These authors contributed equally to this work.
Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease
Article first published online: 7 AUG 2013
Copyright © 2013 American Association for the Study of Liver Diseases
Volume 58, Issue 4, pages 1497–1507, October 2013
How to Cite
Begriche, K., Massart, J., Robin, M.-A., Bonnet, F. and Fromenty, B. (2013), Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease. Hepatology, 58: 1497–1507. doi: 10.1002/hep.26226
Potential conflict of interest: Nothing to report.
Supported by INSERM (Institut National de la Santé et de la Recherche Médicale).
- Issue published online: 1 OCT 2013
- Article first published online: 7 AUG 2013
- Accepted manuscript online: 8 JAN 2013 05:28PM EST
- Manuscript Accepted: 26 NOV 2012
- Manuscript Received: 7 AUG 2012
The worldwide epidemic of obesity and insulin resistance favors nonalcoholic fatty liver disease (NAFLD). Insulin resistance (IR) in the adipose tissue increases lipolysis and the entry of nonesterified fatty acids (NEFAs) in the liver, whereas IR-associated hyperinsulinemia promotes hepatic de novo lipogenesis. However, several hormonal and metabolic adaptations are set up in order to restrain hepatic fat accumulation, such as increased mitochondrial fatty acid oxidation (mtFAO). Unfortunately, these adaptations are usually not sufficient to reduce fat accumulation in liver. Furthermore, enhanced mtFAO without concomitant up-regulation of the mitochondrial respiratory chain (MRC) activity induces reactive oxygen species (ROS) overproduction within different MRC components upstream of cytochrome c oxidase. This event seems to play a significant role in the initiation of oxidative stress and subsequent development of nonalcoholic steatohepatitis (NASH) in some individuals. Experimental investigations also pointed to a progressive reduction of MRC activity during NAFLD, which could impair energy output and aggravate ROS overproduction by the damaged MRC. Hence, developing drugs that further increase mtFAO and restore MRC activity in a coordinated manner could ameliorate steatosis, but also necroinflammation and fibrosis by reducing oxidative stress. In contrast, physicians should be aware that numerous drugs in the current pharmacopoeia are able to induce mitochondrial dysfunction, which could aggravate NAFLD in some patients. (Hepatology 2013;58:1497–1507)