The Role of the Unfolded Protein Response in Fatty Liver Disease

Author

Anusha L. Murshed, University of the PacificFollow

Date of Award

2024

Document Type

Thesis

Degree Name

Master of Science (M.S.)

Department

Biological Sciences

First Advisor

Douglas C. Weiser

First Committee Member

Jane Khudyakov

Second Committee Member

Tara C. Thiemann

Abstract

The unfolded protein response (UPR) is composed of three highly conserved pathways (ATF6, IRE1, PERK). Cellular stressors induce protein misfolding and aggregation in the endoplasmic reticulum (ER). This signaling pathway maintains protein homeostasis when there is stress in the ER. When the UPR is activated, the eukaryotic initiation factor 2 alpha (eIF2α) becomes phosphorylated, which inhibits global mRNA translation. If ER stress remains chronically unmitigated, the UPR induces apoptosis. GADD34 and CReP shift in expression when the UPR is activated and work as phosphatases and dephosphorylate eIF2α in a feedback loop, allowing protein synthesis to resume. Several human diseases, including fatty liver disease (FLD) are affected by cell stress from improper protein folding and accumulation, making the UPR a therapeutic target. Previous studies have indicated the UPR to both cause or become activated by FLD, depending on the duration of cellular stress. At least 25% of humans worldwide have steatosis, and zebrafish are a powerful model organism for FLD studies. Their embryos are easily obtained, and the liver develops quickly in their transparent larvae, which allows us to visualize the development of fat in the liver. It is unknown how exactly the UPR is involved in inducing lipogenesis in hepatocytes. We sought to better understand the link between UPR activation and steatosis. Pharmacological treatments with various drugs, some of which induce ER stress, were administered over different durations in zebrafish embryos and subsequently the expression of UPR network and lipogenesis genes were quantified through RT-qPCR. To visualize whether these drugs induced steatosis, zebrafish livers were stained with Oil Red O and imaged. Our results indicate that all chronic durations of pharmacological treatments resulted in fatty liver, and the expression of atf6 decreased in response to treatment that prevents the dephosphorylation of eIF2α. This data provides insight pertaining to the activity of the UPR network during FLD in zebrafish models.

Pages

83

Recommended Citation

Murshed, Anusha L.. (2024). The Role of the Unfolded Protein Response in Fatty Liver Disease. University of the Pacific, Thesis. https://scholarlycommons.pacific.edu/uop_etds/4277