학술논문
Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity
Document Type
article
Author
Nathalia Araujo; James Sledziona; Sunil K. Noothi; Ravshan Burikhanov; Nikhil Hebbar; Saptadwipa Ganguly; Tripti Shrestha-Bhattarai; Beibei Zhu; Wendy S. Katz; Yi Zhang; Barry S. Taylor; Jinze Liu; Li Chen; Heidi L. Weiss; Daheng He; Chi Wang; Andrew J. Morris; Lisa A. Cassis; Mariana Nikolova-Karakashian; Prabhakar R. Nagareddy; Olle Melander; B. Mark Evers; Philip A. Kern; Vivek M. Rangnekar
Source
Frontiers in Oncology, Vol 12 (2022)
Subject
Language
English
ISSN
2234-943X
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.