[PDF][PDF] Prostaglandin E2 promotes hepatic bile acid synthesis by an E prostanoid receptor 3‐mediated hepatocyte nuclear receptor 4α/cholesterol 7α‐hydroxylase …

S Yan, J Tang, Y Zhang, Y Wang, S Zuo, Y Shen… - …, 2017 - Wiley Online Library
S Yan, J Tang, Y Zhang, Y Wang, S Zuo, Y Shen, Q Zhang, D Chen, Y Yu, K Wang, SZ Duan
Hepatology, 2017Wiley Online Library
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 (EP3hep–/–) results in hypercholesterolemia and augments diet‐induced
atherosclerosis in low‐density lipoprotein receptor knockout (Ldlr–/–) mice. Cholesterol 7α …
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 (EP3hep–/–) 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 EP3hep–/–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 EP3hep–/–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)
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