Author ORCID Identifier

https://orcid.org/0000-0002-1567-6332

Year of Publication

2021

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department/School/Program

Toxicology and Cancer Biology

First Advisor

Dr. Vivek M. Rangnekar

Abstract

Prostate Apoptosis Response-4 (Par-4) is a tumor suppressor ubiquitously expressed in all tissues and able to selectively induce apoptosis in cancer cells. Although well established in the context of cancer, relatively little is known about the function of Par-4 in the healthy and non-tumorigenic context. Observations from our lab showed that Par-4 knockout mouse lines were obese and displayed adipocyte hypertrophy under a normal chow diet when compared to Par-4 wild-type mice. These Par-4 knockout mice exhibited hepatic steatosis and hyperinsulinemia as secondary consequences of obesity. Par-4 knockout mice displayed increased intestinal dietary fat absorption and its subsequent storage in adipocytes. By RNA-Seq analysis, we identified complement factor C3 as a Par-4 downstream target involved in triglyceride storage in the adipose tissue. Deletion of C3 in Par-4 knockout mice rescued the obesity phenotype. Moreover, circulating levels of Par-4 were decreased in obese human subjects when compared to lean individuals, and low levels of Par-4 in non-obese subjects from a cohort study predicted an increased risk of developing obesity later in life. Our ChIP-Seq experiments identified MDM2 as a potential target of Par-4. Further validation studies indicated that Par-4 loss decreased the ubiquitin ligase MDM2 and upregulated its target protein p53 in adipose tissues. Moreover, Par-4 regulated C3 through the MDM2-p53 axis, with p53 activating the C3 promoter. Based on these findings, we conclude that Par-4 regulates adipocyte hypertrophy and obesity, and that low levels of Par-4 in lean human subjects is predictive of future obesity. These effects of Par-4 are mediated by its ability to suppress dietary fat secretion from the enterocytes into the bloodstream and fat storage by inhibition of C3.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2021.016

Funding Information

Lyman T. Johnson Diversity Fellowship, University of Kentucky, 2018-2020.

Science without Borders Doctoral Scholarship, Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), Brazil (ID 13137-13-1), 2014-2018.

Available for download on Friday, February 24, 2023

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