Archived
This content is available here for research, reference, and/or recordkeeping.
Instructions
https://doi.org/10.13023/etd.2026.156
Author ORCID Identifier
https://orcid.org/0009-0008-3871-0020
Date Available
4-29-2028
Year of Publication
2026
Document Type
Master's Thesis
Degree Name
Master of Science in Medical Sciences (MSMS)
College
Medicine
Department/School/Program
Physiology
Faculty
Richard Grondin
Faculty
Gregory A. Graf
Abstract
Sitosterolemia (STSL) is a monogenic, recessive disorder characterized by the accumulation of xenosterols in plasma and is caused by mutations in either ABCG5 or ABCG8, genes that encode ABC half transporters that form a heterodimer (G5G8) that opposes sterol absorption in the intestine and promotes biliary sterol secretion in the liver. Like STSL, cystic fibrosis (CF) is caused by mutations in the ABC transporter cystic fibrosis transmembrane conductance regulator (CFTR, ABCC7). Highly Effective Modulator Therapies (HEMTs) are a collection of drugs used in combination to treat CF. HEMTs have been shown to modulate other ABC transporters, suggesting they may interact with G5G8 to alter wild-type or mutant protein function. We established human hepatocyte cell lines expressing ABCG5 and ABCG8 and tested the effect of HEMTs on G5G8 protein abundance. HEMTs increased G5G8 abundance in cultured cells and the appearance of a high-molecular weight form of ABCG5. Finally, we examined the effect of HEMTs on G5G8 and biliary cholesterol secretion in mice. HEMTs reduced endogenous G5G8 and biliary cholesterol secretion but had no impact on intestinal G5G8 or whole-body sterol balance. HEMTs promoted hepatic triglyceride accumulation and the expression of collagens, suggesting that HEMTs may contribute to CF liver disease (CFLD).
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2026.156
Archival?
Archival
Funding Information
This study was supported by the National Institute of Digestive and Diabetes and Kidney Diseases Grant (R01DK113625).
Recommended Citation
Campbell, Meredith G., "THE IMPACT OF HIGHLY EFFECTIVE MODULATOR THERAPIES ON THE ABCG5 AND ABCG8 STEROL TRANSPORTERS AND BILIARY LIPID SECRETION" (2026). Theses and Dissertations--Medical Sciences. 30.
https://uknowledge.uky.edu/medsci_etds/30
