title: Glucose fluctuation increased hepatocyte apoptosis under lipotoxicity and the involvement of mitochondrial permeability transition opening.
abstract: Oxidative stress is considered to be an important factor in producing lethal hepatocyte injury associated with nonalcoholic fatty liver disease (NAFLD). Glucose fluctuation, more pronounced in patients with diabetes, has been recognized as an even stronger oxidative stress inducer than the sustained hyperglycemia. Here, we investigated the role of glucose variability in the development of the NAFLD based on hepatocyte apoptosis and possible mechanisms. To achieve this goal we studied C57BL/6J mice that were maintained on a high fat diet (HFD) and injected with glucose (3 g/kg) twice daily to induce intermittent high glucose (IHG). We also studied hepatic L02 cells incubated with palmitic acid (PA) to induce steatosis. The following experimental groups were compared: normal glucose (NG), sustained high glucose (SHG) and IHG with or without PA. We found that, although hepatic enzyme levels and liver lipid deposition were comparable between HFD mice injected with glucose or saline, the glucose injected mice displayed marked hepatocyte apoptosis and inflammation, accompanied by increased lipid peroxide in liver. In vitro, in the presence of PA, IHG increased L02 cell apoptosis and oxidative stress and produced pronounced mitochondrial dysfunction relative to the NG and SHG groups. Furthermore, treatment with the mitochondrial permeability transition (MPT) inhibitor, cyclosporin A (1.5 μmol/l), prevented mitochondrial dysfunction, oxidative stress and hepatocyte apoptosis. Our data suggests that IHG under lipotoxicity might contribute to the development of NAFLD by increasing oxidative stress and hepatocyte apoptosis via MPT and its related mitochondrial dysfunction.
authors.affiliation: Department of EndocrinologySchool of Medicine, The Affiliated Sir Run Run Shaw Hospital, Zhejiang University, 3 East Qingchun Road, Hangzhou 310016, China.
authors.forename: Xueyao
authors.initials: X
authors.lastname: Yin
authors.affiliation: Department of EndocrinologySchool of Medicine, The Affiliated Sir Run Run Shaw Hospital, Zhejiang University, 3 East Qingchun Road, Hangzhou 310016, China.
authors.forename: Fenping
authors.initials: F
authors.lastname: Zheng
authors.affiliation: Department of EndocrinologySchool of Medicine, The Affiliated Sir Run Run Shaw Hospital, Zhejiang University, 3 East Qingchun Road, Hangzhou 310016, China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Pan
authors.affiliation: Department of EndocrinologySchool of Medicine, The Affiliated Sir Run Run Shaw Hospital, Zhejiang University, 3 East Qingchun Road, Hangzhou 310016, China.
authors.forename: Saifei
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of EndocrinologySchool of Medicine, The Affiliated Sir Run Run Shaw Hospital, Zhejiang University, 3 East Qingchun Road, Hangzhou 310016, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Yu
authors.affiliation: Department of EndocrinologySchool of Medicine, The Affiliated Sir Run Run Shaw Hospital, Zhejiang University, 3 East Qingchun Road, Hangzhou 310016, China.
authors.forename: Zhiye
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of EndocrinologySchool of Medicine, The Affiliated Sir Run Run Shaw Hospital, Zhejiang University, 3 East Qingchun Road, Hangzhou 310016, China lihongheyi@126.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose; D001835:Body Weight; D004195:Disease Models, Animal; D005355:Fibrosis; D005947:Glucose / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism; D008111:Liver Function Tests; D008297:Male; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D010539:Permeability; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D017382:Reactive Oxygen Species; D013481:Superoxides; D005947:Glucose
keywords: apoptosis; glucose fluctuation; mitochondrial permeability transition; nonalcoholic fatty liver disease