Regulation of the cytochrome P450 epoxyeicosanoid pathway is associated with distinct histologic features in pediatric non-alcoholic fatty liver disease

Prostaglandins Leukot Essent Fatty Acids. 2021 Jan;164:102229. doi: 10.1016/j.plefa.2020.102229. Epub 2020 Dec 17.

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a significant health burden in obese children for which there is currently no specific therapy. Preclinical studies indicate that epoxyeicosanoids, a class of bioactive lipid mediators that are generated by cytochrome P450 (CYP) epoxygenases and inactivated by the soluble epoxide hydrolase (sEH), play a protective role in NAFLD. We performed a comprehensive lipidomics analysis using liver tissue and blood samples of 40 children with NAFLD. Proteomics was performed to determine CYP epoxygenase and sEH expressions. Hepatic epoxyeicosanoids significantly increased with higher grades of steatosis, while their precursor PUFAs were unaltered. Concomitantly, total CYP epoxygenase activity increased while protein level and activity of sEH decreased. In contrast, hepatic epoxyeicosanoids showed a strong decreasing trend with higher stages of fibrosis, accompanied by a decrease of CYP epoxygenase activity and protein expression. These findings suggest that the CYP epoxygenase/sEH pathway represents a potential pharmacologic target for the treatment of NAFLD.

Keywords: Cytochrome p450; Eicosanoids; Enzyme regulation; Lipidomics; Nafld; Proteomics.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Child
  • Cytochrome P-450 Enzyme System / metabolism*
  • Eicosanoids / metabolism*
  • Epoxide Hydrolases / metabolism*
  • Female
  • Humans
  • Lipidomics
  • Male
  • Non-alcoholic Fatty Liver Disease / metabolism*
  • Pediatric Obesity / metabolism*

Substances

  • Eicosanoids
  • Cytochrome P-450 Enzyme System
  • Epoxide Hydrolases
  • EPHX2 protein, human