2022 Spring Research Symposium

Dissecting the unique roles of NCOR1, SMRT, and HDAC3 in hepatic lipid metabolism

As many as 100 million people in the US are affected by non-alcoholic fatty liver disease (NAFLD), a condition of excess fat build-up in the liver. NASH can progress into a more severe stage called non-alcoholic steatohepatitis (NASH), which is marked by liver inflammation and scarring. There is not yet an FDA-approved drug for either disease, so further research on safe treatments is required. My project addresses this need by exploring nuclear receptors and their corepressors, which have been linked to NASH and NAFLD. My current work on the role of the nuclear receptor corepressor (NCOR) complex in hepatic lipid metabolism is a continuation of a project I began in Spring 2021, which was also funded through CURF. I study two NCORs called nuclear receptor corepressor 1 (NCOR1) and silencing mediator of retinoid and thyroid hormone receptors (SMRT), which are essential to maintaining metabolic homeostasis, energy expenditure, and body weight. They recruit histone deacetylase 3 (HDAC3) to mediate and stabilize repression. My research is driven by the preliminary discovery of a dramatic liver phenotype that resembled NASH in NCOR1/SMRT double knock-out (N/S dKO) mice. Unexpectedly, the phenotype of N/S dKO mouse liver did not match the NAFLD phenotype of HDAC3 KO mouse liver, which suggested NCOR1 and SMRT may have roles beyond HDAC3 recruitment. I previously studied the surprising presence of HDAC3 mRNA and absence of HDAC3 protein in N/S dKO mouse liver, which points to a post-translational modification of HDAC3 that occurs in the liver. The next step was to examine whether this pattern of HDAC3 expression occurs in other tissues of N/S dKO mouse. Using a Rosa26-cre-ER whole body knock-out system, several metabolic tissues were extracted from N/S dKO mice to study the presence of HDAC3, as well as other NCOR complex members. I observed differential expression of HDAC3 across the metabolic tissues, suggesting different modification and degradation mechanisms are at play in each tissue. 

PRESENTED BY
College Alumni Society Undergraduate Research Grant
College of Arts & Sciences 2022
Advised By
Mitchell Lazar
Willard and Rhoda Ware Professor of Diabetes and Metabolic Diseases & Director, Institute for Diabetes, Obesity, and Metabolism
Amy Hauck
Postdoctoral researcher; Ph.D.
PRESENTED BY
College Alumni Society Undergraduate Research Grant
College of Arts & Sciences 2022
Advised By
Mitchell Lazar
Willard and Rhoda Ware Professor of Diabetes and Metabolic Diseases & Director, Institute for Diabetes, Obesity, and Metabolism
Amy Hauck
Postdoctoral researcher; Ph.D.

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