title: An ω-3-enriched diet alone does not attenuate CCl4-induced hepatic fibrosis.
abstract: Exposure to the halogenated hydrocarbon carbon tetrachloride (CCl4) leads to hepatic lipid peroxidation, inflammation and fibrosis. Dietary supplementation of ω-3 fatty acids has been increasingly advocated as being generally anti-inflammatory, though its effect in models of liver fibrosis is mixed. This raises the question of whether diets high in ω-3 fatty acids will result in a greater sensitivity or resistance to liver fibrosis as a result of environmental toxicants like CCl4. In this study, we fed CCl4-treated mice a high ω-3 diet (using a mix of docosahexaenoic acid and eicosapentaenoic acid ethyl esters). We also co-administered an inhibitor of soluble epoxide hydrolase, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), which has been shown to boost anti-inflammatory epoxy fatty acids that are produced from both ω-3 and ω-6 dietary lipids. We showed that soluble epoxide inhibitors reduced CCl4-induced liver fibrosis. Three major results were obtained. First, the ω-3-enriched diet did not attenuate CCl4-induced liver fibrosis as judged by collagen deposition and collagen mRNA expression. Second, the ω-3-enriched diet raised hepatic tissue levels of several inflammatory lipoxygenase metabolites and prostaglandins, including PGE2. Third, treatment with TPPU in drinking water in conjunction with the ω-3-enriched diet resulted in a reduction in liver fibrosis compared to all other groups. Taken together, these results indicate that dietary ω-3 supplementation alone did not attenuate CCl4-induced liver fibrosis. Additionally, oxylipin signaling molecules may play role in the CCl4-induced liver fibrosis in the high ω-3 diet groups.
authors.affiliation: Department of Entomology and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.
authors.forename: Todd R
authors.initials: TR
authors.lastname: Harris
authors.affiliation: Department of Entomology and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Kodani
authors.affiliation: Department of Entomology and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Comparative Pathology Laboratory, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
authors.forename: Denise M
authors.initials: DM
authors.lastname: Imai
authors.affiliation: Department of Entomology and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA. Electronic address: bdhammock@ucdavis.edu.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D002252:Carbon Tetrachloride Poisoning / Q000178:diet therapy* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D024042:Collagen Type I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D003131:Combined Modality Therapy; D019587:Dietary Supplements; D015232:Dinoprostone / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000627:therapeutic use*; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D008297:Male; D008810:Mice, Inbred C57BL; D010671:Phenylurea Compounds / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: C581572:1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D004791:Enzyme Inhibitors; D015525:Fatty Acids, Omega-3; D010671:Phenylurea Compounds; D010880:Piperidines; D012333:RNA, Messenger; D004851:Epoxide Hydrolases; C518648:Ephx2 protein, mouse; D015232:Dinoprostone
keywords: Carbon tetrachloride; Liver fibrosis; Oxylipins; Soluble Epoxide Hydrolase; ω-3