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Hepatocyte TMEM16A Deletion Retards NAFLD Progression by Ameliorating Hepatic Glucose Metabolic Disorder
- Source :
- Advanced Science, Vol 7, Iss 10, Pp n/a-n/a (2020), Advanced Science
- Publication Year :
- 2020
- Publisher :
- Wiley, 2020.
-
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.<br />Transmembrane member 16A (TMEM16A) is an essential component of the hepatocyte calcium‐activated chloride channel and is increased in livers with hepatic steatosis. It interacts with vesicle‐associated membrane protein 3 to disrupt soluble Nethylmaleimide‐sensitive factor attachment protein receptors formation, thereby limiting glucose transporter 2 translocation and hepatic glucose uptake. Liver‐specific deficiency of TMEM16A ameliorates glucose metabolic disorder and nonalcoholic fatty liver disease.
- Subjects :
- nonalcoholic fatty liver disease
medicine.medical_specialty
General Chemical Engineering
Glucose uptake
General Physics and Astronomy
Medicine (miscellaneous)
02 engineering and technology
010402 general chemistry
01 natural sciences
Biochemistry, Genetics and Molecular Biology (miscellaneous)
Insulin resistance
Downregulation and upregulation
Internal medicine
Nonalcoholic fatty liver disease
medicine
General Materials Science
lcsh:Science
TMEM16A
Full Paper
biology
Chemistry
hepatic steatosis
Metabolic disorder
General Engineering
Full Papers
021001 nanoscience & nanotechnology
medicine.disease
glucose metabolic disorder
0104 chemical sciences
medicine.anatomical_structure
Endocrinology
VAMP3
Hepatocyte
biology.protein
GLUT2
lcsh:Q
Steatosis
0210 nano-technology
Subjects
Details
- Language :
- English
- ISSN :
- 21983844
- Volume :
- 7
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Advanced Science
- Accession number :
- edsair.doi.dedup.....c4e6f67bb8d1fe24916bfd092eb8bee9