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Serum lipoprotein–derived fatty acids regulate hypoxia-inducible factor

Oxygen regulates hypoxia-inducible factor (HIF) transcription factors to control cell metabolism, erythrogenesis, and angiogenesis. Whereas much has been elucidated about how oxygen regulates HIF, whether lipids affect HIF activity is un-known. Here, using cultured cells and two animal models, we de...

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Autores principales: Shao, Wei, Hwang, Jiwon, Liu, Chune, Mukhopadhyay, Debaditya, Zhao, Shan, Shen, Meng-Chieh, Selen, Ebru S., Wolfgang, Michael J., Farber, Steven A., Espenshade, Peter J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939398/
https://www.ncbi.nlm.nih.gov/pubmed/33109611
http://dx.doi.org/10.1074/jbc.RA120.015238
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author Shao, Wei
Hwang, Jiwon
Liu, Chune
Mukhopadhyay, Debaditya
Zhao, Shan
Shen, Meng-Chieh
Selen, Ebru S.
Wolfgang, Michael J.
Farber, Steven A.
Espenshade, Peter J.
author_facet Shao, Wei
Hwang, Jiwon
Liu, Chune
Mukhopadhyay, Debaditya
Zhao, Shan
Shen, Meng-Chieh
Selen, Ebru S.
Wolfgang, Michael J.
Farber, Steven A.
Espenshade, Peter J.
author_sort Shao, Wei
collection PubMed
description Oxygen regulates hypoxia-inducible factor (HIF) transcription factors to control cell metabolism, erythrogenesis, and angiogenesis. Whereas much has been elucidated about how oxygen regulates HIF, whether lipids affect HIF activity is un-known. Here, using cultured cells and two animal models, we demonstrate that lipoprotein-derived fatty acids are an independent regulator of HIF. Decreasing extracellular lipid supply inhibited HIF prolyl hydroxylation, leading to accumulation of the HIFα subunit of these heterodimeric transcription factors comparable with hypoxia with activation of downstream target genes. The addition of fatty acids to culture medium suppressed this signal, which required an intact mitochondrial respiratory chain. Mechanistically, fatty acids and oxygen are distinct signals integrated to control HIF activity. Finally, we observed lipid signaling to HIF and changes in target gene expression in developing zebrafish and adult mice, and this pathway operates in cancer cells from a range of tissues. This study identifies fatty acids as a physiological modulator of HIF, defining a mechanism for lipoprotein regulation that functions in parallel to oxygen.
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spelling pubmed-79393982021-06-08 Serum lipoprotein–derived fatty acids regulate hypoxia-inducible factor Shao, Wei Hwang, Jiwon Liu, Chune Mukhopadhyay, Debaditya Zhao, Shan Shen, Meng-Chieh Selen, Ebru S. Wolfgang, Michael J. Farber, Steven A. Espenshade, Peter J. J Biol Chem Lipids Oxygen regulates hypoxia-inducible factor (HIF) transcription factors to control cell metabolism, erythrogenesis, and angiogenesis. Whereas much has been elucidated about how oxygen regulates HIF, whether lipids affect HIF activity is un-known. Here, using cultured cells and two animal models, we demonstrate that lipoprotein-derived fatty acids are an independent regulator of HIF. Decreasing extracellular lipid supply inhibited HIF prolyl hydroxylation, leading to accumulation of the HIFα subunit of these heterodimeric transcription factors comparable with hypoxia with activation of downstream target genes. The addition of fatty acids to culture medium suppressed this signal, which required an intact mitochondrial respiratory chain. Mechanistically, fatty acids and oxygen are distinct signals integrated to control HIF activity. Finally, we observed lipid signaling to HIF and changes in target gene expression in developing zebrafish and adult mice, and this pathway operates in cancer cells from a range of tissues. This study identifies fatty acids as a physiological modulator of HIF, defining a mechanism for lipoprotein regulation that functions in parallel to oxygen. American Society for Biochemistry and Molecular Biology 2021-01-13 /pmc/articles/PMC7939398/ /pubmed/33109611 http://dx.doi.org/10.1074/jbc.RA120.015238 Text en © 2020 © 2020 Shao et al. https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Lipids
Shao, Wei
Hwang, Jiwon
Liu, Chune
Mukhopadhyay, Debaditya
Zhao, Shan
Shen, Meng-Chieh
Selen, Ebru S.
Wolfgang, Michael J.
Farber, Steven A.
Espenshade, Peter J.
Serum lipoprotein–derived fatty acids regulate hypoxia-inducible factor
title Serum lipoprotein–derived fatty acids regulate hypoxia-inducible factor
title_full Serum lipoprotein–derived fatty acids regulate hypoxia-inducible factor
title_fullStr Serum lipoprotein–derived fatty acids regulate hypoxia-inducible factor
title_full_unstemmed Serum lipoprotein–derived fatty acids regulate hypoxia-inducible factor
title_short Serum lipoprotein–derived fatty acids regulate hypoxia-inducible factor
title_sort serum lipoprotein–derived fatty acids regulate hypoxia-inducible factor
topic Lipids
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939398/
https://www.ncbi.nlm.nih.gov/pubmed/33109611
http://dx.doi.org/10.1074/jbc.RA120.015238
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