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

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(2+)‐activated chloride channel (CaCC), has recently been impl...

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Autores principales: Guo, Jia‐Wei, Liu, Xiu, Zhang, Ting‐Ting, Lin, Xiao‐Chun, Hong, Yu, Yu, Jie, Wu, Qin‐Yan, Zhang, Fei‐Ran, Wu, Qian‐Qian, Shang, Jin‐Yan, Lv, Xiao‐Fei, Ou, Jing‐Song, Zhou, Jia‐Guo, Pang, Rui‐Ping, Tang, Bao‐Dong, Liang, Si‐Jia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237841/
https://www.ncbi.nlm.nih.gov/pubmed/32440483
http://dx.doi.org/10.1002/advs.201903657
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author Guo, Jia‐Wei
Liu, Xiu
Zhang, Ting‐Ting
Lin, Xiao‐Chun
Hong, Yu
Yu, Jie
Wu, Qin‐Yan
Zhang, Fei‐Ran
Wu, Qian‐Qian
Shang, Jin‐Yan
Lv, Xiao‐Fei
Ou, Jing‐Song
Zhou, Jia‐Guo
Pang, Rui‐Ping
Tang, Bao‐Dong
Liang, Si‐Jia
author_facet Guo, Jia‐Wei
Liu, Xiu
Zhang, Ting‐Ting
Lin, Xiao‐Chun
Hong, Yu
Yu, Jie
Wu, Qin‐Yan
Zhang, Fei‐Ran
Wu, Qian‐Qian
Shang, Jin‐Yan
Lv, Xiao‐Fei
Ou, Jing‐Song
Zhou, Jia‐Guo
Pang, Rui‐Ping
Tang, Bao‐Dong
Liang, Si‐Jia
author_sort Guo, Jia‐Wei
collection PubMed
description 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(2+)‐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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spelling pubmed-72378412020-05-21 Hepatocyte TMEM16A Deletion Retards NAFLD Progression by Ameliorating Hepatic Glucose Metabolic Disorder Guo, Jia‐Wei Liu, Xiu Zhang, Ting‐Ting Lin, Xiao‐Chun Hong, Yu Yu, Jie Wu, Qin‐Yan Zhang, Fei‐Ran Wu, Qian‐Qian Shang, Jin‐Yan Lv, Xiao‐Fei Ou, Jing‐Song Zhou, Jia‐Guo Pang, Rui‐Ping Tang, Bao‐Dong Liang, Si‐Jia Adv Sci (Weinh) Full Papers 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(2+)‐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. John Wiley and Sons Inc. 2020-03-20 /pmc/articles/PMC7237841/ /pubmed/32440483 http://dx.doi.org/10.1002/advs.201903657 Text en © 2020 The Authors. Published by WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Full Papers
Guo, Jia‐Wei
Liu, Xiu
Zhang, Ting‐Ting
Lin, Xiao‐Chun
Hong, Yu
Yu, Jie
Wu, Qin‐Yan
Zhang, Fei‐Ran
Wu, Qian‐Qian
Shang, Jin‐Yan
Lv, Xiao‐Fei
Ou, Jing‐Song
Zhou, Jia‐Guo
Pang, Rui‐Ping
Tang, Bao‐Dong
Liang, Si‐Jia
Hepatocyte TMEM16A Deletion Retards NAFLD Progression by Ameliorating Hepatic Glucose Metabolic Disorder
title Hepatocyte TMEM16A Deletion Retards NAFLD Progression by Ameliorating Hepatic Glucose Metabolic Disorder
title_full Hepatocyte TMEM16A Deletion Retards NAFLD Progression by Ameliorating Hepatic Glucose Metabolic Disorder
title_fullStr Hepatocyte TMEM16A Deletion Retards NAFLD Progression by Ameliorating Hepatic Glucose Metabolic Disorder
title_full_unstemmed Hepatocyte TMEM16A Deletion Retards NAFLD Progression by Ameliorating Hepatic Glucose Metabolic Disorder
title_short Hepatocyte TMEM16A Deletion Retards NAFLD Progression by Ameliorating Hepatic Glucose Metabolic Disorder
title_sort hepatocyte tmem16a deletion retards nafld progression by ameliorating hepatic glucose metabolic disorder
topic Full Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237841/
https://www.ncbi.nlm.nih.gov/pubmed/32440483
http://dx.doi.org/10.1002/advs.201903657
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