Mitochondrial‐Targeted Antioxidant Treatment in a Mouse Model of Non‐Alcoholic Fatty Liver Disease

Abstract

As obesity has become a more common problem in childhood, the prevalence of non‐alcoholic fatty liver disease (NAFLD) among children has increased. Approximately 70‐80% of obese children have some degree of NAFLD, a precursor for liver failure and/or hepatocellular carcinoma as well as an independent risk factor for cardiovascular disease. While the molecular mechanisms of this disease are beginning to be elucidated, there is no standard pharmacologic therapy. Oxidative stress is a significant factor in disease progression, thus antioxidant therapy has potential utility. In the current study, 10 week old normal (Db/db) and obese diabetic mice with NAFLD (db/db) were treated for six weeks with vehicle or Mitotempol, a mitochondrial‐targeted antioxidant. The effect on oxidative stress, inflammation and metabolism in liver was evaluated through measurement of gene (RT‐PCR) and protein expression (immunoblots), along with hepatic triglyceride levels. Enzymes involved in oxidative stress were not affected by treatment. However, lipocalin‐2, a marker of oxidative stress and inflammation, was significantly decreased following treatment. We also observed a decrease in levels of NFκB and caspase‐3. While there was no change in hepatic triglyceride levels or expression of seven genes involved in fatty acid metabolism, an increase in expression of 4 genes involved in glucose metabolism/transport occurred following Mitotempol treatment. The current study shows that treatment with Mitotempol does not affect hepatic lipid metabolism, but does decrease markers of oxidative stress and inflammation. Mitotempol may be effective in targeting oxidative stress in fatty liver and warrants further evaluation as a potential therapy.