TY - JOUR
T1 - Serum lipoprotein–derived fatty acids regulate hypoxia-inducible factor
AU - Shao, Wei
AU - Hwang, Jiwon
AU - Liu, Chune
AU - Mukhopadhyay, Debaditya
AU - Zhao, Shan
AU - Shen, Meng Chieh
AU - Selen, Ebru S.
AU - Wolfgang, Michael J.
AU - Farber, Steven A.
AU - Espenshade, Peter J.
N1 - Funding Information:
Funding and additional information—This project was supported by National Institutes of Health Grants GM126088 (to P. J. E.), DK093399 and DK116079 (to S. A. F.), GM63904 (to S. A. F. and S. Ekker), and P30 CA006973; the Johns Hopkins–Allegheny Health Network Cancer Research Fund (to P. J. E.); the Carnegie Institution for Science endowment; and the G. Harold and Leila Y. Math-ers Charitable Foundation (to S. A. F). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2020 Shao et al.
PY - 2020/12/25
Y1 - 2020/12/25
N2 - 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 unknown. 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 HIFa 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.
AB - 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 unknown. 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 HIFa 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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U2 - 10.1074/jbc.RA120.015238
DO - 10.1074/jbc.RA120.015238
M3 - Article
C2 - 33109611
AN - SCOPUS:85098252780
SN - 0021-9258
VL - 295
SP - 18284
EP - 18300
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 52
ER -