Remodeling of Nutrient Homeostasis by Unfolded Protein Response
Nature is unlikely to maintain systems that are detrimental to survival. Any pathway that causes illness must also have a meaningful role. Endoplasmic reticulum (ER) stress, which mediates obesity-induced insulin resistance, is no exception as it helps maintain nutrient homeostasis.
About one-third of all proteins are synthesized and folded into their native conformation in ER (1). Unfortunately, as much as 30% of all newly synthesized proteins, especially those abundant in cells, are misfolded. These are generally repaired or cleared during the maturation processes (2). ER is also responsible for protein quality control (3). Unfolded proteins in the ER lumen are identified by several ER stress sensors, including activating transcription factor (ATF) 6, protein kinase RNA-like ER kinase (PERK), and inositol-requiring enzyme 1 (IRE-1). These ER stress sensors trigger cellular adaptation to unfolded protein accumulation that restores normal cell function. This is called the unfolded protein response (UPR). The UPR initially 1) activates a signaling pathway that induces a large number of ER chaperones that assist protein folding, 2) halts protein translation and transcription, and 3) ubiquitinates and degrades unfolded proteins by 26S proteasome and through autophagy. The latter process is called ER-associated degradation. If these adaptations fail to maintain cellular homeostasis, the UPR leads the cell toward apoptosis or dedifferentiation (3).
Chronic UPRs are causally linked to the pathogenesis of human metabolic disease including obesity and type 2 diabetes. Accumulating evidence suggests that obesity promotes ER stress, which is detected as enhanced UPR signaling. In turn, this activates c-Jun NH2-terminal kinase (JNK) and impairs insulin signaling at the level of insulin receptor substrates (IRSs) in the liver and adipose tissue (4). However, the signals that activate UPR under this condition are still unknown. Defective autophagy (5) and proteasome dysfunction (6) have recently been …