Roles of peroxisome proliferator-activated receptor α in the pathogenesis of ethanol-induced liver disease

Alcoholic liver disease (ALD) is a progressively aggravated liver disease with high incidence in alcoholics. Ethanol-induced fat accumulation and the subsequent lipopolysaccharide (LPS)-driven inflammation bring liver from reversible steatosis, to irreversible hepatitis, fibrosis, cirrhosis, and even hepatocellular carcinoma. Peroxisome proliferator-activated receptor alpha (PPAR alpha) is a member of the nuclear receptor superfamily of ligandactivated transcription factors and plays pivotal roles in the regulation of fatty acid homeostasis as well as the inflammation control in the liver. It has been well documented that PPAR alpha activity and/or expression are downregulated in liver of mice exposed to ethanol, which is thought to be one of the prime contributors to ethanol-induced steatosis, hepatitis and fibrosis. This article summarizes the current evidences from in vitro and animal models for the critical roles of PPAR alpha in the onset and progression of ALD. Importantly, it should be noted that the expression of PPAR alpha in human liver is reported to be similar to that in mice, and PPAR alpha expression is downregulated in the liver of patients with nonalcoholic fatty liver disease (NAFLD), a disease sharing many similarities with ALD. Therefore, clinical trials investigating the expression of PPAR alpha in the liver of ALD patients and the efficacy of strong PPAR alpha agonists for the prevention and treatment of ALD are warranted.