title: Peroxisome proliferator-activated receptor-α activation and excess energy burning in hepatocarcinogenesis.
abstract: Peroxisome proliferator-activated receptor-α (PPARα) modulates the activities of all three interlinked hepatic fatty acid oxidation systems, namely mitochondrial and peroxisomal β-oxidation and microsomal ω-oxidation pathways. Hyperactivation of PPARα, 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 PPARα 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 PPARα activation-related energy burning in liver. Furthermore, the transcriptional co-activator Med1, a key subunit of the Mediator complex, is essential for PPARα signaling in that both PPARα-null and Med1-null hepatocytes are unresponsive to PPARα activators and fail to give rise to liver tumors when chronically exposed to PPARα activators.
authors.affiliation: Department of Biology, Dr. Reddy's Institute of Life Sciences, An Associate Institute of University of Hyderabad, University of Hyderabad Campus, Hyderabad 500046, India. Electronic address: parimalm@drils.org.
authors.forename: Parimal
authors.initials: P
authors.lastname: Misra
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: jkreddy@northwestern.edu.
authors.forename: Janardan K
authors.initials: JK
authors.lastname: Reddy
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced*; D056913:Mediator Complex Subunit 1 / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000502:physiology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D047493:PPAR alpha / Q000378:metabolism*; D020025:Peroxisome Proliferators / Q000009:adverse effects*; D020675:Peroxisomes / Q000502:physiology*
chemical_list: D005227:Fatty Acids; C538856:Med1 protein, mouse; D056913:Mediator Complex Subunit 1; D035683:MicroRNAs; D047493:PPAR alpha; D020025:Peroxisome Proliferators
keywords: Energy combustion; Fatty acid oxidation; Liver tumors; Med1; Oxidative stress; PPARα