Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Centre for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
School of Nursing, Jiangnan University, Wuxi, China.
Biochim Biophys Acta Mol Basis Dis. 2018 Sep;1864(9 Pt B):2881-2889. doi: 10.1016/j.bbadis.2018.05.022. Epub 2018 May 30.
Alteration of hepatic lipid metabolism contributes to a range of human diseases including steatosis. Sterol response element binding protein (SREBP) is the master regulator of lipid metabolism. The epigenetic mechanism whereby SREBP activity is regulated remains incompletely understood. We have previously shown that systemic knockdown of brahma-related gene 1 (Brg1), a chromatin remodeling protein, attenuates steatosis in mice by down-regulating the synthesis of pro-inflammatory mediators. Here we show that hepatocyte conditional Brg1 knockout (HepcKO) mice were largely protected from high-fat diet (HFD) induced steatosis as evidenced by decelerated weight gains, improved insulin sensitivity, ameliorated steatotic injuries, and diminished hepatic inflammation. Brg1 contributed to lipid metabolism by trans-activating the genes involved in fatty acid esterification. Mechanistically, Brg1 interacted with and was recruited by sterol response element binding protein (SREBP1c) to the promoters of SREBP target genes and optimized the chromatin structure to facilitate SREBP1c binding. Therefore, our data have identified a previously unrecognized role for Brg1 in hepatic lipid metabolism by portraying Brg1 as an essential epigenetic co-factor for SREBP1c.
肝脂质代谢的改变导致了一系列人类疾病，包括脂肪变性。固醇调节元件结合蛋白（SREBP）是脂质代谢的主要调节因子。SREBP 活性的表观遗传调控机制尚不完全清楚。我们之前的研究表明，染色质重塑蛋白 brahma 相关基因 1（Brg1）的系统性敲低可通过下调促炎介质的合成来减轻小鼠的脂肪变性。在这里，我们发现肝条件性 Brg1 敲除（HepcKO）小鼠在很大程度上受到高脂肪饮食（HFD）诱导的脂肪变性的保护，这表现在体重增长减缓、胰岛素敏感性改善、脂肪变性损伤减轻和肝炎症减少。Brg1 通过反式激活参与脂肪酸酯化的基因来参与脂质代谢。在机制上，Brg1 与固醇反应元件结合蛋白（SREBP1c）相互作用并被招募到 SREBP 靶基因的启动子上，优化染色质结构以促进 SREBP1c 结合。因此，我们的数据通过将 Brg1 描绘为 SREBP1c 的必需表观遗传辅助因子，确定了 Brg1 在肝脂质代谢中的先前未被认识到的作用。
