Journal
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Volume 10, Issue 2, Pages 341-364Publisher
ELSEVIER INC
DOI: 10.1016/j.jcmgh.2020.04.005
Keywords
Sirtuin 6; Steatosis; Inflammation; Nonalcoholic Steatohepatitis; Deacetylation
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Funding
- National Institutes of Health [R56DK091592, R21AA024550, R01DK107682]
- Wang Bao En Liver Fibrosis Foundation [CFHPC 2020052]
- Luzhou Science and Technology Bureau project [2019LZXNYDJ27]
- Science and Technology Department of Sichuan Province [20YYJC1989]
- Indiana Diabetes Research Center National Institutes of Health [P30DK097512]
- Indiana Clinical and Translational Sciences Institute - National Institutes of Health National Center for Advancing Translational Sciences [UL1TR002529]
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BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is a chronic liver disease that is manifested clinically by an increase in hepatic triglycerides, inflammation, and fibrosis. The pathogenesis of NASH remains incompletely understood. Sirtuin 6 (Sirt6), a nicotinamide adenine dinucleotide-dependent deacetylase, has been implicated in fatty liver disease; however, the underlying molecular mechanisms in the NASH pathogenesis are elusive. The aims of this study were to elucidate the role of hepatic Sirt6 in NASH. METHODS: Wild-type, liver-specific Sirt6 knockout (KO), hepatic stellate cell (HSC)-specific Sirt6 knockout (HSC-KO), and Sirt6 transgenic mice were subjected to a Western diet for 4 weeks. Hepatic phenotypes were characterized and underlying mechanisms were investigated. RESULTS: Remarkably, both the liver-KO and HSC-KO mice developed much worse NASH than the wild-type mice, whereas the transgenic mice were protected from the diet-induced NASH. Our cell signaling analysis showed that Sirt6 negatively regulates the transforming growth factor beta-Smad family member 3 (Smad3) pathway. Biochemical analysis showed a physical interaction between Sirt6 and Smad3 in hepatic stellate cells. Moreover, our molecular data further showed that Sirt6 deacetylated Smad3 at key lysine residues K333 and K378, and attenuated its transcriptional activity induced by transforming growth factor beta in hepatic stellate cells. CONCLUSIONS: Our data suggest that SIRT6 plays a critical role in the protection against NASH development and it may serve as a potential therapeutic target for NASH.
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