Dataset Information

Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity.

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.

SUBMITTER: Araujo N

PROVIDER: S-EPMC9004617 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity.

Araujo Nathalia N Sledziona James J Noothi Sunil K SK Burikhanov Ravshan R Hebbar Nikhil N Ganguly Saptadwipa S Shrestha-Bhattarai Tripti T Zhu Beibei B Katz Wendy S WS Zhang Yi Y Taylor Barry S BS Liu Jinze J Chen Li L Weiss Heidi L HL He Daheng D Wang Chi C Morris Andrew J AJ Cassis Lisa A LA Nikolova-Karakashian Mariana M Nagareddy Prabhakar R PR Melander Olle O Evers B Mark BM Kern Philip A PA Rangnekar Vivek M VM

Frontiers in oncology 20220329

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<sup>-/-</sup>) 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<sup>-/-</sup> and AKO mice exhibit increased absorption and storage of fat in adipocytes. Mechanistically, Par-4 loss is asso ...[more]

PMID: 35425699

Similar Datasets

Project description:Podocytes are an important part of the glomerular filtration barrier and the key player in the development of proteinuria, which is an early feature of complement mediated renal diseases. Complement factors are mainly liver-born and present in circulation. Nevertheless, there is a growing body of evidence for additional sites of complement protein synthesis, including various cell types in the kidney. We hypothesized that podocytes are able to produce complement components and contribute to the local balance of complement activation and regulation. To investigate the relevant balance between inhibiting and activating sides, our studies focused on complement factor H (CFH), an important complement regulator, and on C3, the early key component for complement activation. We characterized human cultured podocytes for the expression and secretion of activating and regulating complement factors, and analyzed the secretion pathway and functional activity. We studied glomerular CFH and C3 expression in puromycin aminonucleoside (PAN) -treated rats, a model for proteinuria, and the physiological mRNA-expression of both factors in murine kidneys. We found, that C3 and CFH were expressed in cultured podocytes and expression levels differed from those in cultivated glomerular endothelial cells. The process of secretion in podocytes was stimulated with interferon gamma and located in the Golgi apparatus. Cultured podocytes could initiate the complement cascade by the splitting of C3, which can be shown by the generation of C3a, a functional C3 split product. C3 contributed to external complement activation. Podocyte-secreted CFH, in conjunction with factor I, was able to split C3b. Podocytes derived from a patient with a CFH mutation displayed impaired cell surface complement regulation. CFH and C3 were synthesized in podocytes of healthy C57Bl/6-mice and were upregulated in podocytes of PAN treated rats. These data show that podocytes produce functionally active complement components, and could therefore influence the local glomerular complement activation and regulation. This modulating effect should therefore be considered in all diseases where glomerular complement activation occurs. Furthermore, our data indicate a potential novel role of podocytes in the innate immune system.

Dataset Information

Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity.

Publications

Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets