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Endoplasmic reticulum (ER) stress has been causatively linked to the onset of various pathologies. However, if and how inherent variations in the resulting unfolded protein response (UPR) affect the predisposition to ER stress-associated metabolic conditions remains to be established. By using genetically diverse deer mice (Peromyscus maniculatus) as a model, we show that the profile of tunicamycin-induced UPR in fibroblasts isolated at puberty varies between individuals and predicts deregulation of lipid metabolism and diet-induced hepatic steatosis later in life. Among the different UPR targets tested, CHOP more consistently predicted elevated plasma cholesterol and hepatic steatosis. Compared to baseline levels or inducibility, the maximal intensity of the UPR following stimulation best predicts the onset of pathology. Differences in the expression profile of the UPR recorded in cells from different populations of deer mice correlate with the varying response to ER stress in altitude adaptation. Our data suggest that the response to ER stress in cultured cells varies among individuals and its profile early in life may predict the onset of ER stress-associated disease in the elderly.
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Evaluating endoplasmic reticulum stress and unfolded protein response through the lens of ecology and evolution
ABSTRACT Considerable progress has been made in understanding the physiological basis for variation in the life‐history patterns of animals, particularly with regard to the roles of oxidative stress and hormonal regulation. However, an underappreciated and understudied area that could play a role in mediating inter‐ and intraspecific variation of life history is endoplasmic reticulum (ER) stress, and the resulting unfolded protein response (UPRER). ER stress response and the UPRERmaintain proteostasis in cells by reducing the intracellular load of secretory proteins and enhancing protein folding capacity or initiating apoptosis in cells that cannot recover. Proper modulation of the ER stress response and execution of the UPRERallow animals to respond to intracellular and extracellular stressors and adapt to constantly changing environments. ER stress responses are heritable and there is considerable individual variation in UPRERphenotype in animals, suggesting that ER stress and UPRERphenotype can be subjected to natural selection. The variation in UPRERphenotype presumably reflects the way animals respond to ER stress and environmental challenges. Most of what we know about ER stress and the UPRERin animals has either come from biomedical studies using cell culture or from experiments involving conventional laboratory or agriculturally important models that exhibit limited genetic diversity. Furthermore, these studies involve the assessment of experimentally induced qualitative changes in gene expression as opposed to the quantitative variations that occur in naturally existing populations. Almost all of these studies were conducted in controlled settings that are often quite different from the conditions animals experience in nature. Herein, we review studies that investigated ER stress and the UPRERin relation to key life‐history traits including growth and development, reproduction, bioenergetics and physical performance, and ageing and senescence. We then ask if these studies can inform us about the role of ER stress and the UPRERin mediating the aforementioned life‐history traits in free‐living animals. We propose that there is a need to conduct experiments pertaining to ER stress and the UPRERin ecologically relevant settings, to characterize variation in ER stress and the UPRERin free‐living animals, and to relate the observed variation to key life‐history traits. We urge others to integrate multiple physiological systems and investigate how interactions between ER stress and oxidative stress shape life‐history trade‐offs in free‐living animals.
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- PAR ID:
- 10382044
- Publisher / Repository:
- Wiley-Blackwell
- Date Published:
- Journal Name:
- Biological Reviews
- Volume:
- 96
- Issue:
- 2
- ISSN:
- 1464-7931
- Page Range / eLocation ID:
- p. 541-556
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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