The soluble epoxide hydrolase determines cholesterol homeostasis by regulating AMPK and SREBP activity

Prostaglandins Other Lipid Mediat. 2016 Sep;125:30-9. doi: 10.1016/j.prostaglandins.2016.05.003. Epub 2016 May 11.

Abstract

Inhibition or deletion of the soluble epoxide hydrolase (sEH) has been linked to reduced cholesterol and protection against atherosclerosis. This study set out to identify sEH substrate(s) or product(s), altered in livers from sEH(-/-) mice that contribute to these beneficial effects. In livers and isolated hepatocytes, deletion of sEH decreased expression of HMG CoA reductase, fatty acid synthase and low density lipoprotein receptor. Sterol regulatory element binding proteins (SREBPs) regulate the expression of all three enzymes and SREBP activation was attenuated in the absence of sEH. The effect was attributed to the AMPK-activated protein kinase (AMPK) which was activated in the absence of sEH. Livers from wild-type versus sEH(-/-) littermates contained significantly higher levels of the sEH substrate 12,13-epoxyoctadecenoic acid, which elicited AMPK activation, while the corresponding sEH product was inactive. Thus, AMPK activation and subsequent inhibition of SREBP can account for the altered expression of lipid metabolizing enzymes in sEH(-/-) mice.

Keywords: AMP-activated protein kinase; Epoxyoctadecenoic acid; HMG CoA reductase; Sterol regulatory element-binding protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Cholesterol / metabolism*
  • Enzyme Activation
  • Epoxide Hydrolases / antagonists & inhibitors
  • Epoxide Hydrolases / chemistry*
  • Epoxide Hydrolases / metabolism*
  • Gene Expression Regulation, Enzymologic / drug effects
  • Hep G2 Cells
  • Homeostasis* / drug effects
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Liver / drug effects
  • Liver / enzymology
  • Mice
  • Mice, Inbred C57BL
  • Solubility
  • Sterol Regulatory Element Binding Proteins / metabolism*

Substances

  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Sterol Regulatory Element Binding Proteins
  • Cholesterol
  • AMP-Activated Protein Kinases
  • Epoxide Hydrolases