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Publication
Inhibition of soluble epoxide hydrolase attenuates hepatic fibrosis and
endoplasmic reticulum stress induced by carbon tetrachloride in mice.
Authors Harris TR, Bettaieb A, Kodani S, Dong H, Myers R, Chiamvimonvat N, Haj FG,
Hammock BD
Submitted By Submitted Externally on 11/3/2015
Status Published
Journal Toxicology and applied pharmacology
Year 2015
Date Published 7/1/2015
Volume : Pages 286 : 102 - 11
PubMed Reference 25827057
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
(CCl4)-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 CCl4-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 CCl4-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 CCl4-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
CCl4, presumably by reducing endogenous fatty acid epoxide chemical mediators
acting to reduce ER stress.




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