Steven Berberich (Committee Member), Michael Markey (Committee Member), Lawrence Prochaska (Committee Member), S. Dean Rider, Jr. (Advisor)
Master of Science (MS)
Liver X receptor a (LXRa) plays a critical role in the maintenance of energy homeostasis within a cell through tight transcriptional regulation of genes involved in metabolism of lipids, glucose, and cholesterol. Although LXRa has been established to function as a heterodimer with the retinoid X receptor a (RXRa), recent studies have determined that LXRa also interacts directly with peroxisome proliferator-activated receptor a (PPARa). However, little is known regarding the functionality of this heterodimer, if any exists at all. This study determined that a heterodimer of PPARa and LXRa is capable of binding to candidate response elements in vitro with high affinity by electrophoretic mobility shift assays and quenching of intrinsic protein fluorescence. Additionally, LXRa exhibited high affinity binding to DNA in the absence of a heterodimer partner, suggesting homodimeric interaction. Transactivation assays indicated that overexpression of PPARa and LXRa significantly increased activity of the endogenous APOA1 promoter, and overexpression of LXRa alone resulted in increased activity of all of the promoters tested, often even more so than LXRa/RXRa. These results provide new insight into the scope of metabolic regulation by LXRa, and raise important questions and considerations when targeting these proteins for treatment of metabolic disorders.
Department or Program
Department of Biochemistry and Molecular Biology
Year Degree Awarded
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