Peroxisome proliferator activated receptor alpha (PPARα) activation ameliorates alcoholic liver injury in mice

Alcoholic liver disease is a common health problem worldwide. This is a progressive disease encompassing simple fatty liver, steatohepatitis, and may progress to liver fibrosis, cirrhosis and even cancer. To date, there has been no effective drug treatment for patients with alcoholic liver disease. There is a compelling need to identify an agent to treat this disorder.

A new study published by Dr. Jun Yu and colleagues at the Chinese University of Hong Kong and Third Hospital of Hebei Medical University reports that activation of a gene involved in fatty acid oxidation, peroxisome proliferator activated receptor alpha (PPARα), may ameliorate alcoholic liver injury.

The results of the study were published in a recent issue of the open access journal Lipids in Health and Disease.

 
Changes of liver histopathology and hepatocyte ultrastructure in mice under various treatment conditions. (A) Hematoxylin and eosin stained liver sections from mice liver, (B) Effect of PPARα on scores for hepatic steatosis, hepatocyte ballooning, necroinflammation in ethanol induced liver injury, and (C) Electron microscopy for hepatocyte ultrastructure. N, nucleus; LD, lipid droplets; M, mitochondria; R, rough endoplasmic reticulum. Image Credit and Copyright: Dr. Jun Yu and Yuemin Nan.

Dr. Yu and colleagues established an animal model of alcohol-induced liver injury by feeding mice with an ethanol liquid diet for 12 weeks. The ethanol feeding mice displayed liver cell fatty degeneration and inflammatory cells infiltration in the liver sections, accompanied with elevated serum levels of biochemical markers for liver injury including alanine aminotransferase (ALT) and aspartic transaminase (AST). In addition, lipid synthesis promoting genes were up-regulated and lipid oxidation promoting genes were down-regulated, resulting in excess lipids accumulation in the liver. Pro-inflammatory factors were increased in the liver, while anti-inflammatory factors were decreased, which promoted the progression of the liver inflammatory response.

PPARα is a member of the nuclear hormone receptor superfamily. It is a transcription factor that binds to specific sequence segments on certain genes to control their expression. The genes controlled by PPARα include those involved in fatty acid transport, fatty acid oxidation and mitochondrial function. Oxidation of fatty acids takes place inside the mitochondria and therefore mitochondrial functional alteration also play a major role in fatty acid oxidation and clearance.

Expression of PPARα was significantly decreased in the liver of mice fed with ethanol. We therefore investigated the role of PPARα in the evolution of ethanol-induced liver damage, said the first author Dr. Lingbo Kong. The scientists administered two compounds, WY14643 (PPARα agonist) and GW6471 (PPARα antagonist), to mice fed with ethanol for 2 weeks and the effects of these two agents were evaluated. They found that the agonist, WY14643, ameliorated the severity of liver injury and restored aberrant expression of genes induced by ethanol treatment. On the contrary, the hepatic inflammatory injury was further increased in mice treated with GW6471. These results indicated that PPARα played an important protective role in the progression of alcoholic liver disease, said Dr. Yuemin Nan, the corresponding author.

Their study provided an evidence for the therapeutic role of PPARα activation in ethanol related liver injury through modulation of the genes related to lipid metabolism and inflammatory response. The results also suggest that PPARα activation may potentially be a useful therapy to control alcoholic liver disease, said Dr. Jun Yu, a Professor at the Chinese University of Hong Kong.
©SciGuru.com Science News