title: Polyenephosphatidylcholine prevents alcoholic liver disease in PPARalpha-null mice through attenuation of increases in oxidative stress.
abstract: OBJECTIVE
  Alcoholic liver disease (ALD) is one of the leading causes of cirrhosis and yet efficient therapeutic strategies are lacking. Polyenephosphatidylcholine (PPC), a major component of essential phospholipids, prevented alcoholic liver fibrosis in baboons, but its precise mechanism remains uncertain. We aimed to explore the effects of PPC on ALD using ethanol-fed peroxisome proliferator-activated receptor alpha (Ppara)-null mice, showing several similarities to human ALD.
  
  
  METHODS
  Male wild-type and Ppara-null mice were pair-fed a Lieber-DeCarli control or 4% ethanol-containing diet with or without PPC (30 mg/kg/day) for 6 months.
  
  
  RESULTS
  PPC significantly ameliorated ethanol-induced hepatocyte damage and hepatitis in Ppara-null mice. These effects were likely a consequence of decreased oxidative stress through down-regulation of reactive oxygen species (ROS)-generating enzymes, including cytochrome P450 2E1, acyl-CoA oxidase, and NADPH oxidases, in addition to restoration of increases in Toll-like receptor 4 and CD14. PPC also decreased Bax and truncated Bid, thus inhibiting apoptosis. Furthermore, PPC suppressed increases in transforming growth factor-beta1 expression and hepatic stellate cell activation, which retarded hepatic fibrogenesis.
  
  
  CONCLUSIONS
  PPC exhibited anti-inflammatory, anti-apoptotic, and anti-fibrotic effects on ALD as a result of inhibition of the overexpression of ROS-generating enzymes. Our results demonstrate detailed molecular mechanisms of the anti-oxidant action of PPC.
authors.affiliation: Department of Metabolic Regulation, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto 390-8621, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Okiyama
authors.forename: Naoki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Tamie
authors.initials: T
authors.lastname: Nakajima
authors.forename: Eiji
authors.initials: E
authors.lastname: Tanaka
authors.forename: Kendo
authors.initials: K
authors.lastname: Kiyosawa
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Aoyama
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000431:Ethanol / Q000378:metabolism / Q000633:toxicity; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000473:pathology / Q000517:prevention & control; D008108:Liver Diseases, Alcoholic / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D047493:PPAR alpha / Q000172:deficiency* / Q000235:genetics; D010713:Phosphatidylcholines / Q000494:pharmacology*; D010770:Phosphotransferases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000975:Antioxidants; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047493:PPAR alpha; D010713:Phosphatidylcholines; D012333:RNA, Messenger; C029449:polyene phosphatidylcholine; D000431:Ethanol; D010770:Phosphotransferases