Involvement of iron depletion in palmitate-induced lipotoxicity of beta cells.

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.

Jung IR ，Choi SE ，Jung JG ，Lee SA ，Han SJ ，Kim HJ ，Kim DJ ，Lee KW ，Kang Y ... -  《-》

Cytokine-induced beta-cell death is independent of endoplasmic reticulum stress signaling.

Akerfeldt MC ，Howes J ，Chan JY ，Stevens VA ，Boubenna N ，McGuire HM ，King C ，Biden TJ ，Laybutt DR ... -  《-》

Metformin attenuates palmitate-induced endoplasmic reticulum stress, serine phosphorylation of IRS-1 and apoptosis in rat insulinoma cells.

Simon-Szabó L ，Kokas M ，Mandl J ，Kéri G ，Csala M ... -  《-》

Initiation and execution of lipotoxic ER stress in pancreatic beta-cells.

Cunha DA ，Hekerman P ，Ladrière L ，Bazarra-Castro A ，Ortis F ，Wakeham MC ，Moore F ，Rasschaert J ，Cardozo AK ，Bellomo E ，Overbergh L ，Mathieu C ，Lupi R ，Hai T ，Herchuelz A ，Marchetti P ，Rutter GA ，Eizirik DL ，Cnop M ... -  《-》

Iron chelator-induced apoptosis via the ER stress pathway in gastric cancer cells.

Kim JL ，Lee DH ，Na YJ ，Kim BR ，Jeong YA ，Lee SI ，Kang S ，Joung SY ，Lee SY ，Oh SC ，Min BW ... -  《-》