title: Prolonged exposure to insulin induces mitochondrion-derived oxidative stress through increasing mitochondrial cholesterol content in hepatocytes.
abstract: We addressed the link between excessive exposure to insulin and mitochondrion-derived oxidative stress in this study and found that prolonged exposure to insulin increased mitochondrial cholesterol in cultured hepatocytes and in mice and stimulated production of reactive oxygen species (ROS) and decreased the reduced glutathione to glutathione disulfide ratio in cultured hepatocytes. Exposure of isolated hepatic mitochondria to cholesterol alone promoted ROS emission. The oxidative stress induced by the prolonged exposure to insulin was prevented by inhibition of cholesterol synthesis with simvastatin. We further found that prolonged exposure to insulin decreased mitochondrial membrane potential and the increased ROS production came from mitochondrial respiration complex I. Finally, we observed that prolonged exposure to insulin decreased mitochondrial membrane fluidity in a cholesterol synthesis-dependent manner. Together our results demonstrate that excess exposure to insulin causes mitochondrion-derived oxidative stress through cholesterol synthesis in hepatocytes.
authors.affiliation: Department of Nutrition, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, North Carolina 27559, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Mei
authors.forename: Haihua
authors.initials: H
authors.lastname: Gu
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Yang
authors.forename: Huailan
authors.initials: H
authors.lastname: Guo
authors.forename: Zhenqi
authors.initials: Z
authors.lastname: Liu
authors.forename: Wenhong
authors.initials: W
authors.lastname: Cao
mesh_terms: D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology*; D000069036:Insulin Glargine; D049528:Insulin, Long-Acting / Q000494:pharmacology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D049528:Insulin, Long-Acting; D017382:Reactive Oxygen Species; D000069036:Insulin Glargine; D002784:Cholesterol