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

•Genetic deletion of the soluble epoxide hydrolase (sEH) decreases hepatic HMG CoA reductase fatty acid synthase and LDL receptor expression.•AMP-activated protein kinase activity increased while SREBP activation decreased in sEH-deficient hepatocytes.•Downregulation of AMPK increased SERBP1 and hepatic enzyme expression.•Levels of 12,13-epoxyoctadecenoic acid (EpOME) were higher in livers from sEH−/− animals.•12,13-EpOME activated AMPK in hepatocytes to decrease HMG CoA reductase expression.