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Hepatocyte TMEM16A Deletion Retards NAFLD Progression by Ameliorating Hepatic Glucose Metabolic Disorder.

ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease, and the mechanisms underpinning its pathogenesis have not been completely established. Transmembrane member 16A (TMEM16A), a component of the Ca2+-activated chloride channel (CaCC), has recently been implicated in metabolic events. Herein, TMEM16A is shown to be responsible for CaCC activation in hepatocytes and is increased in liver tissues of mice and patients with NAFLD. Hepatocyte-specific ablation of TMEM16A in mice ameliorates high-fat diet-induced obesity, hepatic glucose metabolic disorder, steatosis, insulin resistance, and inflammation. In contrast, hepatocyte-specific TMEM16A transgenic mice exhibit the opposite phenotype. Mechanistically, hepatocyte TMEM16A interacts with vesicle-associated membrane protein 3 (VAMP3) to induce its degradation, suppressing the formation of the VAMP3/syntaxin 4 and VAMP3/synaptosome-associated protein 23 complexes. This leads to the impairment of hepatic glucose transporter 2 (GLUT2) translocation and glucose uptake. Notably, VAMP3 overexpression restrains the functions of hepatocyte TMEM16A in blocking GLUT2 translocation and promoting lipid deposition, insulin resistance, and inflammation. In contrast, VAMP3 knockdown reverses the beneficial effects of TMEM16A downregulation. This study demonstrates a role for TMEM16A in NAFLD and suggests that inhibition of hepatic TMEM16A or disruption of TMEM16A/VAMP3 interaction may provide a new potential therapeutic strategy for NAFLD.

SUBMITTER: Guo JW

PROVIDER: S-EPMC7237841 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Hepatocyte TMEM16A Deletion Retards NAFLD Progression by Ameliorating Hepatic Glucose Metabolic Disorder.

Guo Jia-Wei JW Liu Xiu X Zhang Ting-Ting TT Lin Xiao-Chun XC Hong Yu Y Yu Jie J Wu Qin-Yan QY Zhang Fei-Ran FR Wu Qian-Qian QQ Shang Jin-Yan JY Lv Xiao-Fei XF Ou Jing-Song JS Zhou Jia-Guo JG Pang Rui-Ping RP Tang Bao-Dong BD Liang Si-Jia SJ

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20200320 10

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease, and the mechanisms underpinning its pathogenesis have not been completely established. Transmembrane member 16A (TMEM16A), a component of the Ca<sup>2+</sup>-activated chloride channel (CaCC), has recently been implicated in metabolic events. Herein, TMEM16A is shown to be responsible for CaCC activation in hepatocytes and is increased in liver tissues of mice and patients with NAFLD. Hepatocyte-specifi ...[more]

PMID: 32440483

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Project description:Nonalcoholic fatty liver disease (NAFLD), characterized by excessive fat deposition in the liver unrelated to alcohol consumption, is highly prevalent worldwide. However, effective therapeutic agents approved for NAFLD treatment are lacking. An ileal bile acid transporter inhibitor (IBATi), which represents a new mode of treatment of chronic idiopathic constipation, leads to increased delivery of bile acids to the colon. We investigated the effect of IBATi against NAFLD through modification of the gut microbiota in mice. IBATi treatment significantly suppressed body weight gain, liver dysfunction, and serum low-density lipoprotein levels and significantly decreased NAFLD activity scores in high-fat diet (HFD) mice. Treatment with IBATi ameliorated the decreased hepatic cholesterol 7-a-monooxygenase (Cyp7a1) and increased ileal fibroblast growth factor 15 (Fgf15) mRNA expression in HFD mice. Further, IBATi treatment changed the α-diversity in the gut microbiota reduced by HFD, which was analyzed in feces using 16S rRNA sequencing. To establish the mechanism underlying improvement in NAFLD induced by IBATi, we recolonized antibiotic solution-treated mice by fecal microbiome transplantation (FMT) using stool from HFD or HFD plus IBATi mice. This is the first report that fecally transplanted gut microbiota from HFD plus IBATi mice prevented hepatic steatosis caused by HFD. In conclusion, IBATi improved hepatic steatosis by ameliorating gut microbiota dysbiosis in NAFLD model mice, suggesting a potential therapeutic agent for NAFLD treatment. IMPORTANCE NAFLD is an increasingly recognized condition that may progress to liver cirrhosis and hepatocellular carcinoma, and community surveys have assessed that the prevalence is 14 to 32% worldwide. The first line of treatment for NAFLD is lifestyle modification to achieve weight reduction, particularly through diet and exercise. However, weight reduction is difficult to achieve and maintain, and pharmacological agents approved for the treatment of NAFLD are lacking. This study investigated the influence of the gut microbiota and the effect of an IBATi on NAFLD using a murine model. Treatment with IBATi significantly improved NAFLD in HFD mice. Further, fecal microbiome transplantation using stool from HFD plus IBATi mice prevented hepatic steatosis caused by HFD. Our study makes a significant contribution to the literature because the study findings suggest a potential treatment strategy for NAFLD patients by ameliorating gut microbiota dysbiosis.

Dataset Information

Hepatocyte TMEM16A Deletion Retards NAFLD Progression by Ameliorating Hepatic Glucose Metabolic Disorder.

Publications

Hepatocyte TMEM16A Deletion Retards NAFLD Progression by Ameliorating Hepatic Glucose Metabolic Disorder.

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