| Author |
Zhong, J; Ji, XY; Zhao, YL; Jia, YH; Song, CR; Lv, JH; Chen, YY; Zhou, YP; Lv, X; Yang, ZY; Zhang, ZY; Xu, QY; Wang, WH; Chen, HY; Cui, AY; Li, Y; Meng, ZX |
| Abstract |
Overnutrition has gradually become the primary causative factor in nonalcoholic fatty liver disease (NAFLD). However, how nutritional signals are integrated to orchestrate the transcriptional programs important for NAFLD progression remains poorly understood. We identified hepatic BAF60b as a lipid-sensitive subunit of the switch/sucrose nonfermentable chromatin-remodeling complex that is negatively associated with liver steatosis in mice and humans. Hepatic BAF60b deficiency promotes high-fat diet (HFD)-induced liver steatosis in mice, whereas transgenic expression of BAF60b in the liver attenuates HFD-induced obesity and NAFLD, both accompanied by a marked regulation of peroxisome proliferator-activated receptor gamma (PPAR gamma) expression. Mechanistically, through motif analysis of liver assay for transposase-accessible chromatin sequencing and multiple validation experiments, we identified C/EBP beta as the transcription factor that interacts with BAF60b to suppress Ppar gamma gene expression, thereby controlling hepatic lipid accumulation and NAFLD progression. This work identifies hepatic BAF60b as a negative regulator of liver steatosis through C/EBP beta-dependent chromatin remodeling. |
