Author

Youwen Zhang

Date of Award

Fall 2021

Document Type

Open Access Dissertation

Department

College of Pharmacy

First Advisor

Hippokratis Kiaris

Abstract

Numerous studies linked endoplasmic reticulum (ER) stress and unfolded protein response (UPR) to physiological responses to stress and various human pathologies, including metabolic disorders. Although variability in stress responses among individuals has been widely recognized, how such variations in the UPR affect susceptibility to diseases remains unknown. Using outbred deer mice as a model, we explored the consequences of the differential propensity to UPR at the transcriptomic, cellular, and organismic level.

Initially, we analyzed the correlation between several UPR-related genes in primary fibroblasts, at the whole transcriptome level, after ER stress induction. The analysis of correlated transcripts revealed that their profiles reflect specific UPR branches and biological processes. By using this strategy, we showed that Rassf1 is involved in ER stress-associated apoptosis, downstream of ATF4. In addition, we analyzed the RNA-Seq data derived from human specimens and identified CHOP as a specific regulator of hepatocyte ballooning. We further advanced the approach to assess correlation of each transcript with every other transcript at whole transcriptome level and revealed immune cell engagement progressed robustly in the liver transcriptomes of animals with steatosis even without the presence of histologically detectable inflammation.

At the organismal level, we investigated whether variations in UPR among individuals influence the propensity for metabolic disease. The results indicate the intensity of UPR in primary fibroblasts isolated early in life predicts the extent of body weight gain after HFD consumption. Contrary to those with intense UPR, the animals with moderate UPR in fibroblasts displayed compromised stress resolution and did not gain body weight but developed inflammation in skin. The study suggests UPR operates as a modifier of an individual’s propensity for body weight gain in a manner that involves the regulation of an inflammatory response partly by skin fibroblasts.

Collectively, my results show that UPR is highly variable among individuals and its intensity determines both susceptibility to metabolic disease and other physiological responses such as the extent of body weight gain. Besides its significance in understanding adaptation to stress response my results point to new strategies for analyzing transcriptomes of genetically diverse populations.

Available for download on Friday, May 31, 2024

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