Identification of BAF60b as a chromatin remodeling checkpoint of diet-induced fatty liver disease

Abstract

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.

Keyword：SWI/SNF complex; BAF60b; NAFLD; Transcriptional regulation

Article Highlights

• We aim to understand how nutritional signals are integrated to orchestrate the transcriptional programs important for NAFLD progression.

• Hepatic BAF60b is a dietary-lipid sensor and is negatively associated with liver steatosis. We used liver-specific BAF60b knockout and transgenic mice, combining with multi-omics techniques, to study the role of BAF60b in NAFLD progression.

• Our findings uncover BAF60b as a key chromatin remodeling checkpoint factor in controlling hepatic lipid sensing, accumulation, and NAFLD progression through engaging the C/EBPβ/PPARγ axis.