Peroxisome proliferator-activated receptor-α activation and excess energy burning in hepatocarcinogenesis

Peroxisome proliferator-activated receptor-alpha (PPAR alpha) modulates the activities of all three interlinked hepatic fatty acid oxidation systems, namely mitochondrial and peroxisomal beta-oxidation and microsomal omega-oxidation pathways. Hyperactivation of PPAR alpha, by both exogenous and endogenous activators up-regulates hepatic fatty acid oxidation resulting in excess energy burning in liver contributing to the development of liver cancer in rodents. Sustained PPAR alpha signaling disproportionately increases H2O2-generating fatty acid metabolizing enzymes as compared to H2O2-degrading enzymes in liver leading to enhanced generation of DNA damaging reactive oxygen species, progressive endoplasmic reticulum stress and inflammation. These alterations also contribute to increased liver cell proliferation with changes in apoptosis. Thus, reactive oxygen species, oxidative stress and hepatocellular proliferation are likely the main contributing factors in the pathogenesis of hepatocarcinogenesis, mediated by sustained PPAR alpha activation-related energy burning in liver. Furthermore, the transcriptional co-activator Med1, a key subunit of the Mediator complex, is essential for PPAR alpha signaling in that both PPAR alpha-null and Med1-null hepatocytes are unresponsive to PPAR alpha activators and fail to give rise to liver tumors when chronically exposed to PPAR alpha activators. (C) 2013 Elsevier Masson SAS. All rights reserved.