Unfolded protein response signaling and metabolic diseases

The ever-rising worldwide incidence of metabolic diseases, such as obesity and type 2 diabetes, has made them an important target for researchers. The therapeutic options available so far are rather scarce. Endoplasmic reticulum, or ER, stress, the focus of studies for two decades already, appears to be intimately involved, making it a good candidate for pharmacologic interventions.
In a minireview recently published in the Journal of Biological Chemistry, researchers Jaemin Lee and Umut Ozcan at Boston Children’s Hospital detail the correlation between ER stress and metabolic changes, highlighting some plausible therapeutic solutions.
The ER is an essential organelle for protein biosynthesis. It processes newly synthesized proteins, modifying and folding them according to rigorous quality standards. This process is dynamically adjusted depending on the physiological status of cells. ER stress appears when the workload exceeds the folding possibilities of the ER, activating a compensatory system called the unfolded protein response, or UPR. The UPR tries to increase the resources that the ER needs to fold more proteins and to reduce the protein load in the ER, but if the ER fails to do so for prolonged periods of time, UPR signaling initiates cell death.
The UPR has three branches mediated by three ER transmembrane proteins: IRE1, or inositol-requiring protein-1; PERK, or protein kinase RNA-like ER-kinase; and ATF6, or activating transcription factor-6 (see figure). In their minireview, Lee and Ozcan summarize the current understanding of how IRE1, PERK and ATF6 pathways work and how they interact with other signaling networks.

UPR signaling and its cross-talk mediated by IRE1-XBP1, PERK and ATF6.
UPR signaling and its cross-talk mediated by IRE1, PERK and ATF6.

ER stress can be induced in major metabolic disorders like leptin and insulin resistance, nonalcoholic fatty liver disease, and atherosclerosis. ER stress is caused in these conditions by increased levels of reactive oxygen species and ER calcium depletion by sarco/endoplasmic reticulum calcium ATPase, or SERCA, dysfunction; cholestasis and high levels of circulating homocysteine; and by fatty acids, oxidized lipids, cholesterol and hyperhomocysteinemia. While the causes of ER stress vary, all mechanisms that induce ER stress involve IRE1, PERK and ATF6.
The minireview notes that not only have various studies elucidated the mechanisms responsible for some of the pathophysiological changes, but they’ve also shown that chemical chaperones reducing ER stress (e.g., 4-phenylbutyric acid and tauroursodeoxycholic acid) restore leptin responsivity, improve insulin sensitivity and glucose homeostasis, and reduce hepatic lipogenesis.
Also, attempts have been made to modulate specific components of the UPR as potential treatments for metabolic disorders and multiple myeloma (IRE1 modulators) and for inhibiting tumor growth and neurodegeneration (PERK inhibitors). Lee and Ozcan emphasize the need for more pharmacologic endeavors focused on UPR components.

Teodora DonisanTeodora Donisan (teodora.donisan@
gmail.com) is a medical student at Carol Davila University in Bucharest, Romania.