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

Abstract

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 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: Wataru Okiyama, Naoki Tanaka, Tamie Nakajima, Eiji Tanaka, Kendo Kiyosawa, Frank J Gonzalez, Toshifumi Aoyama
• Journal: Journal of hepatology (J Hepatol) Vol. 50 Issue 6 Pg. 1236-46 (Jun 2009) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 19398233 (Publication Type: Journal Article)

Chemical References

• Antioxidants
• Lipopolysaccharides
• NF-kappa B
• PPAR alpha
• Phosphatidylcholines
• RNA, Messenger
• polyene phosphatidylcholine
• Ethanol
• Phosphotransferases

Topics

• Animals
• Antioxidants (pharmacology)
• Apoptosis (drug effects)
• Ethanol (metabolism, toxicity)
• Lipopolysaccharides (toxicity)
• Liver (drug effects, metabolism, pathology)
• Liver Cirrhosis (pathology, prevention & control)
• Liver Diseases, Alcoholic (genetics, metabolism, pathology, prevention & control)
• Male
• Mice
• Mice, Knockout
• NF-kappa B (metabolism)
• Oxidative Stress (drug effects)
• PPAR alpha (deficiency, genetics)
• Phosphatidylcholines (pharmacology)
• Phosphotransferases (metabolism)
• RNA, Messenger (genetics, metabolism)
• Signal Transduction (drug effects)