Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity

• Published in: Frontiers in oncology Vol. 12; p. 860446
• Main Authors: Araujo, Nathalia, 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, Nagareddy, Prabhakar R, Melander, Olle, Evers, B Mark, Kern, Philip A, Rangnekar, Vivek M
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 29-03-2022
• Subjects: acylation stimulating protein; adipocyte tissue storage; Biologi; Biological Sciences; Cancer and Oncology; Cancer och onkologi; Cell Biology; Cellbiologi; Clinical Medicine; fat absorption; hypertrophic obesity; Klinisk medicin; Medical and Health Sciences; Medicin och hälsovetenskap; Natural Sciences; Naturvetenskap; Oncology; Par-4; C3; hypertrophic obesity; adipocyte tissue storage; acylation stimulating protein; fat absorption; Par-4
• ISSN: 2234-943X; 2234-943X
• DOI: 10.3389/fonc.2022.860446

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
downregulation and activation of p53. We identified complement factor
as a p53-regulated gene linked to fat storage in adipocytes.
re-expression in adipocytes or
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
to regulate obesity.