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

The liver is a central organ in the maintenance of lipid metabolism. It coordinates cholesterol uptake, biosynthesis, excretion and clearance through an intricated transcription network defined in the epigenetic level by transcription factors and coregulators. Those networks differ between males and females, resulting in marked sex differences in lipoprotein patterns and risk of developing atherosclerosis. How sex chromosome-linked epigenetic modulators contribute to such sex-specific metabolism remains unclarified. Here, we have demonstrated that the X- linked histone demethylase 6A (KDM6A) is a crucial coregulator involved in liver cholesterol regulation. KDM6A knockdown in human liver cells induces transcriptional changes annotated to lipoprotein and cholesterol metabolic pathways linked with cardiovascular disorders. Consistently, hepatocyte specific KDM6A knockout (LKO) female, but not male, mice display substantial atherogenic circulating lipoprotein profiles and are prone to developing atherosclerosis upon genetic and dietary challenges. Mechanistically, KDM6A is recruited to chromatin by Hepatic Nuclear Factor 4 Alpha (HNF4A). This creates an active epigenetic microenvironment essential for the binding of cAMP-responsive element-binding protein H (CREBH, encoded by CREB3L3), which subsequently activates the transcription of lipoprotein and cholesterol metabolic genes in hepatocytes. Therefore, our study uncovers a novel mechanistic link of KDM6A with atherosclerosis using both human cell and mouse models. Because KDM6A is an X-inactivation ‘escapee’ with higher expression in female than male hepatocytes, it may contribute to the sex dimorphism of cholesterol metabolism and cardiovascular risk.