Role of endoplasmic reticulum stress in metabolic disease and other disorders

Abstract

Perturbations in the normal functions of the endoplasmic reticulum (ER) trigger a signaling network that coordinates adaptive and apoptotic responses. There is accumulating evidence implicating prolonged ER stress in the development and progression of many diseases, including neurodegeneration, atherosclerosis, type 2 diabetes, liver disease, and cancer. With the improved understanding of the underlying molecular mechanisms, therapeutic interventions that target the ER stress response would be potential strategies to treat various diseases driven by prolonged ER stress.

Figure 1

Endoplasmic reticulum (ER) stress response. Upon accumulation of unfolded proteins in the ER lumen, three stress sensors—IRE1, PERK, and ATF6—are activated and initiate signal transduction events that control cell survival or death. PERK, protein kinase RNA-like ER kinase; IRE1, inositol requiring protein 1; ATF6, activating transcription factor 6; eIF2α, eukaryotic translation initiation factor 2 alpha; CHOP, C/EBPα-homologous protein; Bcl-2, B cell lymphoma 2; Ero1α, ER oxidase 1 alpha; TRAF2, TNF receptor–associated factor 2; JNK, c-Jun N-terminal kinase; ASK1, apoptosis signal-regulating kinase 1; XBP1, X-box binding protein 1; ERAD, endoplasmic reticulum–associated degradation; UPR, unfolded protein response.