Inhibition of soluble epoxide hydrolase attenuates hepatic fibrosis and endoplasmic reticulum stress induced by carbon tetrachloride in mice

Todd R. Harris, Ahmed Bettaieb, Sean Kodani, Hua Dong, Richard Myers, Nipavan Chiamvimonvat, Fawaz Haj, Bruce D. Hammock

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Liver fibrosis is a pathological condition in which chronic inflammation and changes to the extracellular matrix lead to alterations in hepatic tissue architecture and functional degradation of the liver. Inhibitors of the enzyme soluble epoxide hydrolase (sEH) reduce fibrosis in the heart, pancreas and kidney in several disease models. In this study, we assess the effect of sEH inhibition on the development of fibrosis in a carbon tetrachloride (CCl<inf>4</inf>)-induced mouse model by monitoring changes in the inflammatory response, matrix remolding and endoplasmic reticulum stress. The sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) was administered in drinking water. Collagen deposition in the liver was increased five-fold in the CCl<inf>4</inf>-treated group, and this was returned to control levels by TPPU treatment. Hepatic expression of Col1a2 and 3a1 mRNA was increased over fifteen-fold in the CCl<inf>4</inf>-treated group relative to the Control group, and this increase was reduced by 50% by TPPU treatment. Endoplasmic reticulum (ER) stress observed in the livers of CCl<inf>4</inf>-treated animals was attenuated by TPPU treatment. In order to support the hypothesis that TPPU is acting to reduce the hepatic fibrosis and ER stress through its action as a sEH inhibitor we used a second sEH inhibitor, trans-4-{4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzoic acid (t-TUCB), and sEH null mice. Taken together, these data indicate that the sEH may play an important role in the development of hepatic fibrosis induced by CCl<inf>4</inf>, presumably by reducing endogenous fatty acid epoxide chemical mediators acting to reduce ER stress.

Original languageEnglish (US)
Pages (from-to)102-111
Number of pages10
JournalToxicology and Applied Pharmacology
Volume286
Issue number2
DOIs
StatePublished - Jul 5 2015

Keywords

  • Carbon tetrachloride
  • Endoplasmic reticulum stress
  • Fibrosis
  • Soluble epoxide hydrolase

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

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