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

Hepatology. 2017 Mar;65(3):999-1014. doi: 10.1002/hep.28928. Epub 2016 Dec 31.


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).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis / metabolism*
  • Atherosclerosis / pathology
  • Cells, Cultured
  • Cholesterol 7-alpha-Hydroxylase / genetics*
  • Cholesterol 7-alpha-Hydroxylase / metabolism
  • Diet, Western
  • Dinoprostone / metabolism*
  • Disease Models, Animal
  • Gene Expression Regulation, Enzymologic
  • Hepatocyte Nuclear Factor 4 / metabolism*
  • Hepatocytes / metabolism
  • Lipid Metabolism / physiology
  • Lipoproteins, LDL / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Phosphorylation / genetics
  • Random Allocation
  • Receptors, Prostaglandin E, EP3 Subtype / metabolism*
  • Sensitivity and Specificity


  • Hepatocyte Nuclear Factor 4
  • Lipoproteins, LDL
  • Ptger3 protein, mouse
  • Receptors, Prostaglandin E, EP3 Subtype
  • Cholesterol 7-alpha-Hydroxylase
  • Cyp7a1 protein, mouse
  • Dinoprostone