ABCC4 impairs the clearance of plasma LDL cholesterol through suppressing LDLR abundance on hepatic surface

Low expression level of low-density lipoprotein receptor (LDLR) on the surface of hepatocytes contributes to hypercholesterolemia and ultimately is the primary determinant of atherosclerotic cardiovascular disease (ASCVD)，which is the leading cause of death in humans globally. Here, we report that inhibition of hepatocyte ABCC4, identified as a top hit from large-scale CRISPR/Cas9 screens, significantly increases hepatic LDLR abundance and LDL cholesterol clearance. As a hepatic transporter for cAMP efflux, ABCC4 silencing alters its intracellular distribution and activates downstream Epac2/Rap1a signaling pathway, which ultimately downregulates PCSK9 protein expression, thereby blocking lysosomal degradation of LDLR. Furthermore, in both animal and cell models, we demonstrate that liver-specific disruption of ABCC4 and pharmacological inhibition of ABCC4 enhance hepatic plasma membrane LDLR expression and lower plasma LDL cholesterol level through ABCC4-cAMP-PCKS9 pathway. Collectively, genome-wide CRISPR screening offers a valuable resource for identifying LDLR modifiers, providing potential insights for therapeutic strategies in hypercholesterolemia and atherosclerosis.