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

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• 作者：Parimal Misra ; Janardan K. Reddy
• 关键词：PPAR伪 ; Liver tumors ; Fatty acid oxidation ; Energy combustion ; Oxidative stress ; Med1
• 刊名：Biochimie
• 出版年：March, 2014
• 年：2014
• 卷：98
• 期：Complete
• 页码：63-74
• 全文大小：1601 K

文摘

Peroxisome proliferator-activated receptor-伪 (PPAR伪) modulates the activities of all three interlinked hepatic fatty acid oxidation systems, namely mitochondrial and peroxisomal 尾-oxidation and microsomal 蠅-oxidation pathways. Hyperactivation of PPAR伪, 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伪 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伪 activation-related energy burning in liver. Furthermore, the transcriptional co-activator Med1, a key subunit of the Mediator complex, is essential for PPAR伪 signaling in that both PPAR伪-null and Med1-null hepatocytes are unresponsive to PPAR伪 activators and fail to give rise to liver tumors when chronically exposed to PPAR伪 activators.