Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Cells. 2023 Feb 19;12(4):663. doi: 10.3390/cells12040663.
Sirtuin 6 (SIRT6) is an NAD-dependent deacetylase/deacylase/mono-ADP ribosyltransferase, a member of the sirtuin protein family. SIRT6 has been implicated in hepatic lipid homeostasis and liver health. Hepatic lipogenesis is driven by several master regulators including liver X receptor (LXR), carbohydrate response element binding protein (ChREBP), and sterol regulatory element binding protein 1 (SREBP1). Interestingly, these three transcription factors can be negatively regulated by SIRT6 through direct deacetylation. Fatty acid oxidation is regulated by peroxisome proliferator activated receptor alpha (PPARα) in the liver. SIRT6 can promote fatty acid oxidation by the activation of PPARα or the suppression of miR-122. SIRT6 can also directly modulate acyl-CoA synthetase long chain family member 5 (ACSL5) activity for fatty acid oxidation. SIRT6 also plays a critical role in the regulation of total cholesterol and low-density lipoprotein (LDL)-cholesterol through the regulation of SREBP2 and proprotein convertase subtilisin/kexin type 9 (PCSK9), respectively. Hepatic deficiency of Sirt6 in mice has been shown to cause hepatic steatosis, inflammation, and fibrosis, hallmarks of alcoholic and nonalcoholic steatohepatitis. SIRT6 can dampen hepatic inflammation through the modulation of macrophage polarization from M1 to M2 type. Hepatic stellate cells are a key cell type in hepatic fibrogenesis. SIRT6 plays a strong anti-fibrosis role by the suppression of multiple fibrogenic pathways including the transforming growth factor beta (TGFβ)-SMAD family proteins and Hippo pathways. The role of SIRT6 in liver cancer is quite complicated, as both tumor-suppressive and tumor-promoting activities have been documented in the literature. Overall, SIRT6 has multiple salutary effects on metabolic homeostasis and liver health, and it may serve as a therapeutic target for hepatic metabolic diseases. To date, numerous activators and inhibitors of SIRT6 have been developed for translational research.
Sirtuin 6 (SIRT6) 是一种 NAD 依赖性去乙酰化酶/去乙酰化酶/单 ADP 核糖基转移酶，属于 sirtuin 蛋白家族的一员。SIRT6 与肝内脂质稳态和肝脏健康有关。肝内脂肪生成受几种主要调节因子驱动，包括肝 X 受体 (LXR)、碳水化合物反应元件结合蛋白 (ChREBP) 和固醇调节元件结合蛋白 1 (SREBP1)。有趣的是，这三个转录因子可以通过直接去乙酰化被 SIRT6 负调控。脂肪酸氧化受肝脏中的过氧化物酶体增殖物激活受体 alpha (PPARα) 调节。SIRT6 可以通过激活 PPARα 或抑制 miR-122 来促进脂肪酸氧化。SIRT6 还可以直接调节长链酰基辅酶 A 合成酶家族成员 5 (ACSL5) 的活性以进行脂肪酸氧化。SIRT6 在调节总胆固醇和低密度脂蛋白 (LDL)-胆固醇方面也起着关键作用，分别通过调节 SREBP2 和前蛋白转化酶枯草溶菌素/凝血酶 9 (PCSK9)。已经证明，小鼠肝脏中 Sirt6 的缺乏会导致肝脂肪变性、炎症和纤维化，这是酒精性和非酒精性脂肪性肝炎的特征。SIRT6 可以通过调节巨噬细胞从 M1 向 M2 型的极化来抑制肝炎症。肝星状细胞是肝纤维化发生的关键细胞类型。SIRT6 通过抑制转化生长因子β (TGFβ)-SMAD 家族蛋白和 Hippo 通路等多种纤维化途径发挥强烈的抗纤维化作用。SIRT6 在肝癌中的作用相当复杂，因为文献中既记录了其肿瘤抑制作用，也记录了其肿瘤促进作用。总的来说，SIRT6 对代谢稳态和肝脏健康有多种有益影响，它可能成为肝脏代谢疾病的治疗靶点。迄今为止，已经开发出许多 SIRT6 的激活剂和抑制剂用于转化研究。
Zotero 插件
