Abstract

Cardiovascular disease is the leading cause of death worldwide. A major treatment goal is to lower plasma lipids, especially low-density lipoprotein cholesterol (LDL), the cardinal risk factor for coronary artery disease (CAD). Patients with familial hypercholesterolemia (FH) experience early-onset CAD due to extremely high LDL. Underdiagnosis and undertreatment of FH are exacerbated by limited therapeutic options. However, one strategy has successfully lowered LDL in FH patients: Inhibition of the hepatically secreted protein Angiopoietin-like protein 3 (ANGPTL3). Despite promising clinical data, the mechanism by which ANGPTL3 inhibition lowers LDL has not been fully described. Although ANGPTL3 has been shown to modulate the metabolism of circulating lipoproteins, its role in hepatic lipoprotein assembly and secretion remained incompletely characterized. In a hepatocyte cell culture model of ANGPTL3 deficiency, we demonstrate increased LDL receptor (LDLR)-dependent turnover of Apolipoprotein B100 (ApoB100)-containing triglyceride-rich lipoproteins (TRLs) and concomitant impairment of their secretion. Additionally, we show that ANGPTL3-deficient hepatocytes exhibit enhanced lipid catabolism. Our findings suggest an unanticipated intrahepatic role for ANGPTL3, whereby ANGPTL3 deficiency leads to the production of fewer lipoprotein particles and adaptive changes in hepatocyte lipid metabolism.

Committee Chair

Nathan Stitziel

Committee Members

Nicholas Davidson; Brian Finck; Clay Semenkovich; Luis Batista

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Molecular Genetics & Genomics)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

5-6-2025

Language

English (en)

Author's ORCID

https://orcid.org/0000-0003-0740-7834

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