Du Xuan, Cai Can, Yao Jialing, Zhou Youping, Yu Huihong, Shen Wei
Department of Gastroenterology, 2nd Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, PR China.
Department of Gastroenterology, 2nd Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, PR China.
Biochem Biophys Res Commun. 2017 Jan 29;483(1):409-417. doi: 10.1016/j.bbrc.2016.12.129. Epub 2016 Dec 24.
Non-alcoholic fatty liver disease (NAFLD) and its causal factors of hepatic insulin resistance (IR) and type 2 diabetes are rapidly growing worldwide. Developing new therapeutic methods for these conditions requires a comprehensive understanding between hepatic lipid metabolism and IR. Sterol regulatory element-binding transcription factor 1c (SREBP-1c) and carbohydrate responsive-element binding protein (ChREBP) are the major regulators of fatty acid synthase (FASN), a key enzyme of de novo fatty acid synthesis. They are induced by insulin, which directly binds to the sterol regulatory elements (SRE) or carbohydrate-responsive elements (ChORE) of the FASN promoter to induce its expression. The insulin pathway involved in NAFLD has well studied, but the role of histone modification in NAFLD is just beginning to be investigated, and there is minimal data regarding its involvement. In the current study, we investigated histone modifications in FASN under insulin stimulation. H3K4 hypertrimethylation and H3, H4 hyperacetylation in the FASN promoter was found in HepG2 cells and primary hepatocytes following insulin stimulation. We also found that insulin treatment induced the transcription factor SREBP-1c, ChREBP and could accelerate FASN expression by enhancing SREBP-1c, SRE, and ChREBP ChORE binding and inducing H3, H4 hyperacetylation at SRE, ChORE, or transcription start site (TSS) regions of the FASN promoter in hepatocellular carcinoma cell line (HepG2) and primary hepatocytes. Finally, histone acetylation could influence FASN expression by impairing SREBP-1c SRE and ChREBP ChORE binding.
非酒精性脂肪性肝病（NAFLD）及其导致的肝脏胰岛素抵抗（IR）和2型糖尿病在全球范围内正迅速增加。开发针对这些病症的新治疗方法需要全面了解肝脏脂质代谢与IR之间的关系。固醇调节元件结合转录因子1c（SREBP-1c）和碳水化合物反应元件结合蛋白（ChREBP）是脂肪酸合酶（FASN）的主要调节因子，FASN是从头合成脂肪酸的关键酶。它们由胰岛素诱导，胰岛素直接与FASN启动子的固醇调节元件（SRE）或碳水化合物反应元件（ChORE）结合以诱导其表达。参与NAFLD的胰岛素信号通路已得到充分研究，但组蛋白修饰在NAFLD中的作用才刚刚开始被研究，关于其参与的相关数据极少。在本研究中，我们研究了胰岛素刺激下FASN的组蛋白修饰情况。在胰岛素刺激后，HepG2细胞和原代肝细胞中发现FASN启动子上的H3K4超三甲基化以及H3、H4超乙酰化。我们还发现胰岛素处理可诱导转录因子SREBP-1c、ChREBP，并通过增强SREBP-1c、SRE和ChREBP与ChORE的结合以及诱导肝癌细胞系（HepG2）和原代肝细胞中FASN启动子的SRE、ChORE或转录起始位点（TSS）区域的H3、H4超乙酰化来加速FASN表达。最后，组蛋白乙酰化可通过损害SREBP-1c与SRE以及ChREBP与ChORE的结合来影响FASN表达。
