In this issue of Endocrinology, Miani and colleagues (1) provide evidence that increased circulating levels of free fatty acids (FFA) associated with obesity induce a mild endoplasmic reticulum (ER) stress in pancreatic -cells that predisposes them to an augmented inflammatory response when exposed to cytokines such as IL-1 or TNF. They found that rat insulinoma cells (INS-1E), or primary rat -cells, when exposed to the ER stressor sarcoplasmic/endoplasmic reticulum Ca -ATPase (SERCA) blocker (cyctopiazonic acid) or free fatty acids (FFA), followed by exposure to low-dose IL-1 or TNF, had enhanced expression of the inflammatory markers CCL2, CXCL1, iNOS, and Fas. Interrogation of the molecular pathway showed augmented nuclear factorB (NFB) activation, after degradation of forkhead box O1 (FoxO1) protein. Using small interfering RNA that targeted specific ER stress pathways, the investigators demonstrated involvement of the inositol-requiring enzyme 1 (IRE1)/X-box binding protein-1s (XBP1s) pathway. The importance of these findings is that obesity-associated FFA may easily induce mild -cell ER stress that, in turn, triggers a heightened inflammatory response that could drive apoptosis. -cell apoptosis is the primary pathogenic mechanism that underlies type 1 diabetes, an area of growing concern because the worldwide incidence of type 1 diabetes is increasing at a rapid rate. The ER is central for the processing, folding, and exporting of newly synthesized proteins (2). The folding of proteins into their native structure in the ER is mediated by folding enzymes, molecular chaperones, and folding sensor proteins (3). The whole process is regulated by a stringent quality control system that inhibits the export of incompletely folded or misfolded proteins (4). This ensures that potentially malfunctioning proteins that could be detrimental to the cell are not deployed. Excessive demands on the protein-folding capacity of the ER can cause irremediable ER stress that contributes to cell death. ER stress is sensed as intrinsic cell damage, and in turn, this leads to ER release of proapoptotic factors such as BCL2-associated x protein, NADPH oxidase activator 1, v-crk sarcoma virus CT1O oncogene; BCL2antagonist/killer 1, BCL-2 interacting mediator, p53 upregulated modulator of apoptosis, and the newly recognized major player, CRK (5–7). These proteins activate the BAXand/or BAK-dependent mitochondrial apoptotic pathway culminating in outer mitochondrial membrane permeabilization and the release of pro-death mitochondrial proteins (such as cytochrome c) into the cytosol, causing activation of effector caspases (8–10). Before irremediable ER stress, and activation of the pro-death pathway, an unfolded protein response (UPR) is activated, which alters gene expression and translational programs to try and overcome the stressful conditions and to restore ER homeostasis (11–14). ER stress can be caused by a number of different stimuli, including heat shock, energy deprivation, hypoxia, metabolic dysfunction, drugs, increased levels of circulating cytokines, FFA, and nutrient excess (15, 16). Indeed, the ER is highly responsive to cellular nutrient and energy status. The intracellular pathways that mediate the UPR are well characterized. There are three UPR signaling cascades, each of which are initiated through different ERlocalized transmembrane proteins, namely, IRE1, pancreatic ER kinase (PERK), and activating transcription factor
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