Targeting endoplasmic reticulum stress in metabolic disease

Introduction: Endoplasmic reticulum (ER) stress, a condition that dramatically affects protein folding homeostasis in cells, has been associated with a number of metabolic diseases. Emerging preclinical and clinical evidence supports the notion that pharmacological modulators of ER stress have therapeutic potential as novel treatments of metabolic disorders. Areas covered: In this review, the molecular mechanisms of ER stress and the unfolded protein response (UPR) in the pathogenesis of metabolic diseases are discussed, highlighting the roles of various UPR components revealed using disease models in mice. Special emphasis is placed on the use of novel small molecules in animal disease models and human pathologies, including type 2 diabetes, obesity, fatty liver disease, and atherosclerosis. Expert opinion: ER stress is a highly promising therapeutic target for metabolic disease. Small molecular chemical chaperones have already demonstrated therapeutic efficacy in animal and human studies. The emergence of compounds that target specific UPR signaling pathways will provide more options for this purpose. Although the findings are promising, more studies are needed to elucidate the efficacy and side effects of these small molecules for future use in humans.