Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity

Authors

Nathália Araujo, University of Kentucky
James Sledziona, University of Kentucky
Sunil K. Noothi, University of Kentucky
Ravshan Burikhanov, University of Kentucky
Nikhil Hebbar, University of Kentucky
Saptadwipa Ganguly, University of Kentucky
Tripti Shrestha-Bhattarai, Memorial Sloan Kettering Cancer Center
Beibei Zhu, University of Kentucky
Wendy S. Katz, University of KentuckyFollow
Yi Zhang, University of Kentucky
Barry S. Taylor, University of Kentucky
Jinze Liu, University of Kentucky
Li Chen, University of Kentucky
Heidi L. Weiss, University of Kentucky
Daheng He, University of Kentucky
Chi Wang, University of Kentucky
Andrew J. Morris, University of Kentucky
Lisa A. Cassis, University of Kentucky
Mariana N. Nikolova‑Karakashian, University of Kentucky
Prabhakara R. Nagareddy, The Ohio State University
Olle Melander, Lund University, Sweden
B. Mark Evers, University of Kentucky
Phillip A. Kern, University of Kentucky
Vivek M. Rangnekar, University of Kentucky

Abstract

Prostate apoptosis response-4 (Par-4) is a tumor suppressor that induces apoptosis in cancer cells. However, the physiological function of Par-4 remains unknown. Here we show that conventional Par-4 knockout (Par-4^-/-) mice and adipocyte-specific Par-4 knockout (AKO) mice, but not hepatocyte-specific Par-4 knockout mice, are obese with standard chow diet. Par-4^-/- and AKO mice exhibit increased absorption and storage of fat in adipocytes. Mechanistically, Par-4 loss is associated with mdm2 downregulation and activation of p53. We identified complement factor c3 as a p53-regulated gene linked to fat storage in adipocytes. Par-4 re-expression in adipocytes or c3 deletion reversed the obese mouse phenotype. Moreover, obese human subjects showed lower expression of Par-4 relative to lean subjects, and in longitudinal studies, low baseline Par-4 levels denoted an increased risk of developing obesity later in life. These findings indicate that Par-4 suppresses p53 and its target c3 to regulate obesity.

Document Type

Article

Publication Date

3-29-2022

Digital Object Identifier (DOI)

10.3389/fonc.2022.860446

Repository Citation

Araujo, Nathália; Sledziona, James; Noothi, Sunil K.; Burikhanov, Ravshan; Hebbar, Nikhil; Ganguly, Saptadwipa; Shrestha-Bhattarai, Tripti; Zhu, Beibei; Katz, Wendy S.; Zhang, Yi; Taylor, Barry S.; Liu, Jinze; Chen, Li; Weiss, Heidi L.; He, Daheng; Wang, Chi; Morris, Andrew J.; Cassis, Lisa A.; Nikolova‑Karakashian, Mariana N.; Nagareddy, Prabhakara R.; Melander, Olle; Evers, B. Mark; Kern, Phillip A.; and Rangnekar, Vivek M., "Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity" (2022). Clinical and Translational Science Faculty Publications. 5.
https://uknowledge.uky.edu/ccts_facpub/5