title: Effect of excess iron on oxidative stress and gluconeogenesis through hepcidin during mitochondrial dysfunction.
abstract: Excessive tissue iron levels are a risk factor for insulin resistance and type 2 diabetes, which are associated with alterations in iron metabolism. However, the mechanisms underlying this association are not well understood. This study used human liver SK-HEP-1 cells to examine how excess iron induces mitochondrial dysfunction and how hepcidin controls gluconeogenesis. Excess levels of reactive oxygen species (ROS) and accumulated iron due to iron overload induced mitochondrial dysfunction, leading to a decrease in cellular adenosine triphosphate content and cytochrome c oxidase III expression, with an associated increase in gluconeogenesis. Disturbances in mitochondrial function caused excess iron deposition and unbalanced expression of iron metabolism-related proteins such as hepcidin, ferritin H and ferroportin during the activation of p38 mitogen-activated protein kinase (MAPK) and CCAAT/enhancer-binding protein alpha (C/EBPα), which are responsible for increased phosphoenolpyruvate carboxykinase expression. Desferoxamine and n-acetylcysteine ameliorated these deteriorations by inhibiting p38 MAPK and C/EBPα activity through iron chelation and ROS scavenging activity. Based on experiments using hepcidin shRNA and hepcidin overexpression, the activation of hepcidin affects ROS generation and iron deposition, which disturbs mitochondrial function and causes an imbalance in iron metabolism and increased gluconeogenesis. Repression of hepcidin activity can reverse these changes. Our results demonstrate that iron overload is associated with mitochondrial dysfunction and that together they can cause abnormal hepatic gluconeogenesis. Hepcidin expression may modulate this disorder by regulating ROS generation and iron deposition.
authors.affiliation: Division of Metabolic Diseases, Center for Biomedical Sciences, National Institute of Health, 187 Osongsaengmyeong2-ro, Osong-eup, Heungdeok-gu, cheongju-si, Chungcheongbuk-do, 363-951, South Korea.
authors.forename: Hyo Jung
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Division of Metabolic Diseases, Center for Biomedical Sciences, National Institute of Health, 187 Osongsaengmyeong2-ro, Osong-eup, Heungdeok-gu, cheongju-si, Chungcheongbuk-do, 363-951, South Korea; Department of Home Economics Education, College of Education, Kyungnam University, Changwon-si, Gyeongsangnam-do, South Korea.
authors.forename: Joo Sun
authors.initials: JS
authors.lastname: Choi
authors.affiliation: Division of Metabolic Diseases, Center for Biomedical Sciences, National Institute of Health, 187 Osongsaengmyeong2-ro, Osong-eup, Heungdeok-gu, cheongju-si, Chungcheongbuk-do, 363-951, South Korea.
authors.forename: Hye Ja
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Division of Metabolic Diseases, Center for Biomedical Sciences, National Institute of Health, 187 Osongsaengmyeong2-ro, Osong-eup, Heungdeok-gu, cheongju-si, Chungcheongbuk-do, 363-951, South Korea.
authors.forename: Won-Ho
authors.initials: WH
authors.lastname: Kim
authors.affiliation: Division of Metabolic Diseases, Center for Biomedical Sciences, National Institute of Health, 187 Osongsaengmyeong2-ro, Osong-eup, Heungdeok-gu, cheongju-si, Chungcheongbuk-do, 363-951, South Korea.
authors.forename: Sang Ick
authors.initials: SI
authors.lastname: Park
authors.affiliation: Division of Metabolic Diseases, Center for Biomedical Sciences, National Institute of Health, 187 Osongsaengmyeong2-ro, Osong-eup, Heungdeok-gu, cheongju-si, Chungcheongbuk-do, 363-951, South Korea. Electronic address: jhsong10@korea.kr.
authors.forename: Jihyun
authors.initials: J
authors.lastname: Song
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000378:metabolism; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology; D003576:Electron Transport Complex IV / Q000378:metabolism; D005293:Ferritins / Q000378:metabolism; D005943:Gluconeogenesis; D064451:Hepcidins / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000737:chemistry*; D019190:Iron Overload / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009840:Oligomycins / Q000737:chemistry; D018384:Oxidative Stress; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D064451:Hepcidins; D009840:Oligomycins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D000098742:Ferroportin; D005293:Ferritins; D007501:Iron; D003576:Electron Transport Complex IV; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Gluconeogenesis; Hepcidin; Iron overload; Mitochondrial dysfunction; ROS