Ybx1 guides C/EBPα and cBAF chromatin-remodeling complex to promote adipogenic gene expression in steatotic hepatocytes

Abstract

Excessive lipid accumulation by hepatocytes underlies the pathogenesis of metabolic-dysfunction associated steatotic liver disease (MASLD) and metabolic-dysfunction associated steatohepatitis (MASH) from the earliest stages of the disease. How liver cells regulate the commitment to storing large volumes of fat despite resulting tissue damage is not well understood. Here, we show Y box-binding protein 1 (Ybx1) is necessary for ectopic activation of an adipocyte-specific gene expression module that potentiates lipid accumulation in hepatocytes. Diet-induced obese (DIO) mice, with liver-specific depletion of Ybx1 (Ybx1LKO), are resistant to MASLD without becoming hyperlipidemic. Ybx1LKO livers exhibit upregulation of hepatocyte markers, like urea processing enzyme carbamoyl phosphate synthetase I (Cps1), and downregulation of adipocyte markers known to be transcriptionally regulated by peroxisome proliferator-activated receptor gamma (PPAR{gamma}). In nuclei of DIO mice, YBX1 interacts with CCAAT-enhancer-binding proteins alpha (C/EBP) and the canonical BRG1/BRM-associated factor complex (cBAF); and C/EBP is required for Ybx1-dependent PPAR{gamma} expression in cultured liver cells. The chromatin binding pattern of YBX1 from DIO mouse liver overlaps with those of C/EBP and cBAF at key adipogenic loci including Pparg and Cfd. However, most YBX1-DNA binding occurs on C/EBP-cBAF-depleted stretches located on chromosomes 16, 18, and 19, spanning up to five Mb, and overlapping regions which are inaccessible in differentiating preadipocytes, thereby bounding activational C/EBP-cBAF complex-DNA interactions. Moreover, YBX1 expression is increased up to nine-fold in the livers of obese patients with MASLD-MASH compared to healthy obese controls; and adipocyte-specific genes, upregulated by Ybx1, are also upregulated in human MASLD-MASH. Overall, our study uncovers Ybx1 as a critical epigenetic regulator in liver and potential therapeutic target for treatment of MASLD and MASH.