N, Yamaguchi Y, Yasunaga JI, Matsuoka M, Sakai M, Matsumoto M, Hamada S, Okamura H. Circadian clock regulates hepatic polyploidy by modulating Mkp1-Erk1/2 signaling pathway. Nat Commun 2017; 8:2238. [PMID: 29269828 PMCID: PMC5740157 DOI: 10.1038/s41467-017-02207-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 11/13/2017] [Indexed: 01/08/2023] Open
Abstract
Liver metabolism undergoes robust circadian oscillations in gene expression and enzymatic activity essential for liver homeostasis, but whether the circadian clock controls homeostatic self-renewal of hepatocytes is unknown. Here we show that hepatocyte polyploidization is markedly accelerated around the central vein, the site of permanent cell self-renewal, in mice deficient in circadian Period genes. In these mice, a massive accumulation of hyperpolyploid mononuclear and binuclear hepatocytes occurs due to impaired mitogen-activated protein kinase phosphatase 1 (Mkp1)-mediated circadian modulation of the extracellular signal-regulated kinase (Erk1/2) activity. Time-lapse imaging of hepatocytes suggests that the reduced activity of Erk1/2 in the midbody during cytokinesis results in abscission failure, leading to polyploidization. Manipulation of Mkp1 phosphatase activity is sufficient to change the ploidy level of hepatocytes. These data provide clear evidence that the Period genes not only orchestrate dynamic changes in metabolic activity, but also regulate homeostatic self-renewal of hepatocytes through Mkp1-Erk1/2 signaling pathway. Circadian clock regulates hepatic gene expression and functions. Here Chao et al. show that alteration of circadian clock genes by Period deletion induces polyploidy in hepatocytes due to impaired regulation of Erk signaling by mitogen-activated protein kinase phosphatase 1.
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Affiliation(s)
- Hsu-Wen Chao
- Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan.,Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan
| | - Masao Doi
- Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan
| | - Jean-Michel Fustin
- Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan
| | - Huatao Chen
- Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan
| | - Kimihiko Murase
- Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan.,The Department of Respiratory Care and Sleep Control Medicine, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan
| | - Yuki Maeda
- Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan
| | - Hida Hayashi
- Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan
| | - Rina Tanaka
- Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan
| | - Maho Sugawa
- Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan
| | - Naoki Mizukuchi
- Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan
| | - Yoshiaki Yamaguchi
- Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan
| | - Jun-Ichirou Yasunaga
- Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, 606-8507, Japan
| | - Masao Matsuoka
- Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, 606-8507, Japan.,Department of Hematology, Rheumatology, and Infectious Diseases, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, 860-8556, Japan
| | - Mashito Sakai
- Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan
| | - Michihiro Matsumoto
- Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan
| | | | - Hitoshi Okamura
- Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan.
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Geng C, Xu H, Zhang Y, Gao Y, Li M, Liu X, Gao M, Wang X, Liu X, Fang F, Chang Y. Retinoic acid ameliorates high-fat diet-induced liver steatosis through sirt1. SCIENCE CHINA-LIFE SCIENCES 2017; 60:1234-1241. [PMID: 28667519 DOI: 10.1007/s11427-016-9027-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 03/17/2017] [Indexed: 12/17/2022]
Abstract
In this study, treatment of C57BL/6J (wild type, WT) mice fed a high-fat diet (HFD) with retinoic acid (RA) decreased body weight and subcutaneous and visceral fat content, reversed the apparent hepatosteatosis, and reduced hepatic intracellular triglyceride and serum alanine transaminase (ALT) and aspartate aminotransferase (AST) concentrations. Moreover, RA treatment improved glucose tolerance and insulin sensitivity in WT mice fed a HFD. However, these RA-induced effects in WT mice fed a HFD were alleviated in liver specific Sirtuin 1 (Sirt1) deficient (LKO) mice fed a HFD. Furthermore, RA also could not improve glucose tolerance and insulin sensitivity in LKO mice fed a HFD. The mechanism studies indicated that RA indeed increased the expression of hepatic Sirt1 and superoxide dismutase 2 (Sod2), and inhibited the expression of sterol regulatory element binding protein 1c (Srebp-1c) in WT mice in vivo and in vitro. RA decreased mitochondrial reactive oxygen species (ROS) production in WT primary hepatocytes and increased mitochondrial DNA (mtDNA) copy number in WT mice liver. However, these RA-mediated molecular effects were also abolished in the liver and primary hepatocytes from LKO mice. In summary, RA protected against HFD-induced hepatosteatosis by decreasing Srebp-1c expression and improving antioxidant capacity through a Sirt1-mediated mechanism.
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Affiliation(s)
- Chao Geng
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Haifeng Xu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Yinliang Zhang
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Yong Gao
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Meixia Li
- State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Xiaoyan Liu
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Mingyue Gao
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Xiaojuan Wang
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Xiaojun Liu
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing, 100005, China.
| | - Fude Fang
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing, 100005, China.
| | - Yongsheng Chang
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing, 100005, China.
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Horita S, Nakamura M, Suzuki M, Satoh N, Suzuki A, Homma Y, Nangaku M. The role of renal proximal tubule transport in the regulation of blood pressure. Kidney Res Clin Pract 2017; 36:12-21. [PMID: 28428931 PMCID: PMC5331971 DOI: 10.23876/j.krcp.2017.36.1.12] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 10/18/2016] [Accepted: 12/05/2016] [Indexed: 12/15/2022] Open
Abstract
The electrogenic sodium/bicarbonate cotransporter 1 (NBCe1) on the basolateral side of the renal proximal tubule plays a pivotal role in systemic acid-base homeostasis. Mutations in the gene encoding NBCe1 cause severe proximal renal tubular acidosis accompanied by other extrarenal symptoms. The proximal tubule reabsorbs most of the sodium filtered in the glomerulus, contributing to the regulation of plasma volume and blood pressure. NBCe1 and other sodium transporters in the proximal tubule are regulated by hormones, such as angiotensin II and insulin. Angiotensin II is probably the most important stimulator of sodium reabsorption. Proximal tubule AT1A receptor is crucial for the systemic pressor effect of angiotensin II. In rodents and rabbits, the effect on proximal tubule NBCe1 is biphasic; at low concentration, angiotensin II stimulates NBCe1 via PKC/cAMP/ERK, whereas at high concentration, it inhibits NBCe1 via NO/cGMP/cGKII. In contrast, in human proximal tubule, angiotensin II has a dose-dependent monophasic stimulatory effect via NO/cGMP/ERK. Insulin stimulates the proximal tubule sodium transport, which is IRS2-dependent. We found that in insulin resistance and overt diabetic nephropathy, stimulatory effect of insulin on proximal tubule transport was preserved. Our results suggest that the preserved stimulation of the proximal tubule enhances sodium reabsorption, contributing to the pathogenesis of hypertension with metabolic syndrome. We describe recent findings regarding the role of proximal tubule transport in the regulation of blood pressure, focusing on the effects of angiotensin II and insulin.
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Affiliation(s)
- Shoko Horita
- Department of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan
| | - Motonobu Nakamura
- Department of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan
| | - Masashi Suzuki
- Department of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan
| | - Nobuhiko Satoh
- Department of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan
| | - Atsushi Suzuki
- Department of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan
| | - Yukio Homma
- Department of Urology, The University of Tokyo Hospital, Tokyo, Japan
| | - Masaomi Nangaku
- Department of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan
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25
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Luque GM, Lopez-Vicchi F, Ornstein AM, Brie B, De Winne C, Fiore E, Perez-Millan MI, Mazzolini G, Rubinstein M, Becu-Villalobos D. Chronic hyperprolactinemia evoked by disruption of lactotrope dopamine D2 receptors impacts on liver and adipocyte genes related to glucose and insulin balance. Am J Physiol Endocrinol Metab 2016; 311:E974-E988. [PMID: 27802964 DOI: 10.1152/ajpendo.00200.2016] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Revised: 10/21/2016] [Accepted: 10/23/2016] [Indexed: 12/21/2022]
Abstract
We studied the impact of high prolactin titers on liver and adipocyte gene expression related to glucose and insulin homeostasis in correlation with obesity onset. To that end we used mutant female mice that selectively lack dopamine type 2 receptors (D2Rs) from pituitary lactotropes (lacDrd2KO), which have chronic high prolactin levels associated with increased body weight, marked increments in fat depots, adipocyte size, and serum lipids, and a metabolic phenotype that intensifies with age. LacDrd2KO mice of two developmental ages, 5 and 10 mo, were used. In the first time point, obesity and increased body weight are marginal, although mice are hyperprolactinemic, whereas at 10 mo there is marked adiposity with a 136% increase in gonadal fat and a 36% increase in liver weight due to lipid accumulation. LacDrd2KO mice had glucose intolerance, hyperinsulinemia, and impaired insulin response to glucose already in the early stages of obesity, but changes in liver and adipose tissue transcription factors were time and tissue dependent. In chronic hyperprolactinemic mice liver Prlr were upregulated, there was liver steatosis, altered expression of the lipogenic transcription factor Chrebp, and blunted response of Srebp-1c to refeeding at 5 mo of age, whereas no effect was observed in the glycogenesis pathway. On the other hand, in adipose tissue a marked decrease in lipogenic transcription factor expression was observed when morbid obesity was already settled. These adaptive changes underscore the role of prolactin signaling in different tissues to promote energy storage.
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Affiliation(s)
- Guillermina María Luque
- Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
| | - Felicitas Lopez-Vicchi
- Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
| | - Ana María Ornstein
- Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
| | - Belén Brie
- Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
| | - Catalina De Winne
- Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
| | - Esteban Fiore
- Laboratorio de Terapia Génica, Instituto de Investigaciones en Medicina Traslacional (IIMT-CONICET), Universidad Austral, Buenos Aires, Argentina; and
| | - Maria Inés Perez-Millan
- Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
| | - Guillermo Mazzolini
- Laboratorio de Terapia Génica, Instituto de Investigaciones en Medicina Traslacional (IIMT-CONICET), Universidad Austral, Buenos Aires, Argentina; and
| | - Marcelo Rubinstein
- Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, CONICET, and Departamento de Fisiología, y Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, University of Buenos Aires, Argentina
| | - Damasia Becu-Villalobos
- Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina;
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26
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Sakai M, Tujimura-Hayakawa T, Yagi T, Yano H, Mitsushima M, Unoki-Kubota H, Kaburagi Y, Inoue H, Kido Y, Kasuga M, Matsumoto M. The GCN5-CITED2-PKA signalling module controls hepatic glucose metabolism through a cAMP-induced substrate switch. Nat Commun 2016; 7:13147. [PMID: 27874008 PMCID: PMC5121418 DOI: 10.1038/ncomms13147] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 09/08/2016] [Indexed: 01/31/2023] Open
Abstract
Hepatic gluconeogenesis during fasting results from gluconeogenic gene activation via the glucagon-cAMP-protein kinase A (PKA) pathway, a process whose dysregulation underlies fasting hyperglycemia in diabetes. Such transcriptional activation requires epigenetic changes at promoters by mechanisms that have remained unclear. Here we show that GCN5 functions both as a histone acetyltransferase (HAT) to activate fasting gluconeogenesis and as an acetyltransferase for the transcriptional co-activator PGC-1α to inhibit gluconeogenesis in the fed state. During fasting, PKA phosphorylates GCN5 in a manner dependent on the transcriptional coregulator CITED2, thereby increasing its acetyltransferase activity for histone and attenuating that for PGC-1α. This substrate switch concomitantly promotes both epigenetic changes associated with transcriptional activation and PGC-1α-mediated coactivation, thereby triggering gluconeogenesis. The GCN5-CITED2-PKA signalling module and associated GCN5 substrate switch thus serve as a key driver of gluconeogenesis. Disruption of this module ameliorates hyperglycemia in obese diabetic animals, offering a potential therapeutic strategy for such conditions.
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Affiliation(s)
- Mashito Sakai
- Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan
| | - Tomoko Tujimura-Hayakawa
- Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan
| | - Takashi Yagi
- Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.,Department of Bioregulation, Nippon Medical School, 1-396 Kosugi-machi, Nakahara-ku, Kawasaki 211-8533, Japan
| | - Hiroyuki Yano
- Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.,Department of Bioregulation, Nippon Medical School, 1-396 Kosugi-machi, Nakahara-ku, Kawasaki 211-8533, Japan
| | - Masaru Mitsushima
- Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan
| | - Hiroyuki Unoki-Kubota
- Department of Diabetic Complications, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan
| | - Yasushi Kaburagi
- Department of Diabetic Complications, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan
| | - Hiroshi Inoue
- Metabolism and Nutrition Research Unit, Innovative Integrated Bio-research Core, Institute for Frontier Science Initiative, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan
| | - Yoshiaki Kido
- Division of Medical Chemistry, Department of Metabolism and Disease, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Suma-ku, Kobe 654-0142, Japan.,Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan
| | - Masato Kasuga
- National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan
| | - Michihiro Matsumoto
- Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan
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27
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Zhang Y, Geng C, Liu X, Li M, Gao M, Liu X, Fang F, Chang Y. Celastrol ameliorates liver metabolic damage caused by a high-fat diet through Sirt1. Mol Metab 2016; 6:138-147. [PMID: 28123944 PMCID: PMC5220393 DOI: 10.1016/j.molmet.2016.11.002] [Citation(s) in RCA: 93] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2016] [Revised: 10/31/2016] [Accepted: 11/08/2016] [Indexed: 12/11/2022] Open
Abstract
Objective Celastrol was recently identified as a potential novel treatment for obesity. However, the effect of Celastrol on nonalcoholic fatty liver disease (NAFLD) remains elusive. The aim of this study is to evaluate the role of Celastrol in NAFLD. Methods Functional studies were performed using wild-type C57BL/6J (WT) mice and liver specific Sirt1-deficient (LKO) mice. The molecular mechanism was explored in primary mouse liver and primary hepatocytes. Results When WT mice receiving a high-fat diet (HFD) were treated with Celastrol, reductions in body weight, subcutaneous and visceral fat content, and liver lipid droplet formation were observed, along with reduced hepatic intracellular triglyceride and serum triglyceride, free fatty acid, and ALT concentrations. Furthermore, Celastrol decreased hepatic sterol regulatory element binding protein 1c (Srebp-1c) expression, enhanced the phosphorylation of hepatic AMP-activated protein kinase α (AMPKα), and increased the expression of hepatic serine–threonine liver kinase B1 (LKB1). Additionally, Celastrol treatment improved glucose tolerance and insulin sensitivity in WT mice fed the HFD. Celastrol administration also improved the anti-inflammatory and anti-oxidative status by inhibiting nuclear factor kappa B (NFκB) activity and the mRNA levels of proinflammatory cytokines and increasing mitochondrial DNA copy number and anti-oxidative stress genes expression in WT mice liver, in vivo and in vitro. Moreover, Celastrol induced hepatic Sirt1 expression in WT mice, in vivo and in vitro. These Celastrol-mediated protective effects in WT mice fed a HFD were abolished in LKO mice fed a HFD. It was more interesting that Celastrol aggravated HFD-induced liver damage in LKO mice fed a HFD by inhibiting the phosphorylation of AMPKα and boosting the translocation of NFκB into the nucleus, thereby resulting in the increase of Srebp-1c expression and the mRNA levels of liver proinflammatory cytokines. Conclusions Celastrol ameliorates NAFLD by decreasing lipid synthesis and improving the anti-oxidative and anti-inflammatory status. And Sirt1 has an important role in Celastrol-ameliorating liver metabolic damage caused by HFD.
Celastrol alleviates high-fat diet-induced hepatic steatosis in wild type mice. Celastrol improves anti-inflammatory and antioxidant status in wild type mice. Celastrol induces the expression of hepatic Sirt1 in wild type mice. Celastrol promotes AMPKα phosphorylation in liver specific Sirt1-deficient mice. Celastrol increases the activity of NFκB in liver specific Sirt1-deficient mice.
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Affiliation(s)
- Yinliang Zhang
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100005, China
| | - Chao Geng
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100005, China
| | - Xiaoyan Liu
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100005, China
| | - Meixia Li
- State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Mingyue Gao
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100005, China
| | - Xiaojun Liu
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100005, China.
| | - Fude Fang
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100005, China.
| | - Yongsheng Chang
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100005, China.
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28
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Affiliation(s)
- Loranne Agius
- Institutes of Cellular Medicine and Ageing and Health, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH United Kingdom;
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Gao LL, Li M, Wang Q, Liu SA, Zhang JQ, Cheng J. HCBP6 Modulates Triglyceride Homeostasis in Hepatocytes Via the SREBP1c/FASN Pathway. J Cell Biochem 2016; 116:2375-84. [PMID: 25855506 DOI: 10.1002/jcb.25188] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2015] [Accepted: 04/03/2015] [Indexed: 02/06/2023]
Abstract
Hypertriglyceridemia leads to liver steatosis, cardiovascular disease, and type 2 diabetes. Although HCBP6 (hepatitis C virus core-binding protein 6) was previously shown to be an HCV (hepatitis C virus) core-binding protein, its biological function remains unclear. Here, we demonstrate that HCBP6 negatively regulates intracellular triglyceride (TG) levels in hepatocytes. We found that bidirectional manipulation of hepatocyte HCBP6 expression by knockdown or overexpression results in increased or decreased TG accumulation, respectively. In addition, HCBP6 mRNA and protein levels exhibited significant time- and dose-dependent increases in a cellular model of lipid-overload hepatic steatosis. Furthermore, TG levels are regulated by HCBP6-sterol regulatory element binding protein 1c (SREBP1c)-mediated fatty acid synthase (FASN) expression. We also demonstrate that HCBP6 mRNA and protein expression is inhibited by microRNA-122 (miR-122), and miR-122 overexpression elicited more robust translational repression of luciferase activity driven by the full 3'-UTR of HCBP6. Taken together, our results provide new evidence that miR-122-regulated HCBP6 functions as a sensor protein to maintain intrahepatocyte TG levels.
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Affiliation(s)
- Li-Li Gao
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China.,Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, 100015, China
| | - Min Li
- The First Hospital of Lanzhou University, Gansu Province, Gansu, 730000, China
| | - Qi Wang
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China.,Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, 100015, China
| | - Shun-Ai Liu
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China.,Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, 100015, China
| | - Jin-Qian Zhang
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China.,Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, 100015, China
| | - Jun Cheng
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China.,Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, 100015, China
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Selective Insulin Resistance in the Kidney. BIOMED RESEARCH INTERNATIONAL 2016; 2016:5825170. [PMID: 27247938 PMCID: PMC4876201 DOI: 10.1155/2016/5825170] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Revised: 04/04/2016] [Accepted: 04/07/2016] [Indexed: 12/12/2022]
Abstract
Insulin resistance has been characterized as attenuation of insulin sensitivity at target organs and tissues, such as muscle and fat tissues and the liver. The insulin signaling cascade is divided into major pathways such as the PI3K/Akt pathway and the MAPK/MEK pathway. In insulin resistance, however, these pathways are not equally impaired. For example, in the liver, inhibition of gluconeogenesis by the insulin receptor substrate (IRS) 2 pathway is impaired, while lipogenesis by the IRS1 pathway is preserved, thus causing hyperglycemia and hyperlipidemia. It has been recently suggested that selective impairment of insulin signaling cascades in insulin resistance also occurs in the kidney. In the renal proximal tubule, insulin signaling via IRS1 is inhibited, while insulin signaling via IRS2 is preserved. Insulin signaling via IRS2 continues to stimulate sodium reabsorption in the proximal tubule and causes sodium retention, edema, and hypertension. IRS1 signaling deficiency in the proximal tubule may impair IRS1-mediated inhibition of gluconeogenesis, which could induce hyperglycemia by preserving glucose production. In the glomerulus, the impairment of IRS1 signaling deteriorates the structure and function of podocyte and endothelial cells, possibly causing diabetic nephropathy. This paper mainly describes selective insulin resistance in the kidney, focusing on the proximal tubule.
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Geng C, Zhang Y, Gao Y, Tao W, Zhang H, Liu X, Fang F, Chang Y. Mst1 regulates hepatic lipid metabolism by inhibiting Sirt1 ubiquitination in mice. Biochem Biophys Res Commun 2016; 471:444-9. [PMID: 26903296 DOI: 10.1016/j.bbrc.2016.02.059] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Accepted: 02/15/2016] [Indexed: 12/11/2022]
Abstract
Previous study showed mammalian Ste20-like kinase (Mst1) may serve as target for the development of new therapies for diabetes. However, the function of Mst1 involved in liver lipid metabolism has remained elusive. In this study, we report that the liver of Mst1 knockout (Mst1(-/-)) mice showed more severe liver metabolic damage under fasting and high-fat diet than that of control mice. And fasting induced hepatic Mst1 expression. Mst1 overexpression inhibited Srebp-1c expression and increased the expression of antioxidant genes in primary hepatocytes. We also found that fasting-induced expression of hepatic Sirt1 was attenuated in Mst1(-/-) mice. Mst1 overexpression promoted Sirt1 expression, probably due to inhibiting Sirt1 ubiquitination. In summary, our study suggests that Mst1 regulates hepatic lipid metabolism by inhibiting Sirt1 ubiquitination in mice.
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Affiliation(s)
- Chao Geng
- National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, #5 Dongdansantiao, Beijing 100005, China
| | - Yinliang Zhang
- National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, #5 Dongdansantiao, Beijing 100005, China
| | - Yong Gao
- National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, #5 Dongdansantiao, Beijing 100005, China
| | - Wufan Tao
- State Key Laboratory of Genetic Engineering and Institute of Developmental Biology, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, China
| | - Huabing Zhang
- Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei 230032, China
| | - Xiaojun Liu
- National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, #5 Dongdansantiao, Beijing 100005, China.
| | - Fude Fang
- National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, #5 Dongdansantiao, Beijing 100005, China.
| | - Yongsheng Chang
- National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, #5 Dongdansantiao, Beijing 100005, China.
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Liu X, Gao Y, Li M, Geng C, Xu H, Yang Y, Guo Y, Jiao T, Fang F, Chang Y. Sirt1 mediates the effect of the heme oxygenase inducer, cobalt protoporphyrin, on ameliorating liver metabolic damage caused by a high-fat diet. J Hepatol 2015; 63:713-21. [PMID: 26026874 DOI: 10.1016/j.jhep.2015.05.018] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Revised: 05/14/2015] [Accepted: 05/19/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Heme oxygenase 1 (HO-1)-mediated increases in adiponectin, ameliorate the deleterious effects of obesity and metabolic syndrome; however, the effect of HO-1 on hepatic lipid metabolism remains elusive. The aim of this study is to evaluate the role of HO-1 in hepatic lipid metabolism. METHODS Functional studies were performed using C57BL/6J (WT) mice and Sirt1 liver specific mutant (Sirt1-deficient) mice. The molecular mechanism was explored in primary hepatocytes and mouse liver. RESULTS Chronic exposure to high-fat diet (HFD) induced hepatic steatosis in WT mice. Treatment of WT mice on HFD with cobalt protoporphyrin (CoPP), an inducer of HO-1 activity, decreased body weight and visceral fat content, reduced intracellular hepatic triglyceride and serum total cholesterol concentrations, and decreased liver lipid droplet formation. Compared with WT mice, the administration of CoPP to Sirt1-deficient mice on HFD increased visceral fat content, and slightly promoted liver lipid droplet formation. CoPP improved glucose tolerance and insulin sensitivity in WT mice on HFD, but compromised insulin sensitivity in Sirt1-deficient mice on HFD. Furthermore, CoPP-induced Sirt1 expression and decreased sterol regulatory element binding protein 1c (SREBP-1c) expression in WT mice on HFD. However, CoPP promoted SREBP-1c expression in Sirt1-deficient hepatocytes, which was reversed by a protein tyrosine phosphatase 1b inhibitor. Additionally, while the administration of CoPP to WT mice on HFD improved antioxidant and anti-inflammatory states, these CoPP-mediated effects were abolished in Sirt1-deficient mice. CONCLUSIONS Sirt1 mediates the effect of CoPP on ameliorating liver metabolic damage caused by HFD.
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Affiliation(s)
- Xiaojun Liu
- National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100005, China.
| | - Yong Gao
- National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100005, China
| | - Meixia Li
- State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Chao Geng
- National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100005, China
| | - Haifeng Xu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Yaoguo Yang
- The Department of Vascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Yongjun Guo
- The Department of Clinical Laboratory, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Tao Jiao
- National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100005, China
| | - Fude Fang
- National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100005, China.
| | - Yongsheng Chang
- National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100005, China.
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Thorup AC, Gregersen S, Jeppesen PB. Ancient Wheat Diet Delays Diabetes Development in a Type 2 Diabetes Animal Model. Rev Diabet Stud 2015; 11:245-57. [PMID: 26177485 DOI: 10.1900/rds.2014.11.245] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
AIM The main objective was to investigate the physiological effects of ancient wheat whole grain flour diets on the development and progression of type 2 diabetes in Zucker diabetic fatty (ZDF) rats, and specifically to look at the acute glycemic responses. METHODS An intervention study was conducted, involving 40 ZDF rats consuming one of 5 different diets (emmer, einkorn, spelt, rye and refined wheat) for 9 weeks. Refined wheat flour and whole grain rye flour were included as negative and positive controls, respectively. RESULTS After 9 weeks of intervention, a downregulation of the hepatic genes PPAR-α, GLUT2, and SREBP-1c was observed in the emmer group compared to the control wheat group. Likewise, expression of hepatic SREBP-2 was lower for emmer, einkorn, and rye compared with the control group. Furthermore, spelt and rye induced a low acute glycemic response. The wheat group had higher HDL- and total cholesterol levels. CONCLUSIONS Ancient wheat diets caused a downregulation of key regulatory genes involved in glucose and fat metabolism, equivalent to a prevention or delay of diabetes development. Spelt and rye induced a low acute glycemic response compared to wheat.
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Affiliation(s)
- Anne Cathrine Thorup
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Tage-Hansens Gade 2, Aarhus C, Denmark
| | - Søren Gregersen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Tage-Hansens Gade 2, Aarhus C, Denmark
| | - Per Bendix Jeppesen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Tage-Hansens Gade 2, Aarhus C, Denmark
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Qin H, Zhang X, Ye F, Zhong L. High-fat diet-induced changes in liver thioredoxin and thioredoxin reductase as a novel feature of insulin resistance. FEBS Open Bio 2014; 4:928-35. [PMID: 25426412 PMCID: PMC4239481 DOI: 10.1016/j.fob.2014.10.015] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2014] [Revised: 10/28/2014] [Accepted: 10/28/2014] [Indexed: 12/25/2022] Open
Abstract
High-fat diet (HFD) can induce oxidative stress. Thioredoxin (Trx) and thioredoxin reductase (TrxR) are critical antioxidant proteins but how they are affected by HFD remains unclear. Using HFD-induced insulin-resistant mouse model, we show here that liver Trx and TrxR are significantly decreased, but, remarkably, the degree of their S-acylation is increased after consuming HFD. These HFD-induced changes in Trx/TrxR may reflect abnormalities of lipid metabolism and insulin signaling transduction. HFD-driven accumulation of 4-hydroxynonenal is another potential mechanism behind inactivation and decreased expression of Trx/TrxR. Thus, we propose HFD-induced impairment of liver Trx/TrxR as major contributor to oxidative stress and as a novel feature of insulin resistance.
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Key Words
- 4-HNE, 4-hydroxynonenal
- ASK-1, apoptosis signal-regulating kinase-1
- Gpx, glutathione peroxidase
- HFD, high-fat diet
- High-fat diet
- IRS-1, insulin receptor substrate-1
- ITT, insulin tolerance test
- Insulin resistance
- OGTT, oral glucose tolerance test
- PTP-1B, protein-tyrosine phophatase-1B
- S-acylation
- Thioredoxin
- Thioredoxin reductase
- Trx, thioredoxin
- TrxR, thioredoxin reductase
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Affiliation(s)
- Huijun Qin
- College of Life Sciences, University of Chinese Academy of Sciences, 100049 Beijing, China
| | - Xiaolin Zhang
- Institute of Materia Medica, Chinese Academy of Medical Sciences & Perking Union Medical College, 100050 Beijing, China
| | - Fei Ye
- Institute of Materia Medica, Chinese Academy of Medical Sciences & Perking Union Medical College, 100050 Beijing, China
| | - Liangwei Zhong
- College of Life Sciences, University of Chinese Academy of Sciences, 100049 Beijing, China
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35
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Preserved Na/HCO3 cotransporter sensitivity to insulin may promote hypertension in metabolic syndrome. Kidney Int 2014; 87:535-42. [PMID: 25354240 DOI: 10.1038/ki.2014.351] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Revised: 08/29/2014] [Accepted: 09/04/2014] [Indexed: 01/01/2023]
Abstract
Hyperinsulinemia can contribute to hypertension through effects on sodium transport. To test whether the stimulatory effect of insulin on renal proximal tubule sodium transport is preserved in insulin resistance, we compared the effects of insulin on abdominal adipocytes and proximal tubules in rats and humans. Insulin markedly stimulated the sodium-bicarbonate cotransporter (NBCe1) activity in isolated proximal tubules through the phosphoinositide 3-kinase (PI3-K) pathway. Gene silencing in rats showed that while insulin receptor substrate (IRS)1 mediates the insulin effect on glucose uptake into adipocytes, IRS2 mediates the insulin effect on proximal tubule transport. The stimulatory effect of insulin on glucose uptake into adipocytes was severely reduced, but its stimulatory effect on NBCe1 activity was completely preserved in insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rats and patients with insulin resistance. Despite widespread reduction of IRS1 and IRS2 expression in insulin-sensitive tissues, IRS2 expression in the kidney cortex was exceptionally preserved in both OLETF rats and patients with insulin resistance. Unlike liver, acute insulin injection failed to change the expression levels of IRS2 and sterol regulatory element-binding protein 1 in rat kidney cortex, indicating that regulatory mechanisms of IRS2 expression are distinct in liver and kidney. Thus, preserved stimulation of proximal tubule transport through the insulin/IRS2/PI3-K pathway may play an important role in the pathogenesis of hypertension associated with metabolic syndrome.
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36
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Antonelli A, Ferrari SM, Giuggioli D, Di Domenicantonio A, Ruffilli I, Corrado A, Fabiani S, Marchi S, Ferri C, Ferrannini E, Fallahi P. Hepatitis C virus infection and type 1 and type 2 diabetes mellitus. World J Diabetes 2014; 5:586-600. [PMID: 25317237 PMCID: PMC4138583 DOI: 10.4239/wjd.v5.i5.586] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Revised: 04/10/2014] [Accepted: 07/12/2014] [Indexed: 02/05/2023] Open
Abstract
Hepatitis C virus (HCV) infection and diabetes mellitus are two major public health problems that cause devastating health and financial burdens worldwide. Diabetes can be classified into two major types: type 1 diabetes mellitus (T1DM) and T2DM. T2DM is a common endocrine disorder that encompasses multifactorial mechanisms, and T1DM is an immunologically mediated disease. Many epidemiological studies have shown an association between T2DM and chronic hepatitis C (CHC) infection. The processes through which CHC is associated with T2DM seem to involve direct viral effects, insulin resistance, proinflammatory cytokines, chemokines, and other immune-mediated mechanisms. Few data have been reported on the association of CHC and T1DM and reports on the potential association between T1DM and acute HCV infection are even rarer. A small number of studies indicate that interferon-α therapy can stimulate pancreatic autoimmunity and in certain cases lead to the development of T1DM. Diabetes and CHC have important interactions. Diabetic CHC patients have an increased risk of developing cirrhosis and hepatocellular carcinoma compared with non-diabetic CHC subjects. However, clinical trials on HCV-positive patients have reported improvements in glucose metabolism after antiviral treatment. Further studies are needed to improve prevention policies and to foster adequate and cost-effective programmes for the surveillance and treatment of diabetic CHC patients.
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Nakasa T, Yamagami S, Tanaka T, Tanaka H, Hariu H, Okinaka O. Improving Effects of Narazuke Lees on Fatty Liver of Rats Induced by High-Fat and High-Cholesterol Diets. FOOD SCIENCE AND TECHNOLOGY RESEARCH 2014. [DOI: 10.3136/fstr.20.849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
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38
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Koh HJ, Toyoda T, Didesch MM, Lee MY, Sleeman MW, Kulkarni RN, Musi N, Hirshman MF, Goodyear LJ. Tribbles 3 mediates endoplasmic reticulum stress-induced insulin resistance in skeletal muscle. Nat Commun 2013; 4:1871. [PMID: 23695665 PMCID: PMC3707125 DOI: 10.1038/ncomms2851] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2012] [Accepted: 04/09/2013] [Indexed: 12/23/2022] Open
Abstract
Endoplasmic Reticulum (ER) stress has been linked to insulin resistance in multiple tissues but the role of ER stress in skeletal muscle has not been explored. ER stress has also been reported to increase tribbles 3 (TRB3) expression in multiple cell lines. Here, we report that high fat feeding in mice, and obesity and type 2 diabetes in humans significantly increases TRB3 and ER stress markers in skeletal muscle. Overexpression of TRB3 in C2C12 myotubes and mouse tibialis anterior muscles significantly impairs insulin signaling. Incubation of C2C12 cells and mouse skeletal muscle with ER stressors thapsigargin and tunicamycin increases TRB3 and impairs insulin signaling and glucose uptake, effects reversed in cells overexpressing RNAi for TRB3 and in muscles from TRB3 knockout mice. Furthermore, TRB3 knockout mice are protected from high fat diet-induced insulin resistance in skeletal muscle. These data demonstrate that TRB3 mediates ER stress-induced insulin resistance in skeletal muscle.
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Affiliation(s)
- Ho-Jin Koh
- Research Division, Joslin Diabetes Center, Boston, Massachusetts 02215, USA.
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Liu X, Cui Y, Li M, Xu H, Zuo J, Fang F, Chang Y. Cobalt protoporphyrin induces HO-1 expression mediated partially by FOXO1 and reduces mitochondria-derived reactive oxygen species production. PLoS One 2013; 8:e80521. [PMID: 24255720 PMCID: PMC3821864 DOI: 10.1371/journal.pone.0080521] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Accepted: 10/14/2013] [Indexed: 12/23/2022] Open
Abstract
Background Reactive oxygen species arise in the mitochondria as byproducts of respiration and oxidase activity and have important roles in many physiological and pathophysiological conditions. The level of reactive oxygen species is regulated by a number of enzymes and physiological antioxidants, including HO-1, Sod2, catalase and COX-2, etc. And HO-1 against oxidative stress requires an increase in stress-responsive genes, such as Sod2 and catalase. Especially for the activity of HO-1, cobalt protoporphyrin is known to be a potent and effective inducer in many tissues. The transcription factor, FOXO1 is resistant to oxidative stress through downregulating reactive oxygen species production. Previous study showed that FOXO1 induces HO-1 expression by binding to HO-1 promoter. The question whether cobalt protoporphyrin induces HO-1 expression mediated by FOXO1 and subsequently lessens reactive oxygen species production remains to be elucidated. Results Cobalt protoporphyrin enhances the expression of FOXO1 and facilitates FOXO1 binding to HO-1 promoter and increasing its transcriptional activity without influencing the FOXO1 protein stability. CoPP induces HO-1 and other oxidative stress-responsive genes expression, such as catalase, cytochrome c, Sod2, and COX-2, and decreases mitochondria-derived reactive oxygen species production, which are mediated partially by FOXO1. Conclusions Cobalt protoporphyrin induces HO-1 and other oxidative stress-responsive genes expression mediated partially by FOXO1, and has an important role in reducing cellular reactive oxygen species level. Cobalt protoporphyrin may be a more promising therapeutic agent to upregulate some antioxidantive genes.
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Affiliation(s)
- Xiaojun Liu
- The National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- * E-mail: (XL); (FF); (YC)
| | - Ying Cui
- The National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Meixia Li
- State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Haifeng Xu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, China
| | - Jin Zuo
- The National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fude Fang
- The National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- * E-mail: (XL); (FF); (YC)
| | - Yongsheng Chang
- The National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- * E-mail: (XL); (FF); (YC)
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40
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Abstract
MicroRNAs (miRNAs) have recently emerged as key regulators of metabolism. For example, miR-33a and miR-33b have a crucial role in controlling cholesterol and lipid metabolism in concert with their host genes, the sterol-regulatory element-binding protein (SREBP) transcription factors. Other metabolic miRNAs, such as miR-103 and miR-107, regulate insulin and glucose homeostasis, whereas miRNAs such as miR-34a are emerging as key regulators of hepatic lipid homeostasis. The discovery of circulating miRNAs has highlighted their potential as both endocrine signalling molecules and disease markers. Dysregulation of miRNAs may contribute to metabolic abnormalities, suggesting that miRNAs may potentially serve as therapeutic targets for ameliorating cardiometabolic disorders.
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Affiliation(s)
- Veerle Rottiers
- Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USA
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41
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Abstract
MicroRNAs (miRNAs) have recently emerged as key regulators of metabolism. For example, miR-33a and miR-33b have a crucial role in controlling cholesterol and lipid metabolism in concert with their host genes, the sterol-regulatory element-binding protein (SREBP) transcription factors. Other metabolic miRNAs, such as miR-103 and miR-107, regulate insulin and glucose homeostasis, whereas miRNAs such as miR-34a are emerging as key regulators of hepatic lipid homeostasis. The discovery of circulating miRNAs has highlighted their potential as both endocrine signalling molecules and disease markers. Dysregulation of miRNAs may contribute to metabolic abnormalities, suggesting that miRNAs may potentially serve as therapeutic targets for ameliorating cardiometabolic disorders.
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CITED2 links hormonal signaling to PGC-1α acetylation in the regulation of gluconeogenesis. Nat Med 2012; 18:612-7. [PMID: 22426420 DOI: 10.1038/nm.2691] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2011] [Accepted: 01/27/2012] [Indexed: 12/11/2022]
Abstract
During fasting, induction of hepatic gluconeogenesis is crucial to ensure proper energy homeostasis. Such induction is dysregulated in type 2 diabetes, resulting in the development of fasting hyperglycemia. Hormonal and nutrient regulation of metabolic adaptation during fasting is mediated predominantly by the transcriptional coactivator peroxisome proliferative activated receptor γ coactivator 1α (PGC-1α) in concert with various other transcriptional regulators. Although CITED2 (CBP- and p300-interacting transactivator with glutamic acid- and aspartic acid-rich COOH-terminal domain 2) interacts with many of these molecules, the role of this protein in the regulation of hepatic gluconeogenesis was previously unknown. Here we show that CITED2 is required for the regulation of hepatic gluconeogenesis through PGC-1α. The abundance of CITED2 was increased in the livers of mice by fasting and in cultured hepatocytes by glucagon-cAMP-protein kinase A (PKA) signaling, and the amount of CITED2 in liver was higher in mice with type 2 diabetes than in non-diabetic mice. CITED2 inhibited the acetylation of PGC-1α by blocking its interaction with the acetyltransferase general control of amino acid synthesis 5-like 2 (GCN5). The consequent downregulation of PGC-1α acetylation resulted in an increase in its transcriptional coactivation activity and an increased expression of gluconeogenic genes. The interaction of CITED2 with GCN5 was disrupted by insulin in a manner that was dependent on phosphoinositide 3-kinase (PI3K)-thymoma viral proto-oncogene (Akt) signaling. Our results show that CITED2 functions as a transducer of glucagon and insulin signaling in the regulation of PGC-1α activity that is associated with the transcriptional control of gluconeogenesis and that this function is mediated through the modulation of GCN5-dependent PGC-1α acetylation. We also found that loss of hepatic CITED2 function suppresses gluconeogenesis in diabetic mice, suggesting it as a therapeutic target for hyperglycemia.
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Koo HJ, Piao Y, Pak YK. Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals 2012; 20:265-80. [PMID: 22378314 DOI: 10.1159/000333069] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2011] [Accepted: 08/30/2011] [Indexed: 01/07/2023] Open
Abstract
Endoplasmic reticulum (ER) and mitochondrial stress are considered causal factors that induce neurodegenerative diseases. However, the relationship between these stresses remains poorly understood. To investigate the molecular mechanism underlying crosstalk between the ER and mitochondria in neurodegeneration, we treated SH-SY5Y human neuroblastoma cells with thapsigargin and tunicamycin, two inducers of ER stress, and atrazine, a promoter of mitochondrial stress. Each pharmacological agent caused mitochondrial dysfunction, which was characterized by reduced intracellular ATP, mitochondrial membrane potential, and endogenous cellular respiration as well as an augmentation of oxidative stress. Oligonucleotide microarray analysis followed by semiquantitative RT-PCR validation assays revealed that thapsigargin and tunicamycin downregulated the expression of most mitochondria-related genes in a manner similar to that induced by atrazine. In contrast, atrazine did not alter the expression of markers of ER stress. Three-dimensional principal component analysis showed that the gene expression profile produced by atrazine treatment was distinct from that generated by ER stress. However, all three agents impaired insulin receptor substrate-1 and Akt phosphorylation in the insulin signaling pathway. Ectopic overexpression of mitochondrial transcription factor A reversed the effects of thapsigargin on mitochondria and Akt signaling. We conclude that ER stress induces neuronal cell death through common perturbation of mitochondrial function and Akt signaling.
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Affiliation(s)
- Hyun-Jung Koo
- Neurodegeneration Control Research Center, Department of Neuroscience, Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Korea
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44
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Kimura K, Yamada T, Matsumoto M, Kido Y, Hosooka T, Asahara SI, Matsuda T, Ota T, Watanabe H, Sai Y, Miyamoto K, Kaneko S, Kasuga M, Inoue H. Endoplasmic reticulum stress inhibits STAT3-dependent suppression of hepatic gluconeogenesis via dephosphorylation and deacetylation. Diabetes 2012; 61:61-73. [PMID: 22124464 PMCID: PMC3237645 DOI: 10.2337/db10-1684] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
In the liver, signal transducer and activator of transcription 3 (STAT3) plays an important role in the suppression of gluconeogenic enzyme expression. While obesity-associated endoplasmic reticulum (ER) stress has been shown to increase hepatic gluconeogenic enzyme expression, the role of ER stress in STAT3-dependent regulation of such expression is unclear. The current study aimed to elucidate the effect of ER stress on the STAT3-dependent regulation of hepatic gluconeogenic enzyme expression. Genetically obese/diabetic db/db mice and db/db mouse-derived isolated hepatocytes were used as ER stress models. A tyrosine phosphatase inhibitor, a deacetylation inhibitor, and an acetylated mutant of STAT3 were used to examine the effect of ER stress on hepatic STAT3 action. ER stress inhibited STAT3-dependent suppression of gluconeogenic enzyme gene expression by suppressing hepatic Janus kinase (JAK)2 and STAT3 phosphorylation. A tyrosine phosphatase inhibitor restored ER stress-induced suppression of JAK2 phosphorylation but exhibited no improving effect on suppressed STAT3 phosphorylation. STAT3 acetylation is known to correlate with its phosphorylation. ER stress also decreased STAT3 acetylation. An acetylated mutant of STAT3 was resistant to ER stress-induced inhibition of STAT3-phosphorylation and STAT3-dependent suppression of hepatic gluconeogenic enzyme gene expression in vitro and in vivo. Trichostatin A, a histone deacetylase (HDAC) inhibitor, ameliorated ER stress-induced inhibition of STAT3 acetylation and phosphorylation. The current study revealed that ER stress inhibits STAT3-dependent suppression of hepatic gluconeogenic enzymes via JAK2 dephosphorylation and HDAC-dependent STAT3 deacetylation, playing an important role in the increase of hepatic glucose production in obesity and diabetes.
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Affiliation(s)
- Kumi Kimura
- Frontier Science Organization, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Tomoko Yamada
- Frontier Science Organization, Kanazawa University, Kanazawa, Ishikawa, Japan
- Department of Medicinal Informatics, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Michihiro Matsumoto
- Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Yoshiaki Kido
- Department of Internal Medicine, Division of Diabetes, Metabolism, and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan
- Department of Biophysics, Division of Medical Chemistry, Kobe University Graduate School of Health Sciences, Kobe, Japan
| | - Tetsuya Hosooka
- Department of Internal Medicine, Division of Diabetes, Metabolism, and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Shun-ichiro Asahara
- Department of Internal Medicine, Division of Diabetes, Metabolism, and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Tomokazu Matsuda
- Department of Internal Medicine, Division of Diabetes, Metabolism, and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Tsuguhito Ota
- Frontier Science Organization, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hiroshi Watanabe
- Brand's Brain Research Centre, Cerebos Pacific Limited, Singapore
| | - Yoshimichi Sai
- Department of Medicinal Informatics, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Kenichi Miyamoto
- Department of Medicinal Informatics, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Shuichi Kaneko
- Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Masato Kasuga
- Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Hiroshi Inoue
- Frontier Science Organization, Kanazawa University, Kanazawa, Ishikawa, Japan
- Corresponding author: Hiroshi Inoue,
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45
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Rottiers V, Najafi-Shoushtari SH, Kristo F, Gurumurthy S, Zhong L, Li Y, Cohen DE, Gerszten RE, Bardeesy N, Mostoslavsky R, Näär AM. MicroRNAs in metabolism and metabolic diseases. COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY 2011; 76:225-33. [PMID: 22156303 PMCID: PMC3880782 DOI: 10.1101/sqb.2011.76.011049] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Aberrant cholesterol/lipid homeostasis is linked to a number of diseases prevalent in the developed world, including metabolic syndrome, type II diabetes, and cardiovascular disease. We have previously uncovered gene regulatory mechanisms of the sterol regulatory element-binding protein (SREBP) family of transcription factors, which control the expression of genes involved in cholesterol and lipid biosynthesis and uptake. Intriguingly, we recently discovered conserved microRNAs (miR-33a/b) embedded within intronic sequences of the human SREBF genes that act in a concerted manner with their host gene products to regulate cholesterol/lipid homeostasis. Indeed, miR-33a/b control the levels of ATP-binding cassette (ABC) transporter ABCA1, a cholesterol efflux pump critical for high-density lipoprotein (HDL) synthesis and reverse cholesterol transport from peripheral tissues. Importantly, antisense inhibition of miR-33 in mice results in elevated HDL and decreased atherosclerosis. Interestingly, miR-33a/b also act in the fatty acid/lipid homeostasis pathway by controlling the fatty acid β-oxidation genes carnitine O-octanoyltransferase (CROT), hydroxyacyl-coenzyme A-dehydrogenase (HADHB), and carnitine palmitoyltransferase 1A (CPT1A), as well as the energy sensor AMP-activated protein kinase (AMPKα1), the NAD(+)-dependent sirtuin SIRT6, and the insulin signaling intermediate IRS2, key regulators of glucose and lipid metabolism. These results have revealed a highly integrated microRNA (miRNA)-host gene circuit governing cholesterol/lipid metabolism and energy homeostasis in mammals that may have important therapeutic implications for the treatment of cardiometabolic disorders.
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Affiliation(s)
- Veerle Rottiers
- Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
| | - S. Hani Najafi-Shoushtari
- Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
| | - Fjoralba Kristo
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, MA 02129, USA
| | - Sushma Gurumurthy
- Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA
| | - Lei Zhong
- Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA
| | - Yingxia Li
- Department of Medicine, Division of Gastroenterology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - David E Cohen
- Department of Medicine, Division of Gastroenterology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Robert E. Gerszten
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, MA 02129, USA
- Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA
| | - Nabeel Bardeesy
- Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA
- Department of Medicine, Harvard Medical School, MA 02115, USA
| | - Raul Mostoslavsky
- Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA
- Department of Medicine, Harvard Medical School, MA 02115, USA
| | - Anders M. Näär
- Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
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46
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Choi SH, Ginsberg HN. Increased very low density lipoprotein (VLDL) secretion, hepatic steatosis, and insulin resistance. Trends Endocrinol Metab 2011; 22:353-63. [PMID: 21616678 PMCID: PMC3163828 DOI: 10.1016/j.tem.2011.04.007] [Citation(s) in RCA: 272] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2011] [Revised: 04/18/2011] [Accepted: 04/19/2011] [Indexed: 12/14/2022]
Abstract
Insulin resistance (IR) affects not only the regulation of carbohydrate metabolism but all aspects of lipid and lipoprotein metabolism. IR is associated with increased secretion of VLDL and increased plasma triglycerides, as well as with hepatic steatosis, despite the increased VLDL secretion. Here we link IR with increased VLDL secretion and hepatic steatosis at both the physiologic and molecular levels. Increased VLDL secretion, together with the downstream effects on high density lipoprotein (HDL) cholesterol and low density lipoprotein (LDL) size, is proatherogenic. Hepatic steatosis is a risk factor for steatohepatitis and cirrhosis. Understanding the complex inter-relationships between IR and these abnormalities of liver lipid homeostasis will provide insights relevant to new therapies for these increasing clinical problems.
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Affiliation(s)
- Sung Hee Choi
- Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seoul, Korea
| | - Henry N Ginsberg
- Columbia University College of Physicians and Surgeons, New York, NY, USA
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Li S, Ogawa W, Emi A, Hayashi K, Senga Y, Nomura K, Hara K, Yu D, Kasuga M. Role of S6K1 in regulation of SREBP1c expression in the liver. Biochem Biophys Res Commun 2011; 412:197-202. [PMID: 21806970 DOI: 10.1016/j.bbrc.2011.07.038] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2011] [Accepted: 07/12/2011] [Indexed: 11/18/2022]
Abstract
The transcription factor sterol regulatory element-binding protein 1c (SREBP1c) plays an important role in the control of fatty acid metabolism in the liver. Evidence suggests that mammalian target of rapamycin (mTOR) complex 1 (mTORC1) contributes to the regulation of SREBP1c expression, but signaling downstream of mTORC1 remains unclear. We have now shown that medium rich in branched-chain amino acids stimulates expression of the SREBP1c gene in cultured hepatocytes in a manner sensitive both to rapamycin, a pharmacological inhibitor of mTORC1, and to a short hairpin RNA (shRNA) specific for S6 kinase 1 (S6K1), a downstream effector of mTORC1. The phosphorylation of S6K1 was increased in the liver of obese db/db mice. Furthermore, depletion of hepatic S6K1 in db/db mice with the use of an adenovirus vector encoding S6K1 shRNA resulted in down-regulation of SREBP1c gene expression in the liver as well as a reduced hepatic triglyceride content and serum triglyceride concentration. These results thus suggest that S6K1 regulates SREBP1c expression both in cultured hepatocytes and in mouse liver, and that increased hepatic activity of S6K1 contributes at least in part to the pathogenesis of obesity-induced hepatic steatosis and hypertriglyceridemia.
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Affiliation(s)
- Shuying Li
- Department of Medicine, Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
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Abstract
Type 2 Diabetes mellitus (T2D) is the most common endocrine disorder associated to metabolic syndrome (MS) and occurs when insulin secretion can no compensate peripheral insulin resistance. Among peripheral tissues, the liver controls glucose homeostasis due to its ability to consume and produce glucose. The molecular mechanism underlying hepatic insulin resistance is not completely understood; however, it involves the impairment of the insulin signalling network. Among the critical nodes of hepatic insulin signalling, insulin receptor substrate 2 (IRS2) and protein tyrosine phosphatase 1B (PTP1B) modulate the phosphatidylinositol (PI) 3-kinase/Akt/Foxo1 pathway that controls the suppression of gluconeogenic genes. In this review, we will focus on recent findings regarding the molecular mechanism by which IRS2 and PTP1B elicit opposite effects on carbohydrate metabolism in the liver in response to insulin. Finally, we will discuss the involvement of the critical nodes of insulin signalling in non-alcoholic fatty liver disease (NAFLD) in humans.
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Affiliation(s)
- Angela M Valverde
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC/UAM), C/Arturo Duperier 4, 28029 Madrid, Spain.
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Ferré P, Foufelle F. Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c. Diabetes Obes Metab 2010; 12 Suppl 2:83-92. [PMID: 21029304 DOI: 10.1111/j.1463-1326.2010.01275.x] [Citation(s) in RCA: 534] [Impact Index Per Article: 35.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Steatosis is an accumulation of triglycerides in the liver. Although an excessive availability of plasma fatty acids is an important determinant of steatosis, lipid synthesis from glucose (lipogenesis) is now also considered as an important contributing factor. Lipogenesis is an insulin- and glucose-dependent process that is under the control of specific transcription factors, sterol regulatory element binding protein 1c (SREBP-1c), activated by insulin and carbohydrate response element binding protein (ChREBP) activated by glucose. Insulin induces the maturation of SREBP-1c by a proteolytic mechanism initiated in the endoplasmic reticulum (ER). SREBP-1c in turn activates glycolytic gene expression, allowing glucose metabolism, and lipogenic genes in conjunction with ChREBP. Lipogenesis activation in the liver of obese markedly insulin-resistant steatotic rodents is then paradoxical. Recent data suggest that the activation of SREBP-1c and thus of lipogenesis is secondary in the steatotic liver to an ER stress. The ER stress activates the cleavage of SREBP-1c independent of insulin, thus explaining the paradoxical stimulation of lipogenesis in an insulin-resistant liver. Inhibition of the ER stress in obese rodents decreases SREBP-1c activation and lipogenesis and improves markedly hepatic steatosis and insulin sensitivity. ER is thus a new partner in steatosis and metabolic syndrome which is worth considering as a potential therapeutic target.
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Affiliation(s)
- P Ferré
- INSERM, UMR-S 872, Centre de Recherches des Cordeliers and Université Pierre et Marie Curie-Paris, Paris, France
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50
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Transcriptional regulation of glucose sensors in pancreatic β-cells and liver: an update. SENSORS 2010; 10:5031-53. [PMID: 22399922 PMCID: PMC3292162 DOI: 10.3390/s100505031] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/01/2010] [Revised: 05/07/2010] [Accepted: 05/13/2010] [Indexed: 01/17/2023]
Abstract
Pancreatic β-cells and the liver play a key role in glucose homeostasis. After a meal or in a state of hyperglycemia, glucose is transported into the β-cells or hepatocytes where it is metabolized. In the β-cells, glucose is metabolized to increase the ATP:ADP ratio, resulting in the secretion of insulin stored in the vesicle. In the hepatocytes, glucose is metabolized to CO(2), fatty acids or stored as glycogen. In these cells, solute carrier family 2 (SLC2A2) and glucokinase play a key role in sensing and uptaking glucose. Dysfunction of these proteins results in the hyperglycemia which is one of the characteristics of type 2 diabetes mellitus (T2DM). Thus, studies on the molecular mechanisms of their transcriptional regulations are important in understanding pathogenesis and combating T2DM. In this paper, we will review a recent update on the progress of gene regulation of glucose sensors in the liver and β-cells.
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