Hepatocyte-specific deletion of Brg1 alleviates methionine-and-choline-deficient diet (MCD) induced non-alcoholic steatohepatitis in mice
Hepatocyte-specific deletion of Brg1 alleviates methionine-and-choline-deficient diet (MCD) induced non-alcoholic steatohepatitis in mice
复制标题
肝细胞特异性删除 Brg1 可减轻蛋氨酸和胆碱缺乏饮食 (MCD) 诱导的小鼠非酒精性脂肪性肝炎。
DOI：
10.1016/j.bbrc.2018.06.027
复制
发表时间：
2018-09-03
影响因子：
3.1
通讯作者：
Xu, Yong
中科院分区：
文献类型：
--
作者：
Kong, Ming;Chen, Xuyang;Xu, Yong
炎症反应失控和脂质堆积是非酒精性脂肪性肝炎(NASH)发病机制中的两个重要病理生理事件。核因子-kappa B和SREBP1c分别对细胞炎症反应和脂质代谢进行转录调控。依赖于NF-kappa B的促炎转录和依赖于SREBP1c的促脂转录的表观遗传学机制仍不完全清楚。在本研究中，我们研究了染色质重塑蛋白BRG1在蛋氨酸和胆碱缺乏饮食(MCD)诱导的小鼠NASH发病机制中的作用。在喂食MCD饮食的小鼠的肝脏和暴露于游离脂肪酸的原代肝细胞中，BRG1的表达上调。与野生型(WT)小鼠相比，饲喂MCD饮食的肝细胞特异性BRG1基因敲除(CKO)小鼠的肝脏损伤和肝脏炎症减轻。同样，与WT小鼠相比，从CKO小鼠分离的原代肝细胞中促炎症介质的合成被下调，这导致巨噬细胞趋化能力降低。BRG1可能通过调节核因子-kappa B与其辅助因子MRTF-A之间的相互作用参与了促炎介质的转录。另一方面，喂食MCD的CKO小鼠的甘油三酯和胆固醇的积累得到改善，同时SREBP1c靶基因减少。BRG1与SREBP1c相互作用，通过影响主动的组蛋白修饰，调节肝脏中SREBP1c靶基因的转录，以响应MCD的喂养。总而言之，靶向BRG1可通过同时使NASH患者的肝脏炎症状态和代谢特征正常化而产生新的抗NASH治疗药物。(C)2018 Elsevier Inc.保留所有权利。
Uncontrolled inflammatory response and augmented lipid accumulation represent two key patho-physiological events in the pathogenesis of non-alcoholic steatohepatitis (NASH). NF-kappa B and SREBP1c program transcriptional regulation of cellular inflammatory response and lipid metabolism, respectively. The epigenetic mechanism underlying NF-kappa B-dependent pro-inflammatory transcription and SREBP1c-dependent pro-lipogenic transcription remains incompletely understood. In the present study we investigated the involvement of Brg1, a chromatin remodeling protein, in NASH pathogenesis in a methionine-and-choline deficient diet (MCD) induced mouse model. Brg1 expression was up-regulated in the liver in mice fed on the MCD diet and in primary hepatocytes exposed to free fatty acids. Liver injury and hepatic inflammation attenuated in hepatocyte-specific Brg1 knockout (CKO) mice fed on the MCD diet compared to the wild type (WT) littermates. Likewise, synthesis of pro-inflammatory mediators was down-regulated in primary hepatocytes isolated from CKO mice compared to WT mice, which resulted in reduced macrophage chemotaxis. Brg1 contributed to the transcription of pro-inflammatory mediators possibly by regulating the interaction between NF-kappa B and its co-factor MRTF-A. On the other hand, accumulation of triglyceride and cholesterol was ameliorated in MCD-fed CKO mice with a concomitant reduction of SREBP1c target genes. Brg1 interacted with SREBP1c and modulated the transcription of SREBP1c target genes in the liver in response to MCD feeding by influencing active histone modifications. In conclusion, targeting Brg1 may yield novel anti-NASH therapeutics by simultaneously normalizing hepatic inflammatory status and metabolic profile in NASH patients. (C) 2018 Elsevier Inc. All rights reserved.