Overnutrition has gradually become the primary causative factor of nonalcoholic fatty liver disease (NAFLD). However, how nutritional signals are integrated to orchestrate the transcriptional programs important for NAFLD progression remains poorly understood. Here, we identified hepatic BAF60b as a lipid-sensitive subunit of the switch/sucrose-nonfermentable (SWI/SNF) chromatin-remodeling complex and is negatively associated with liver steatosis in mice and humans. Hepatic BAF60b deficiency promotes high-fat diet (HFD)-induced liver steatosis in mice, while transgenic expression of BAF60b in the liver attenuates HFD-induced obesity and NAFLD, both accompanied by a marked regulation of PPARγ expression. Mechanistically, through motif analysis of liver ATAC-Seq and multiple validation experiments, we identified CCAAT/enhancer-binding protein β (C/EBPβ) as the transcription factor that interacts with BAF60b to suppress PPARγ gene expression, thereby controlling hepatic lipid accumulation and NAFLD progression. This work uncovers hepatic BAF60b as a negative regulator of liver steatosis through C/EBPβ dependent chromatin remodeling.

中文翻译：

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鉴定 BAF60b 作为饮食诱发脂肪肝疾病的染色质重塑检查点


营养过剩已逐渐成为非酒精性脂肪肝（NAFLD）的首要致病因素。然而，如何整合营养信号来协调对 NAFLD 进展至关重要的转录程序仍然知之甚少。在这里，我们将肝脏 BAF60b 鉴定为开关/蔗糖不可发酵 (SWI/SNF) 染色质重塑复合物的脂质敏感亚基，并且与小鼠和人类的肝脏脂肪变性呈负相关。肝脏 BAF60b 缺乏会促进高脂饮食 (HFD) 诱导的小鼠肝脏脂肪变性，而肝脏中 BAF60b 的转基因表达可减轻 HFD 诱导的肥胖和 NAFLD，两者均伴有 PPARγ 表达的显着调节。从机制上来说，通过肝脏ATAC-Seq的基序分析和多重验证实验，我们确定CCAAT/增强子结合蛋白β（C/EBPβ）是与BAF60b相互作用的转录因子，抑制PPARγ基因表达，从而控制肝脏脂质积累和NAFLD进展。这项工作揭示了肝脏 BAF60b 通过 C/EBPβ 依赖性染色质重塑作为肝脏脂肪变性的负调节因子。