title: The soluble epoxide hydrolase determines cholesterol homeostasis by regulating AMPK and SREBP activity.
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.
authors.affiliation: Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt, Germany; German Centre for Cardiovascular Research (DZHK) partner site RheinMain, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Mangels
authors.affiliation: Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt, Germany.
authors.forename: Khader
authors.initials: K
authors.lastname: Awwad
authors.affiliation: Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt, Germany; German Centre for Cardiovascular Research (DZHK) partner site RheinMain, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Wettenmann
authors.affiliation: Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt, Germany; German Centre for Cardiovascular Research (DZHK) partner site RheinMain, Germany.
authors.forename: Laila Romagueira Bichara
authors.initials: LR
authors.lastname: Dos Santos
authors.affiliation: Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt, Germany; German Centre for Cardiovascular Research (DZHK) partner site RheinMain, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Frömel
authors.affiliation: Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt, Germany; German Centre for Cardiovascular Research (DZHK) partner site RheinMain, Germany. Electronic address: fleming@em.uni-frankfurt.de.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Fleming
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D004789:Enzyme Activation; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D056945:Hep G2 Cells; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D012995:Solubility; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D051779:Sterol Regulatory Element Binding Proteins; D002784:Cholesterol; D055372:AMP-Activated Protein Kinases; D004851:Epoxide Hydrolases
keywords: AMP-activated protein kinase; Epoxyoctadecenoic acid; HMG CoA reductase; Sterol regulatory element-binding protein