Department of Biology, Dr. Reddy's Institute of Life Sciences, An Associate Institute of University of Hyderabad, University of Hyderabad Campus, Hyderabad 500046, India.
Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Biochimie. 2014 Mar;98:63-74. doi: 10.1016/j.biochi.2013.11.011. Epub 2013 Nov 28.
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.
过氧化物酶体增殖物激活受体-α（PPARα）调节所有三种相互关联的肝脂肪酸氧化系统的活性，即线粒体和过氧化物酶体β-氧化以及微粒体ω-氧化途径。PPARα 的过度激活，无论是外源性还是内源性激活剂，都会上调肝脂肪酸氧化，导致肝脏过度燃烧能量，从而导致啮齿动物肝癌的发生。持续的 PPARα 信号转导与肝脏中 H2O2 降解酶相比，不成比例地增加了产生 H2O2 的脂肪酸代谢酶的生成，导致 DNA 损伤活性氧的产生增加、进行性内质网应激和炎症。这些改变还导致肝细胞增殖增加和凋亡改变。因此，活性氧、氧化应激和肝细胞增殖可能是持续的 PPARα 激活相关能量燃烧介导的肝癌发病机制的主要因素。此外，转录共激活因子 Med1 是 Mediator 复合物的关键亚基，是 PPARα 信号转导所必需的，因为 PPARα 缺失和 Med1 缺失的肝细胞对 PPARα 激活剂无反应，并且当长期暴露于 PPARα 激活剂时不会导致肝癌的发生。
