The ins and outs of mitochondrial dysfunction in NASH.
Rich diet and lack of exercise are causing a surge in obesity, insulin resistance and steatosis, which can evolve into steatohepatitis. Steatosis and nonalcoholic steatohepatitis (NASH) can also be induced by drugs such as amiodarone, tamoxifen and some antiretroviral drugs. There is growing evidence that mitochondrial dysfunction, and more specifically respiratory chain deficiency, plays a role in the pathophysiology of NASH whatever its initial cause. In contrast, the B-oxidation of fatty acids can be either increased (as in insulin resistance-associated NASH) or decreased (as in drug-induced NASH). However, in both circumstances, the generation of reactive oxygen species (ROS) by the damaged respiratory chain is augmented, as components of this chain are over-reduced by electrons, which then abnormally react with oxygen to form increased amounts of ROS. Concomitantly, ROS oxidize fat deposits to release lipid peroxidation products that have detrimental effects on hepatocytes and other hepatic cells. In hepatocytes, ROS and lipid peroxidation products further impair the respiratory chain, either directly or indirectly through oxidative damage to the mitochondrial genome. This, in turn, leads to the generation of more ROS and a vicious cycle ensues. Mitochondrial dysfunction can also lead to apoptosis or necrosis depending on the energy status of the cell. ROS and lipid peroxidation products also activate stellate cells, thus resulting in fibrosis. Finally, ROS and lipid peroxidation increase the generation of several cytokines (TNF-alpha, TGF-B, Fas ligand) that play sundry roles in the pathogenesis of NASH. Recent investigations have shown that some genetic polymorphisms can significantly increase the risk of steatohepatitis and that several drugs can prevent or even reverse NASH. For the next decade, reducing the incidence of NASH will be a major challenge for hepatologists.
Fromenty
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Institut national de la Santé et de la Recherche médicale (INSERM) Unité 481, Faculté de Médecine Xavier Bichat, 750118 Paris, France. fromenty@bichat.inserm.fr
Robin
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Igoudjil
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Mansouri
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Pessayre
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D000818:Animals; D005230:Fatty Acids, Nonesterified / Q000097:blood / Q000378:metabolism; D006505:Hepatitis / Q000503:physiopathology*; D006801:Humans; D007333:Insulin Resistance; D050356:Lipid Metabolism; D015227:Lipid Peroxidation; D008928:Mitochondria / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000502:physiology*; D008954:Models, Biological; D013231:Steatitis / Q000503:physiopathology*
D005230:Fatty Acids, Nonesterified