journal article·2020-05Open access

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

Jia‐Wei Guo, Xiu Liu, Ting‐Ting Zhang, Xiao‐Chun Lin, Yu Hong, Jie Yu, Qin‐Yan Wu, Fei‐Ran Zhang, Qian‐Qian Wu, Jin‐Yan Shang, Xiao‐Fei Lv, Jing‐Song Ou, Jia‐Guo Zhou, Rui‐Ping Pang, Bao‐Dong Tang, Si‐Jia Liang

Advanced Science· Volume 7· Issue 10

Abstract

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.
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Research context

OpenAlex topics: Liver Disease Diagnosis and Treatment · Diet, Metabolism, and Disease · Pancreatic function and diabetes

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Pharmacology Cardiac and Cerebral Vascular Research Center Zhongshan School of Medicine Sun Yat‐Sen University Guangzhou 510080 China

Department of Gastrointestinal Surgery The First Affiliated Hospital Sun Yat‐Sen University Guangzhou 510080 China

Department of Gastroenterology The First People's Hospital of Foshan Foshan 528000 China

Key Laboratory of Metabolic Cardiovascular Diseases Research of National Health Commission Ningxia Medical University Yinchuan 750004 China

Division of Cardiac Surgery The Key Laboratory of Assisted Circulation Ministry of Health The First Affiliated Hospital Sun Yat‐Sen University Guangzhou 510080 China

National‐Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases The First Affiliated Hospital Sun Yat‐Sen University Guangzhou 510080 China

Program of Kidney and Cardiovascular Disease The Fifth Affiliated Hospital Sun Yat‐Sen University Guangzhou 510080 China

Department of Cardiology Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou 510120 China

Guangdong Province Key Laboratory of Brain Function and Disease Zhongshan School of Medicine Sun Yat‐Sen University Guangzhou 510080 China

Department of Physiology Pain Research Center Zhongshan School of Medicine Sun Yat‐Sen University Guangzhou 510080 China

Department of Gastroenterology The First Affiliated Hospital Sun Yat‐Sen University Guangzhou 510080 China

Funding

National Natural Science Foundation of China · Natural Science Foundation of Guangdong Province · Fundamental Research Funds for the Central Universities

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