An update on lipotoxic endoplasmic reticulum stress in pancreatic β-cells

The UPR (unfolded protein response) or ER (endoplasmic reticulum) stress response was first described 20 years ago. The field of ER stress has expanded tremendously since, moving from basic biology in yeast to human neurodegenerative, inflammatory, cardiovascular and neoplastic diseases. The ER stress response has also been implicated in diabetes development, affecting both insulin production by pancreatic β-cells and insulin sensitivity in peripheral tissues. In the present mini-review, we focus on recent progress in the field of ER stress in pancreatic β-cells. Recent advances in the understanding of lipotoxic ER stress and β-cell recovery from ER stress are discussed. ER (endoplasmic reticulum) stress signalling The ER stress response is an important adaptive cellular signalling response in cells with high secretory activity. It aims to balance secretory protein synthesis in the ER against ER protein folding capacity. An imbalance between ER folding needs and capacity leads to activation of the ER stress response, also known as the UPR (unfolded protein response). This cellular response aims to restore ER homoeostasis by attenuating global protein translation, up-regulating ER chaperones (thereby increasing ER folding capacity), and degrading misfolded proteins [1,2]. These co-ordinated transcriptional and translational responses (schematically represented in Figure 1) are initiated by the ER stress transducers IRE (inositol requiring ER-to-nucleus signal kinase) 1, ATF (activating transcription factor) 6 and PERK [PKR (double-strandedRNA-dependent protein kinase)-like ER kinase]. These three ER membrane proteins are inactive when bound to the ER chaperone BiP (immunoglobulin heavy-chain-binding protein), also known as GRP (glucose-regulated protein) 78 or HSPA5 (heat-shock protein A5). Dissociation of BiP from their luminal side leads to their activation and downstream ER stress signalling. Active IRE1 alternatively splices XBP (X-box-binding protein) 1 mRNA. XBP1s (spliced XBP1) induces genes involved in ER expansion, protein folding and misfolded protein degradation [3–5].