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 β–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 β 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.

中文翻译：

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SIRT6通过在肝星状细胞中脱乙酰化和抑制SMAD3来防止肝纤维化。

背景与目标

非酒精性脂肪性肝炎（NASH）是一种慢性肝病，在临床上表现为肝甘油三酸酯增加，炎症和纤维化。NASH的发病机理仍未完全了解。Sirtuin 6（Sirt6），一种烟酰胺腺嘌呤二核苷酸依赖性脱乙酰基酶，已与脂肪肝疾病有关。然而，NASH发病机理的潜在分子机制尚不清楚。这项研究的目的是阐明肝Sirt6在NASH中的作用。

方法

对野生型肝特异性Sirt6基因敲除（KO），肝星状细胞（HSC）特异性Sirt6基因敲除（HSC-KO）和Sirt6转基因小鼠进行Western饮食4周。表征肝表型并研究其潜在机制。

结果

值得注意的是，肝-KO和HSC-KO小鼠的NASH均比野生型小鼠差得多，而转基因小鼠受到饮食诱导的NASH的保护。我们的细胞信号分析表明，Sirt6负调节转化生长因子β–Smad家族成员3（Smad3）途径。生化分析表明，肝星状细胞中Sirt6和Smad3之间存在物理相互作用。此外，我们的分子数据进一步表明，Sirt6使关键赖氨酸残基K333和K378上的Smad3脱乙酰基化，并减弱了肝星状细胞中转化生长因子β诱导的Smad3转录活性。

结论

我们的数据表明，SIRT6在防止NASH发育中起着至关重要的作用，并且可能成为NASH的潜在治疗靶标。