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

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 stu...

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Autores principales: Lin, Yijun, Chen, Lingling, You, Xue, Li, Zixuan, Li, Chenchen, Chen, Yan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452888/
https://www.ncbi.nlm.nih.gov/pubmed/34474167
http://dx.doi.org/10.1016/j.molmet.2021.101331
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author Lin, Yijun
Chen, Lingling
You, Xue
Li, Zixuan
Li, Chenchen
Chen, Yan
author_facet Lin, Yijun
Chen, Lingling
You, Xue
Li, Zixuan
Li, Chenchen
Chen, Yan
author_sort Lin, Yijun
collection PubMed
description 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.
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spelling pubmed-84528882021-09-27 PAQR9 regulates hepatic ketogenesis and fatty acid oxidation during fasting by modulating protein stability of PPARα Lin, Yijun Chen, Lingling You, Xue Li, Zixuan Li, Chenchen Chen, Yan Mol Metab Original Article 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. Elsevier 2021-08-30 /pmc/articles/PMC8452888/ /pubmed/34474167 http://dx.doi.org/10.1016/j.molmet.2021.101331 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Lin, Yijun
Chen, Lingling
You, Xue
Li, Zixuan
Li, Chenchen
Chen, Yan
PAQR9 regulates hepatic ketogenesis and fatty acid oxidation during fasting by modulating protein stability of PPARα
title PAQR9 regulates hepatic ketogenesis and fatty acid oxidation during fasting by modulating protein stability of PPARα
title_full PAQR9 regulates hepatic ketogenesis and fatty acid oxidation during fasting by modulating protein stability of PPARα
title_fullStr PAQR9 regulates hepatic ketogenesis and fatty acid oxidation during fasting by modulating protein stability of PPARα
title_full_unstemmed PAQR9 regulates hepatic ketogenesis and fatty acid oxidation during fasting by modulating protein stability of PPARα
title_short PAQR9 regulates hepatic ketogenesis and fatty acid oxidation during fasting by modulating protein stability of PPARα
title_sort paqr9 regulates hepatic ketogenesis and fatty acid oxidation during fasting by modulating protein stability of pparα
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452888/
https://www.ncbi.nlm.nih.gov/pubmed/34474167
http://dx.doi.org/10.1016/j.molmet.2021.101331
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