PAQR9 regulates hepatic ketogenesis and fatty acid oxidation during fasting by modulating protein stability of PPARα

Yijun Lin; Lingling Chen; Xue You; Zixuan Li; Chenchen Li; Yan Chen

Molecular Metabolism (Nov 2021)

PAQR9 regulates hepatic ketogenesis and fatty acid oxidation during fasting by modulating protein stability of PPARα

Yijun Lin,
Lingling Chen,
Xue You,
Zixuan Li,
Chenchen Li,
Yan Chen

Affiliations

Yijun Lin: CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
Lingling Chen: CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
Xue You: CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
Zixuan Li: CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
Chenchen Li: School of Life Science and Technology, ShanghaiTech University, Shanghai, China
Yan Chen: CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, China; Corresponding author. CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.

Journal volume & issue: Vol. 53
p. 101331

Abstract

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Background: The cycle of feeding and fasting is fundamental to life and closely coordinated with changes of metabolic programs. During extended starvation, ketogenesis coupled with fatty acid oxidation in the liver supplies ketone bodies to extrahepatic tissues as the major form of fuel. In this study, we demonstrated that PAQR9, a member of the progesterone and adipoQ receptor family, has a regulatory role on hepatic ketogenesis. Methods: We analyzed the phenotype of Paqr9-deleted mice. We also used biochemical methods to investigate the interaction of PAQR9 with PPARα and HUWE1, an E3 ubiquitin ligase. Results: The expression of Paqr9 was decreased during fasting partly depending on PPARγ. The overall phenotype of the mice was not altered by Paqr9 deletion under normal chow feeding. However, fasting-induced ketogenesis and fatty acid oxidation were attenuated by Paqr9 deletion. Mechanistically, Paqr9 deletion decreased protein stability of PPARα via enhancing its poly-ubiquitination. PAQR9 competed with HUWE1 for interaction with PPARα, thus preventing ubiquitin-mediated degradation of PPARα. Conclusion: Our study reveals that PAQR9 impacts starvation-mediated metabolic changes in the liver via post-translational regulation of PPARα.

Published in Molecular Metabolism

ISSN: 2212-8778 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine
Website: https://www.journals.elsevier.com/molecular-metabolism/

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