Mitochondria-targeted ubiquinone (MitoQ) decreases ethanol-dependent micro and macro hepatosteatosis.

TitleMitochondria-targeted ubiquinone (MitoQ) decreases ethanol-dependent micro and macro hepatosteatosis.
Publication TypeJournal Article
Year of Publication2011
AuthorsChacko, BK, Srivastava, A, Johnson, MS, Benavides, GA, Chang, MJung, Ye, Y, Jhala, N, Murphy, MP, Kalyanaraman, B, Darley-Usmar, VM
JournalHepatology
Volume54
Issue1
Pagination153-63
Date Published2011 Jul
ISSN1527-3350
KeywordsAMP-Activated Protein Kinases, Animals, Antioxidants, Cytochrome P-450 CYP2E1, Disease Models, Animal, Dose-Response Relationship, Drug, Electron Transport, Ethanol, Fatty Liver, Hypoxia-Inducible Factor 1, alpha Subunit, Lipid Metabolism, Liver, Male, Mitochondria, Liver, Organophosphorus Compounds, Rats, Rats, Sprague-Dawley, Reactive Oxygen Species, Ubiquinone
Abstract

UNLABELLED: Chronic alcohol-induced liver disease results in inflammation, steatosis, and increased oxidative and nitrosative damage to the mitochondrion. We hypothesized that targeting an antioxidant to the mitochondria would prevent oxidative damage and attenuate the steatosis associated with alcoholic liver disease. To test this we investigated the effects of mitochondria-targeted ubiquinone (MitoQ) (5 and 25 mg/kg/day for 4 weeks) in male Sprague-Dawley rats consuming ethanol using the Lieber-DeCarli diet with pair-fed controls. Hepatic steatosis, 3-nitrotyrosine (3-NT), 4-hydroxynonenal (4-HNE), hypoxia inducible factor α (HIF1α), and the activity of the mitochondrial respiratory chain complexes were assessed. As reported previously, ethanol consumption resulted in hepatocyte ballooning, increased lipid accumulation in the form of micro and macrovesicular steatosis, and induction of cytochrome P450 2E1 (CYP2E1). MitoQ had a minor effect on the ethanol-dependent decrease in mitochondrial respiratory chain proteins and their activities; however, it did decrease hepatic steatosis in ethanol-consuming animals and prevented the ethanol-induced formation of 3-NT and 4-HNE. Interestingly, MitoQ completely blocked the increase in HIF1α in all ethanol-fed groups, which has previously been demonstrated in cell culture models and shown to be essential in ethanol-dependent hepatosteatosis.CONCLUSION: These results demonstrate the antioxidant capacity of MitoQ in alleviating alcohol-associated mitochondrial reactive oxygen species (ROS) and several downstream effects of ROS/RNS (reactive nitrogen species) production such as inhibiting protein nitration and protein aldehyde formation and specifically ROS-dependent HIF1α stabilization.

DOI10.1002/hep.24377
Alternate JournalHepatology
Citation Key10.1002/hep.24377
PubMed ID21520201
PubMed Central IDPMC3125473
Grant ListMC_U105663142 / / Medical Research Council / United Kingdom
R01 AA013395 / AA / NIAAA NIH HHS / United States
R01 AA013395-10 / AA / NIAAA NIH HHS / United States
AA013395 / AA / NIAAA NIH HHS / United States