Prostaglandin E2 Promotes Hepatic Bile Acid Synthesis by an E Prostanoid Receptor 3-Mediated Hepatocyte Nuclear Receptor 4α/Cholesterol 7α-Hydroxylase Pathway in Mice

Prostaglandin E-2(PGE(2)) is an important lipid mediator of inflammation. However, whether and how PGE2 regulates hepatic cholesterol metabolism remains unknown. We found that expression of the PGE2 receptor, E prostanoid receptor 3 (EP3) expression is remarkably increased in hepatocytes in response to hyperlipidemic stress. Hepatocyte- specific deletion of EP3 receptor (EP3(hep-/-)) results in hypercholesterolemia and augments diet-induced atherosclerosis in low- density lipoprotein receptor knockout (Ldlr(-/-)) mice. Cholesterol 7 alpha- hydroxylase (CYP7A1) is down- regulated in livers of EP3(hep-/-)Ldlr(-/-) 2 mice, leading to suppressed hepatic bile acid (BA) biosynthesis. Mechanistically, hepatic- EP3 deficiency suppresses CYP7A1 expression by elevating protein kinase A (PKA)-dependent Ser143 phosphorylation of hepatocyte nuclear receptor 4 alpha(HNF4 alpha). Disruption of the PKA- HNF4a interaction and BA sequestration rescue impaired BA excretion and ameliorated atherosclerosis in EP3(hep-/-) Ldlr (-/-) mice. Conclusion: Our results demonstrated an unexpected role of proinflammatory mediator PGE(2) in improving hepatic cholesterol metabolism through activation of the EP3-mediated PKA/ HNF4 alpha/CYP7A1 pathway, indicating that inhibition of this pathway may be a novel therapeutic strategy for dyslipidemia and atherosclerosis. (HEPATOLOGY 2017;65: 999-1014)