title: PINK1 alleviates palmitate induced insulin resistance in HepG2 cells by suppressing ROS mediated MAPK pathways.
abstract: Oxidative stress is an important pathogenesis of insulin resistance (IR) and Type 2 diabetes mellitus (T2DM). Studies have shown that knockdown of PTEN-induced putative kinase 1 (PINK1) causes oxidative stress and mitophagy. In db/db mice, PINK1 protein level is down-regulated. However, little is known regarding the mechanism by which PINK1 modulates IR in response to reactive oxygen species (ROS) induced stress. In our study, PINK1 expression decreased during palmitate (PA) induced IR in HepG2 cells and the hepatic tissues of high fat diet (HFD) fed mice. Additionally, free fatty acids (FFAs) could increase ROS and suppress insulin signaling pathway, which was indicated by reduced phosphorylation of protein kinase B (AKT) and glycogen synthase kinase 3β (GSK-3β). In addition, insulin induced glucose uptake decreased and the expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), two key gluconeogenic enzymes, was up-regulated after PA treatment. Intriguingly, PINK1 overexpression could lead to opposite results. Moreover, PA induced hepatic IR through C-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) pathways, which were rescued by PINK1 overexpression. In summary, our results demonstrate that PINK1 promoted hepatic IR via JNK and ERK pathway in PA treated HepG2 cells, implying a novel molecular target for the therapy of diabetes.
authors.affiliation: Department of Endocrinology, The Second Affiliated Hospital of Nantong University, Nantong University, 226001, Nantong, Jiangsu, People's Republic of China; Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Cang
authors.affiliation: Department of Endocrinology, The Second Affiliated Hospital of Nantong University, Nantong University, 226001, Nantong, Jiangsu, People's Republic of China; Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Endocrinology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu, People's Republic of China.
authors.forename: Pingli
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Endocrinology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu, People's Republic of China.
authors.forename: Xue
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Endocrinology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu, People's Republic of China.
authors.forename: Jin
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Endocrinology, The Second Affiliated Hospital of Nantong University, Nantong University, 226001, Nantong, Jiangsu, People's Republic of China.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Endocrinology, The Second Affiliated Hospital of Nantong University, Nantong University, 226001, Nantong, Jiangsu, People's Republic of China.
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Endocrinology, The Second Affiliated Hospital of Nantong University, Nantong University, 226001, Nantong, Jiangsu, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of Endocrinology, The Second Affiliated Hospital of Nantong University, Nantong University, 226001, Nantong, Jiangsu, People's Republic of China.
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.affiliation: Department of Endocrinology, The Second Affiliated Hospital of Nantong University, Nantong University, 226001, Nantong, Jiangsu, People's Republic of China.
authors.forename: Jianbin
authors.initials: J
authors.lastname: Su
authors.affiliation: Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China; Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Wan
authors.affiliation: Department of Endocrinology, The Second Affiliated Hospital of Nantong University, Nantong University, 226001, Nantong, Jiangsu, People's Republic of China. Electronic address: wangxueqin@medmail.com.cn.
authors.forename: Xueqin
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D019308:Palmitic Acid / Q000008:administration & dosage*; D011494:Protein Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D007328:Insulin; D019308:Palmitic Acid; D011494:Protein Kinases; D017382:Reactive Oxygen Species; D000099202:PTEN-Induced Putative Kinase
keywords: ERK; HepG2 cells; Insulin resistance; JNK; PINK1; ROS