Keywords
Cholesterol, Hypercholesterolemia, LDLR, Prostasin, Hepsin, Matriptase
Abstract
Hypercholesterolemia is a disease affecting many Americans and adults worldwide and can lead to further complications such as atherosclerosis, stroke, or pulmonary embolisms making it a major risk factor for heart disease. The disease states are caused by chronically elevated levels of VLDLs that get broken down into LDLs. Cells expressing the LDLR can endocytose LDLs from the blood for use intracellularly as cholesterol and prevent plasma cholesterol deposition in the endothelium. Current treatments include leading healthier lifestyles through dieting and exercise, or pharmacological treatments targeting cellular cholesterol production or dietary cholesterol uptake from the GI tract. The SREBPs are known to upregulate the expression of the LDLR and prostasin, a serine protease. A connection between the receptor and protease would elucidate the LDL uptake pathway and prompt investigations into regulating cholesterol plasma levels through pharmacological inhibition to elevate the LDLR’s expression. However, this study’s results indicate the absence of a direct relationship between the cleavage of the LDLR and prostasin in vitro. Cleavage products were not observed in the HEK293 co-transfected with prostasin and the LDLR, or in the prostasin-expressing HeLa cells transfected with the LDLR. Cleavage of the LDLR extracellular domain (ECD) at sites close to the membrane was observed in HEK293 cells co-transfected with hepsin or matriptase, two closely related proteases to prostasin. It had been shown previously that matriptase can be activated by prostasin and hepsin, and matriptase cleavage of the EGFR ECD can be enhanced by prostasin. Further study is necessary to determine the precise mechanisms by which these membrane serine proteases regulate the LDLR presentation at the cell surface. Prostasin may still have an unknown role in the LDLR expression pathway as they are both regulated by the SREBPs, however, prostasin appears to lack the ability to cleave the ECD of the LDLR directly.
Thesis Completion Year
2025
Thesis Completion Semester
Spring
Thesis Chair
Chai, Karl
College
College of Medicine
Department
Biomedical Sciences
Thesis Discipline
Biomedical Sciences
Language
English
Access Status
Open Access
Length of Campus Access
None
Campus Location
Orlando (Main) Campus
STARS Citation
Ruiz, Matthew E., "Post-Translational Modification Of The Low-Density Lipoprotein Receptor By Serine Proteases" (2025). Honors Undergraduate Theses. 329.
https://stars.library.ucf.edu/hut2024/329
Rights Statement
