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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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Coordination of the unfolded protein response during hepatic steatosis identifies CHOP as a specific regulator of hepatocyte ballooning
The unfolded protein response (UPR) is an adaptive response that is implicated in multiple metabolic pathologies, including hepatic steatosis. In the present study we analyzed publicly available RNAseq data to explore how the execution of the UPR is orchestrated in specimens that exhibit hepatocyte ballooning, a landmark feature of steatosis. By focusing on a panel of well-established UPR genes we assessed how the UPR is coordinated with the whole transcriptome in specimens with or without hepatocyte ballooning. Our analyses showed that neither average levels nor correlation in expression between major UPR genes such as HSPA5 (BiP/GRP78), HSP90b1 (GRP94) or DDIT3 (CHOP), is altered in different groups. However, a panel of transcripts that depending on the stringency of the analysis ranged from 16 to 372, lost its coordination with HSPA5, the major UPR chaperone, when hepatocyte ballooning occurred. In 13 genes the majority of which is associated with metabolic processes, the coordination with the HSPA5 was reversed from positive to negative in livers with ballooning hepatocytes. In order to examine if during ballooning, UPR genes abolish established and acquire novel functionalities we performed gene ontology analyses. These studies showed that among the various UPR genes interrogated, DDIT3 was the only that during ballooning was not associated with conventional functions linked to endoplasmic reticulum stress while HSPA90b1 exhibited the highest function retention between the specimens with or without ballooning. Our results challenge conventional notions on the impact of specific genes in disease and suggest that besides abundance, the mode of coordination of UPR may be more important for disease development.
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- Award ID(s):
- 1736150
- PAR ID:
- 10164411
- Date Published:
- Journal Name:
- Cell Stress and Chaperones
- ISSN:
- 1355-8145
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1007/s12192-020-01132-x
