Abstract
BackgroundPeroxisome proliferator activated receptor alpha (PPARα) regulates lipids metabolism and inhibits inflammatory response. However, the role of PPARα in alcoholic liver disease is largely unknown. We aim to elucidate the effect and the molecular basis of PPARα in ethanol induced hepatic injury in mice.ResultsC57BL/6J mice fed with 4% ethanol-containing Lieber-DeCarli liquid diet for 12 weeks exhibited hepatocyte steatosis, necrosis and inflammatory infiltration, accompanied with elevated serum alanine aminotransferase (ALT) and aspartic transaminase (AST) levels, decreased hepatic expression of PPARα, lipids oxidation promoting genes and anti-inflammatory factors, as well as enhanced hepatic expression of fatty acids synthesis promoting genes and pro-inflammatory cytokines. Induction of PPARα by PPARα agonist WY14643 treatment for 2 weeks ameliorated the severity of liver injury and restored expression of genes altered by ethanol treatment. However, administration of PPARα antagonist GW6471 for 2 weeks promoted the inflammatory response.ConclusionsThe present study provided the evidence for the protective role of PPARα in ameliorating ethanol induced liver injury through modulation of the genes related to lipid metabolism and inflammatory response.
Highlights
Peroxisome proliferator activated receptor alpha (PPARa) regulates lipids metabolism and inhibits inflammatory response
Activation of PPARa by WY14643 lowered the serum levels of alanine aminotransferase (ALT) and aspartic transaminase (AST) in mice fed with ethanol liquid diet As shown in Figure 1, mice fed with 4% ethanolcontaining Lieber-DeCarli liquid diet for 12 weeks showed significantly higher serum ALT and AST levels (P < 0.001) compared with Control group, indicating hepatic injury
Activation of PPARa ameliorated liver injury in mice fed with ethanol liquid diet The liver sections from mice fed with ethanol-containing liquid diet exhibited disordered lobule structure, hepatocyte ballooning, moderate steatosis, inflammatory infiltration and mild hepatocyte necrosis
Summary
Peroxisome proliferator activated receptor alpha (PPARa) regulates lipids metabolism and inhibits inflammatory response. Alcoholic liver injury is a progressive process encompassing hepatic steatosis and steatohepatitis. The latter may progress to liver fibrosis, cirrhosis and even hepatocellular carcinoma [1]. Chronic ethanol exposure impairs fatty acid oxidation and enhances lipogenesis by targeting key transcriptional regulators of genes controlling these metabolic processes, including peroxisome proliferators activated receptor gamma coactivator 1 alpha (PGC-1a) [2], sterol regulatory element binding protein 1 (SREBP-1) and its downstream genes, such as fatty acid synthase (FAS) [2], resulting in the accumulation of triglyceride in the liver (steatosis). There is compelling need to identify agent to protect liver against ethanol-related inflammatory injury
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