title: Involvement of iron depletion in palmitate-induced lipotoxicity of beta cells.
abstract: High levels of plasma free fatty acid are thought to contribute to the loss of pancreatic beta-cells in type 2 diabetes. In particular, saturated fatty acid such as palmitate or stearate can induce apoptosis in cultured beta cells (lipotoxicity). Endoplasmic reticulum stress is a critical mediator of free fatty acid-induced lipotoxicity. Recently, disorders in mitochondrial respiratory metabolism have been linked to lipotoxicity. Since iron is a critical component of respiratory metabolism, this study is initiated to determine whether abnormal iron metabolism is involved in palmitate-induced beta cell death. Immunoblotting analysis showed that treatment of INS-1 beta cells with palmitate reduced the level of transferrin receptor 1 (TfR1), but increased the level of heavy chain ferritin (FTH). In addition, palmitate reduced intracellular labile iron pool. Whereas iron depletion through treatment with iron-chelators deferoxamine or deferasirox augmented palmitate-induced cell death, iron supplementation with ferric chloride, ferrous sulfate, or holo-transferrin significantly protected cells against palmitate-induced death. Furthermore, overexpression of TfR1 reduced palmitate-induced cell death, whereas knockdown of TfR1 augmented cell death. In particular, treatment with deferoxamine increased the level of endoplasmic reticulum (ER) stress markers phospho-PERK, phospho-eIF2α, CHOP and phospho-c-Jun N-terminal kinase. Treatment with chemical chaperone significantly protected cells against deferoxamine-induced apoptosis. Iron supplementation also protected cells against palmitate-induced primary islet death. These data suggest that iron depletion plays an important role in palmitate-induced beta cell death through inducing ER stress. Therefore, attempts to block iron depletion might be able to prevent beta cell loss in type 2 diabetes.
authors.affiliation: Department of Physiology, Ajou University School of Medicine, Suwon, Kyunggi-do 442-749, Republic of Korea; Department of Biomedical Science, The Graduate School, Ajou University School of Medicine, Suwon, Kyunggi-do 442-749, Republic of Korea.
authors.forename: Ik-Rak
authors.initials: IR
authors.lastname: Jung
authors.affiliation: Department of Physiology, Ajou University School of Medicine, Suwon, Kyunggi-do 442-749, Republic of Korea.
authors.forename: Sung-E
authors.initials: SE
authors.lastname: Choi
authors.affiliation: Department of Biomedical Science, The Graduate School, Ajou University School of Medicine, Suwon, Kyunggi-do 442-749, Republic of Korea; Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Kyunggi-do 442-749, Republic of Korea.
authors.forename: Jong-Gab
authors.initials: JG
authors.lastname: Jung
authors.affiliation: Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Kyunggi-do 442-749, Republic of Korea.
authors.forename: Sang-A
authors.initials: SA
authors.lastname: Lee
authors.affiliation: Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Kyunggi-do 442-749, Republic of Korea.
authors.forename: Seung Jin
authors.initials: SJ
authors.lastname: Han
authors.affiliation: Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Kyunggi-do 442-749, Republic of Korea.
authors.forename: Hae Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Kyunggi-do 442-749, Republic of Korea.
authors.forename: Dae Jung
authors.initials: DJ
authors.lastname: Kim
authors.affiliation: Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Kyunggi-do 442-749, Republic of Korea.
authors.forename: Kwan-Woo
authors.initials: KW
authors.lastname: Lee
authors.affiliation: Department of Physiology, Ajou University School of Medicine, Suwon, Kyunggi-do 442-749, Republic of Korea; Department of Biomedical Science, The Graduate School, Ajou University School of Medicine, Suwon, Kyunggi-do 442-749, Republic of Korea. Electronic address: kangy@ajou.ac.kr.
authors.forename: Yup
authors.initials: Y
authors.lastname: Kang
mesh_terms: D000818:Animals; D001052:Apoferritins / Q000235:genetics / Q000378:metabolism; D001565:Benzoates / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002712:Chlorides / Q000494:pharmacology; D000077588:Deferasirox; D003676:Deferoxamine / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000235:genetics; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism; D005290:Ferric Compounds / Q000494:pharmacology; D005296:Ferrous Compounds / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology*; D000090463:Iron Deficiencies; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D019308:Palmitic Acid / Q000633:toxicity*; D051381:Rats; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014168:Transferrin / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D001052:Apoferritins; D001565:Benzoates; D002712:Chlorides; D000077588:Deferasirox; D003676:Deferoxamine; D015852:Eukaryotic Initiation Factor-2; D005290:Ferric Compounds; D005296:Ferrous Compounds; D007502:Iron Chelating Agents; D048031:JNK Mitogen-Activated Protein Kinases; D019308:Palmitic Acid; D011990:Receptors, Transferrin; D051742:Transcription Factor CHOP; D014168:Transferrin; D014230:Triazoles; D019892:eIF-2 Kinase; C497251:Ddit3 protein, rat; C545564:Tfrc protein, rat; C110714:holotransferrin; C020748:ferrous sulfate; C024555:ferric chloride
keywords: Apoptosis; Endoplasmic reticulum (ER) stress; INS-1 beta cell; Iron; Lipotoxicity; Palmitate