Consistent with the data shown in Fig. 4, chronic alcohol consumption resulted in extensive accumulation of osmium tetroxide-stained lipids in macrovesicular steatotic vesicles (Fig. 5A) around the central vein and as microvesicular steatosis in the periportal region. MitoQ PD0332991 nmr treatment decreased the number and size of steatotic vesicles containing unsaturated lipids in ethanol-fed animals as reflected in the

quantification of area of osmium tetroxide staining (Fig. 5B). Alcohol-induced fatty liver enhances the susceptibility of the liver to develop steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma.1, 5, 6 It has recently been shown that steatosis in response to ethanol consumption is modulated by the regulation of hypoxia in the

liver and this pathway is known to be responsive to mitochondrial function.29, 33, 40 Because selleckchem mitochondria are both a source and target for ROS/RNS, it is not surprising that they are thought to play a central role in the pathophysiology of ethanol-dependent hepatotoxicity,3, 4, 13, 14, 50, 51 but the link to hypoxia in this pathology is not clear. Taken together, these data and other studies have closely linked the production of ROS/RNS to mitochondrial DNA and protein damage and alcohol-dependent metabolic derangements in the liver. On the basis of these findings we hypothesized that a mitochondria-targeted antioxidant could potentially alleviate pathological changes which occur in response to chronic alcohol consumption. To test this we used oral treatment of MitoQ, an amphipathic conjugate of ubiquinone with the triphenylphosphonium cation (TPP+), which has been shown to be nontoxic and orally bioavailable in animal models and humans.31, 42, 52

Recent reports demonstrate MitoQ mediated protection against cardiac ischemia-reperfusion injury, diabetic nephropathy, adriamycin-induced cardiotoxicity, and hepatitis C-induced liver injury.37, 39, 53, 54 The TPP+ moiety targets the quinone functional group to the mitochondrion, where it is reduced to the quinol form by complex II, unlike the endogenous coenzyme Q, it interacts poorly with mitochondrial respiratory chain complexes I and III.55 Overall, Orotic acid this allows MitoQ to act as a source of reducing equivalents in this portion of the respiratory chain without greatly impacting the normal electron transfer process. This increased concentration of MitoQ in the mitochondrial inner membrane can act as an inhibitor of lipid peroxidation that generates 4-HNE and can also prevent peroxynitrite mediated protein modification or potentially scavenge peroxynitrite directly.35, 36 Importantly, alcohol-induced 4-HNE modification of key proteins has been reported in the mitochondria, including cytochrome c oxidase and aconitase, which are associated with the severity of steatosis in human subjects.