Prostaglandin E2 promotes hepatic bile acid synthesis by an E prostanoid receptor 3-mediated hepatocyte nuclear receptor 4α/cholesterol 7α-hydroxylase pathway in mice

Abstract

Prostaglandin E₂ (PGE₂ ) 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 7α-hydroxylase (CYP7A1) is down-regulated in livers of EP3^hep-/- Ldlr^-/- 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 4α (HNF4α). Disruption of the PKA-HNF4α 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 PGE₂ in improving hepatic cholesterol metabolism through activation of the EP3-mediated PKA/HNF4α/CYP7A1 pathway, indicating that inhibition of this pathway may be a novel therapeutic strategy for dyslipidemia and atherosclerosis. (Hepatology 2017;65:999-1014).