Sex-specific KDM6A-HNF4A-CREBH network controls lipoprotein cholesterol metabolism and atherosclerosis via epigenetic reprograming of hepatocytes

The liver is a central organ controlling lipid and cholesterol metabolism and plays a key role in regulating lipoprotein profiles and cardiovascular disease risk. Males and females show clear differences in cholesterol handling and susceptibility to atherosclerosis, but the molecular basis for these sex-specific effects remains incompletely understood. Here we show that the X-linked histone demethylase 6A (KDM6A) is essential for maintaining healthy cholesterol metabolism in the liver. Reducing KDM6A levels in human liver cells disrupts gene programs involved in lipoprotein regulation linked to cardiovascular disorders. Consistently, female mice lacking KDM6A specifically in hepatocytes develops pro-atherogenic blood lipoprotein profiles and increased atherosclerosis under genetic and dietary stress, whereas males are largely unaffected. Mechanistically, KDM6A cooperates with Hepatocyte Nuclear Factor 4 Alpha (HNF4A) to promote chromatin activation and enable CREBH (encoded by CREB3L3)-dependent transcription of lipid metabolic genes. These findings identify KDM6A as a sex-linked regulator of hepatic cholesterol metabolism. Overall design: ChIP-seq of histone modification H3K4me1, H3K4me2, H3K27ac, H3K27me3 in HROHep03 cells, Huh1 cells(siLuc, siKDM6A and siHNF4A groups) and mice(WT and KO groups). ChIP-seq of CREBH in PCSK9+WD mice(WT and LKO groups). ChIP-seq of CREBH in HRO cells (siLuc and siKDM6A groups).