Graduation Date

Fall 12-20-2019

Document Type

Thesis

Degree Name

Master of Science (MS)

Programs

Biochemistry & Molecular Biology

First Advisor

Željka Korade

Second Advisor

Laurey Steinke

Third Advisor

William B. Rizzo

Abstract

Cholesterol biosynthesis is integral to proper neurodevelopment due to the reliance on de novo synthesis of cholesterol in the brain. Disruptions in this process have devastating outcomes for human life characterized by several phenotypic manifestations concomitant with developmental delay. The cholesterol biosynthesis disorder desmosterolosis is an extremely rare disorder with a severe clinical phenotype, however, the models used to study this disease are not well characterized. In addition to genetic disruptions in cholesterol biosynthesis, pharmacological perturbation is an understudied side effect of many commonly prescribed drugs. Here we present a characterization of the sterol profile of the mouse model of desmosterolosis followed by an examination of one such pharmacological inhibitor of cholesterol biosynthesis, amiodarone. Amiodarone is a commonly prescribed medication used to treat life-threatening atrial and ventricular arrhythmias with the primary target being potassium channels and beta adrenergic receptors. We show that amiodarone is also a potent inhibitor of several cholesterol biosynthesis enzymes in various cell culture models, affecting the enzymes 24-dehydrocholesterol reductase (Dhcr24) and emopamil binding protein (Ebp). Additionally we show that the serum of amiodarone users have elevated levels of desmosterol, zymosterol, zymostenol and 8-dehydrocholesterol. Our study provides evidence that the use of various medications, unrelated to cholesterol metabolism, may lead to potentially severe clinical consequences related to the inhibition of sterol biosynthetic enzymes.

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