Involvement of iron depletion in palmitate-induced lipotoxicity of beta cells. (15th May 2015)

• Record Type: Journal Article
• Authors: Jung, Ik-Rak; Choi, Sung-E.; Jung, Jong-Gab; Lee, Sang-A.; Han, Seung Jin; Kim, Hae Jin; Kim, Dae Jung; Lee, Kwan-Woo; Kang, Yup
• Is Part Of: Molecular and cellular endocrinology. Volume 407(2015)
• Page Start: 74
• Page End: 84
• Publication Date: 2015-05-15
• Subjects: Apoptosis -- Endoplasmic reticulum (ER) stress -- Lipotoxicity -- INS-1 beta cell -- Iron -- Palmitate; ATF6 activating transcription factor-6 -- CHOP C/EBP homologous protein -- DFO deferoxamine -- DS deferasirox -- ER endoplasmic reticulum -- FFA free fatty acid -- FTH ferritin heavy chain -- h-Tf holo-transferrin -- IRE1 Inositol-requiring enzyme-1 -- IRP iron regulatory protein -- JNK C-Jun N-terminal kinase -- LIP labile iron pool -- OCR oxygen consumption rate -- PA palmitate -- 4-PBA 4-phenylbutyrate -- PERK protein kinase RNA (PKR)-like ER kinase -- ROS reactive oxygen species -- SD Sprague–Dawley -- TfR transferrin receptor -- TCA tricarboxylic acid -- UPR unfolded protein response; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2015.03.007
• Languages: English
• ISSNs: 0303-7207

Abstract

Highlights: Palmitate treatment reduced the level of transferrin receptor 1 in INS-1 beta cells. Palmitate treatment reduced labile iron pool in INS-1 cells. Iron depletion augmented palmitate-induced INS-1 cell death. Iron depletion induced ER stress responses and augmented palmitate-induced ER stress. Iron supplementation protected palmitate-induced lipotoxicity. 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.