Fatty liver disease is the most prevalent chronic liver disorder, which is manifested by hepatic triglyceride elevation, inflammation, and fibrosis. Sirtuin 6 (Sirt6), an NAD⁺-dependent deacetylase, has been implicated in hepatic glucose and lipid metabolism; however, the underlying mechanisms are incompletely understood. The aim of this study was to identify and characterize novel players and mechanisms that are responsible for the Sirt6-mediated metabolic regulation in the liver. We generated and characterized Sirt6 liver-specific knockout mice regarding its role in the development of fatty liver disease. We used cell models to validate the molecular alterations observed in the animal models. Biochemical and molecular biological approaches were used to illustrate protein-protein interactions and gene regulation. Our data show that Sirt6 liver-specific knockout mice develop more severe fatty liver disease than wild-type mice do on a Western diet. Hepatic Sirt6 deficiency leads to elevated levels and transcriptional activities of carbohydrate response element binding protein (ChREBP) and sterol regulatory element binding protein 1 (SREBP1). Mechanistically, our data reveal protein-protein interactions between Sirt6 and liver X receptor α (LXRα), ChREBP, or SREBP1c in hepatocytes. Moreover, Sirt6 suppresses transcriptional activities of LXRα, ChREBP, and SREBP1c through direct deacetylation. In conclusion, this work has identified a key mechanism that is responsible for the salutary function of Sirt6 in the inhibition of hepatic lipogenesis by suppressing LXR, ChREBP, and SREBP1.

脂肪肝是最常见的慢性肝脏疾病，表现为肝脏甘油三酯升高、炎症和纤维化。 Sirtuin 6 (Sirt6) 是一种 NAD ⁺依赖性脱乙酰酶，与肝脏葡萄糖和脂质代谢有关；然而，其根本机制尚不完全清楚。本研究的目的是鉴定和表征负责 Sirt6 介导的肝脏代谢调节的新参与者和机制。我们生成了 Sirt6 肝脏特异性基因敲除小鼠，并对其在脂肪肝疾病发展中的作用进行了表征。我们使用细胞模型来验证在动物模型中观察到的分子变化。使用生物化学和分子生物学方法来说明蛋白质-蛋白质相互作用和基因调控。我们的数据显示，Sirt6 肝脏特异性基因敲除小鼠比采用西方饮食的野生型小鼠患上更严重的脂肪肝疾病。肝脏 Sirt6 缺乏会导致碳水化合物反应元件结合蛋白 (ChREBP) 和甾醇调节元件结合蛋白 1 (SREBP1) 的水平和转录活性升高。从机制上讲，我们的数据揭示了肝细胞中 Sirt6 与肝脏 X 受体 α (LXRα)、ChREBP 或 SREBP1c 之间的蛋白质-蛋白质相互作用。此外，Sirt6 通过直接脱乙酰化来抑制 LXRα、ChREBP 和 SREBP1c 的转录活性。总之，这项工作确定了 Sirt6 通过抑制 LXR、ChREBP 和 SREBP1 来抑制肝脏脂肪生成的有益功能的关键机制。