Involvement of iron depletion in palmitate-induced lipotoxicity of beta cells
| Autor: | Yup Kang, Jong-Gab Jung, Sung-E Choi, Hae Jin Kim, Seung Jin Han, Ik-Rak Jung, Kwan Woo Lee, Dae Jung Kim, Sang-A Lee |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Programmed cell death
medicine.medical_specialty Eukaryotic Initiation Factor-2 Palmitic Acid Transferrin receptor Deferoxamine Biology Iron Chelating Agents Benzoates Ferric Compounds Biochemistry eIF-2 Kinase Endocrinology Chlorides Cell Line Tumor Insulin-Secreting Cells Internal medicine Receptors Transferrin medicine Animals Humans Ferrous Compounds Molecular Biology chemistry.chemical_classification Cell Death JNK Mitogen-Activated Protein Kinases Transferrin Iron Deficiencies Triazoles Endoplasmic Reticulum Stress Rats Ferritin Deferasirox Gene Expression Regulation chemistry Lipotoxicity Apoferritins Saturated fatty acid biology.protein Beta cell Transcription Factor CHOP Signal Transduction medicine.drug |
| Zdroj: | Molecular and Cellular Endocrinology. 407:74-84 |
| ISSN: | 0303-7207 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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