Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity
(2022) In Frontiers in Oncology 12.- 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,... (More)
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.
(Less)
- author
- organization
- publishing date
- 2022-03-29
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- acylation stimulating protein, adipocyte tissue storage, C3, fat absorption, hypertrophic obesity, Par-4
- in
- Frontiers in Oncology
- volume
- 12
- article number
- 860446
- publisher
- Frontiers Media S. A.
- external identifiers
-
- scopus:85128400591
- pmid:35425699
- ISSN
- 2234-943X
- DOI
- 10.3389/fonc.2022.860446
- language
- English
- LU publication?
- yes
- id
- cda31091-556c-4107-8f7f-1b5bc2d2f324
- date added to LUP
- 2022-07-06 14:51:34
- date last changed
- 2024-09-20 18:30:03
@article{cda31091-556c-4107-8f7f-1b5bc2d2f324, abstract = {{<p>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 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.</p>}}, author = {{Araujo, Nathalia and Sledziona, James and Noothi, Sunil K. and Burikhanov, Ravshan and Hebbar, Nikhil and Ganguly, Saptadwipa and Shrestha-Bhattarai, Tripti and Zhu, Beibei and Katz, Wendy S. and Zhang, Yi and Taylor, Barry S. and Liu, Jinze and Chen, Li and Weiss, Heidi L. and He, Daheng and Wang, Chi and Morris, Andrew J. and Cassis, Lisa A. and Nikolova-Karakashian, Mariana and Nagareddy, Prabhakar R. and Melander, Olle and Evers, B. Mark and Kern, Philip A. and Rangnekar, Vivek M.}}, issn = {{2234-943X}}, keywords = {{acylation stimulating protein; adipocyte tissue storage; C3; fat absorption; hypertrophic obesity; Par-4}}, language = {{eng}}, month = {{03}}, publisher = {{Frontiers Media S. A.}}, series = {{Frontiers in Oncology}}, title = {{Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity}}, url = {{http://dx.doi.org/10.3389/fonc.2022.860446}}, doi = {{10.3389/fonc.2022.860446}}, volume = {{12}}, year = {{2022}}, }