染色质重构蛋白BRG1调控肝细胞脂质合成及非酒精性脂肪肝病的机制研究

Non-alcoholic fatty liver disease, or NAFLD, has become a major health risk to the Chinese population for the last decade. The transcription factor sterol response element binding protein (SREBP) promotes the pathogenesis of NAFLD by trans-activating the genes involved in de novo lipogenesis, but the underlying epigenetic mechanism is not clearly understood. Our preliminary data suggest that NAFLD induced by the methionine-and-choline deficient diet (MCD) was attenuated in mice harboring hepatocyte-specific deletion of brahma related gene 1 (BRG1) compared to wild type littermates. BRG1 interacted with SREBP1c in hepatocyte to activate the transcription of SREBP1c target genes. In addition, BRG1 deficiency down-regulated the the expression of SREBP cleavage activating protein (SCAP). Based on these results, we hypothesize that BRG1 may regulate SREBP1c activity and hence the NALFD pathogenesis by altering the chromatin structure to stabilize the binding of SREBP1c to target promoters and by activating SCAP expression to potentially influence the processing and maturation of SREBP1c. We aim to further investigate the mechanism whereby BRG1 regulates hepatic lipogenesis and NAFLD to provide novel diagnostic and therapeutic targets in the intervention of NAFLD.

非酒精性脂肪肝病（NAFLD）已经成为威胁我国民众健康的重大疾病之一。固醇反应元件结合蛋白（SREBP）通过调控脂质合成促进NAFLD发生发展，但其中的表观遗传机制并不明确。我们的预实验结果提示，肝细胞特异敲除染色质重构蛋白BRG1的小鼠相较野生型小鼠对MCD饮食诱导的NAFLD有明显拮抗作用。BRG1与SREBP1c互相作用调控SREBP靶基因转录。BRG1缺陷还导致SREBP剪切激活蛋白（SCAP）表达下调。因此我们提出假说：在肝细胞中，BRG1一方面通过改变染色质结构，稳定SREBP1c在染色质上的结合；另一方面，BRG1通过调控SCAP表达，影响SREBP1c的成熟入核，从而激活脂肪酸合成相关基因表达，促进肝脏脂质积聚及NAFLD的发生发展。我们将进一步深入研究BRG1调控肝细胞脂质合成及NAFLD的机制，从而揭示调控NAFLD新的表观遗传机制，并为临床诊疗提供新的靶点。

非酒精性脂肪性肝炎(NASH)已成为我国严重的公共卫生问题。固醇反应原件结合蛋白（SREBP）剪切/激活蛋白（SCAP）通过调控SREBP成熟在肝细胞脂代谢过程中发挥重要调控作用。本项目研究了染色质重构蛋白BRG1对SCAP基因的转录调控机制，阐明了在BRG1缺陷肝细胞中过表达外源性SCAP部分恢复了nSREBP水平及SREBP下游靶基因表达水平（Front Cell Dev Biol，2021）。NASH发病的一个重要机制是系统性代谢综合征和胰岛素抵抗。此外，NASH患者经常伴有其他器官功能障碍如慢性肾病及肾纤维化。本项目研究了系统性胰岛素抵抗对肾纤维化过程中CTGF转录激活的调控机制，发现MKL1通过与组蛋白H3K9去甲基酶KDM3A互相作用共同结合到CTGF启动子上激活CTGF转录（Cell Tissue Res，2020）。NASH的一个重要病理学特征是广泛的肝纤维化，本项目研究了BRG1通过调控血管内皮angiocrine功能参与肝纤维化的机制，揭示了BRG1通过和转录因子Sp1互相作用招募组蛋白H3K4甲基转移酶MLL1共同激活CAV1表达，从而促进血管内皮损伤及肝纤维化（Biochem Biophys Res Commun，2020）。本项目围绕NASH发生发展过程中相关转录事件调控机制进行深入研究，为临床药物干预NASH提供理论依据和药物靶标。