title: Beneficial effect of docosahexaenoic acid on cholestatic liver injury in rats.
abstract: Bile duct obstruction and subsequent cholestasis are associated with hepatocellular injury, cholangiocyte proliferation, stellate cell activation, Kupffer cell activation, oxidative stress, inflammation and fibrosis. Docosahexaenoic acid (DHA) is an essential polyunsaturated fatty acid that has been shown to possess health beneficial effects, including hepatoprotection. However, the molecular mechanism of DHA-mediated hepatoprotection is not fully understood. In the present study, we report the protective effect of DHA on cholestatic liver injury. Cholestasis was produced by bile duct ligation (BDL) in male Sprague-Dawley rats for 3 weeks. Daily administration of DHA was started 2 weeks before injury and lasted for 5 weeks. In comparison with the control group, the BDL group showed hepatic damage as evidenced by histological changes and elevation in serum biochemicals, ductular reaction, fibrosis, inflammation and oxidative stress. These pathophysiological changes were attenuated by chronic DHA supplementation. DHA alleviated BDL-induced transforming growth factor beta-1 (TGF-β1), intereukin-1beta, connective tissue growth factor and collagen expression. The anti-fibrotic effect of DHA was accompanied by reductions in α-smooth muscle actin-positive matrix-producing cells and Smad 2/3 activity critical to the fibrogenic potential of TGF-β1. DHA also attenuated BDL-induced leukocyte accumulation and nuclear factor-κB (NF-κB) activation. Further studies demonstrated an inhibitory effect of DHA on redox-sensitive intracellular signaling molecule extracellular signal-regulated kinase (ERK). Taken together, the hepatoprotective, anti-inflammatory and anti-fibrotic effects of DHA seem to be multifactorial. The beneficial effects of chronic DHA supplementation are associated with anti-oxidative and anti-inflammatory potential as well as down-regulation of NF-κB and transforming growth factor beta/Smad signaling probably via interference with ERK activation.
authors.affiliation: Department of Education and Research, Taichung Veterans General Hospital, Taichung 407, Taiwan.
authors.forename: Wen-Ying
authors.initials: WY
authors.lastname: Chen
authors.forename: Shih-Yi
authors.initials: SY
authors.lastname: Lin
authors.forename: Hung-Chuan
authors.initials: HC
authors.lastname: Pan
authors.forename: Su-Lan
authors.initials: SL
authors.lastname: Liao
authors.forename: Yu-Han
authors.initials: YH
authors.lastname: Chuang
authors.forename: Yu-Ju
authors.initials: YJ
authors.lastname: Yen
authors.forename: Szu-Yin
authors.initials: SY
authors.lastname: Lin
authors.forename: Chun-Jung
authors.initials: CJ
authors.lastname: Chen
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000378:metabolism / Q000473:pathology; D002779:Cholestasis / Q000150:complications / Q000473:pathology*; D019587:Dietary Supplements; D004281:Docosahexaenoic Acids / Q000008:administration & dosage*; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis / Q000188:drug therapy; D053583:Interleukin-1beta / Q000378:metabolism; D008026:Ligation; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000150:complications / Q000473:pathology* / Q000601:surgery; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D016328:NF-kappa B; D053773:Transforming Growth Factor beta1; D004281:Docosahexaenoic Acids; D048049:Extracellular Signal-Regulated MAP Kinases