Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity
oleh: Nathalia Araujo, James Sledziona, Sunil K. Noothi, Ravshan Burikhanov, Nikhil Hebbar, Saptadwipa Ganguly, Tripti Shrestha-Bhattarai, Beibei Zhu, Beibei Zhu, Wendy S. Katz, Wendy S. Katz, Yi Zhang, Barry S. Taylor, Jinze Liu, Li Chen, Li Chen, Heidi L. Weiss, Heidi L. Weiss, Daheng He, Chi Wang, Chi Wang, Andrew J. Morris, Andrew J. Morris, Lisa A. Cassis, Lisa A. Cassis, Mariana Nikolova-Karakashian, Mariana Nikolova-Karakashian, Prabhakar R. Nagareddy, Olle Melander, Olle Melander, B. Mark Evers, B. Mark Evers, Philip A. Kern, Philip A. Kern, Vivek M. Rangnekar, Vivek M. Rangnekar, Vivek M. Rangnekar, Vivek M. Rangnekar
| Format: | Article |
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| Diterbitkan: | Frontiers Media S.A. 2022-03-01 |
Deskripsi
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.