Polyenephosphatidylcholine prevents alcoholic liver disease in PPARα-null mice through attenuation of increases in oxidative stress

• Published in: Journal of hepatology 2009-06, Vol.50 (6), p.1236-1246
• Main Authors: Okiyama, Wataru, Tanaka, Naoki, Nakajima, Tamie, Tanaka, Eiji, Kiyosawa, Kendo, Gonzalez, Frank J, Aoyama, Toshifumi
• Format: Article
• Language: English
• Subjects: Acyl-CoA oxidase; Biological and medical sciences; Cytochrome P450 2E1; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Liver. Biliary tract. Portal circulation. Exocrine pancreas; MCP-1; Medical sciences; NOX-4; Other diseases. Semiology; TLR-4
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2009.01.025

Background/Aims 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 α ( 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-β1 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.