Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity

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

doi:10.3389/fonc.2022.860446

Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity

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. NagareddyOlle Melander, B. Mark Evers, Philip A. Kern, Vivek M. Rangnekar

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

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.

Original language	English
Article number	860446
Journal	Frontiers in Oncology
Volume	12
DOIs	https://doi.org/10.3389/fonc.2022.860446
State	Published - Mar 29 2022

Bibliographical note

Publisher Copyright:
Copyright © 2022 Araujo, Sledziona, Noothi, Burikhanov, Hebbar, Ganguly, Shrestha-Bhattarai, Zhu, Katz, Zhang, Taylor, Liu, Chen, Weiss, He, Wang, Morris, Cassis, Nikolova-Karakashian, Nagareddy, Melander, Evers, Kern and Rangnekar.

Keywords

C3
Par-4
acylation stimulating protein
adipocyte tissue storage
fat absorption
hypertrophic obesity

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.3389/fonc.2022.860446

Cite this

Araujo, N., Sledziona, J., Noothi, S. K., Burikhanov, R., Hebbar, N., Ganguly, S., Shrestha-Bhattarai, T., Zhu, B., Katz, W. S., Zhang, Y., Taylor, B. S., Liu, J., Chen, L., Weiss, H. L., He, D., Wang, C., Morris, A. J., Cassis, L. A., Nikolova-Karakashian, M., ... Rangnekar, V. M. (2022). Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity. Frontiers in Oncology, 12, Article 860446. https://doi.org/10.3389/fonc.2022.860446

@article{c8dd61eb607140199c9f11e65ef556c7,

title = "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.",

keywords = "C3, Par-4, acylation stimulating protein, adipocyte tissue storage, fat absorption, hypertrophic obesity",

author = "Nathalia Araujo and James Sledziona and Noothi, {Sunil K.} and Ravshan Burikhanov and Nikhil Hebbar and Saptadwipa Ganguly and Tripti Shrestha-Bhattarai and Beibei Zhu and Katz, {Wendy S.} and Yi Zhang and Taylor, {Barry S.} and Jinze Liu and Li Chen and Weiss, {Heidi L.} and Daheng He and Chi Wang and Morris, {Andrew J.} and Cassis, {Lisa A.} and Mariana Nikolova-Karakashian and Nagareddy, {Prabhakar R.} and Olle Melander and Evers, {B. Mark} and Kern, {Philip A.} and Rangnekar, {Vivek M.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2022 Araujo, Sledziona, Noothi, Burikhanov, Hebbar, Ganguly, Shrestha-Bhattarai, Zhu, Katz, Zhang, Taylor, Liu, Chen, Weiss, He, Wang, Morris, Cassis, Nikolova-Karakashian, Nagareddy, Melander, Evers, Kern and Rangnekar.",

year = "2022",

month = mar,

day = "29",

doi = "10.3389/fonc.2022.860446",

language = "English",

volume = "12",

}

Araujo, N, Sledziona, J, Noothi, SK, Burikhanov, R, Hebbar, N, Ganguly, S, Shrestha-Bhattarai, T, Zhu, B, Katz, WS, Zhang, Y, Taylor, BS, Liu, J, Chen, L , Weiss, HL, He, D, Wang, C, Morris, AJ, Cassis, LA , Nikolova-Karakashian, M, Nagareddy, PR, Melander, O, Evers, BM , Kern, PA & Rangnekar, VM 2022, 'Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity', Frontiers in Oncology, vol. 12, 860446. https://doi.org/10.3389/fonc.2022.860446

TY - JOUR

T1 - Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity

AU - Araujo, Nathalia

AU - Sledziona, James

AU - Noothi, Sunil K.

AU - Burikhanov, Ravshan

AU - Hebbar, Nikhil

AU - Ganguly, Saptadwipa

AU - Shrestha-Bhattarai, Tripti

AU - Zhu, Beibei

AU - Katz, Wendy S.

AU - Zhang, Yi

AU - Taylor, Barry S.

AU - Liu, Jinze

AU - Chen, Li

AU - Weiss, Heidi L.

AU - He, Daheng

AU - Wang, Chi

AU - Morris, Andrew J.

AU - Cassis, Lisa A.

AU - Nikolova-Karakashian, Mariana

AU - Nagareddy, Prabhakar R.

AU - Melander, Olle

AU - Evers, B. Mark

AU - Kern, Philip A.

AU - Rangnekar, Vivek M.

N1 - Publisher Copyright: Copyright © 2022 Araujo, Sledziona, Noothi, Burikhanov, Hebbar, Ganguly, Shrestha-Bhattarai, Zhu, Katz, Zhang, Taylor, Liu, Chen, Weiss, He, Wang, Morris, Cassis, Nikolova-Karakashian, Nagareddy, Melander, Evers, Kern and Rangnekar.

PY - 2022/3/29

Y1 - 2022/3/29

N2 - 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.

AB - 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.

KW - C3

KW - Par-4

KW - acylation stimulating protein

KW - adipocyte tissue storage

KW - fat absorption

KW - hypertrophic obesity

UR - http://www.scopus.com/inward/record.url?scp=85128400591&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85128400591&partnerID=8YFLogxK

U2 - 10.3389/fonc.2022.860446

DO - 10.3389/fonc.2022.860446

M3 - Article

AN - SCOPUS:85128400591

SN - 2234-943X

VL - 12

JO - Frontiers in Oncology

JF - Frontiers in Oncology

M1 - 860446

ER -

Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this