PUBLICATION

Serum lipoprotein-derived fatty acids regulate hypoxia-inducible factor

Authors
Shao, W., Hwang, J., Liu, C., Mukhopadhyay, D., Zhao, S., Shen, M.C., Alpergin, E.S.S., Wolfgang, M.J., Farber, S.A., Espenshade, P.J.
ID
ZDB-PUB-201029-4
Date
2020
Source
The Journal of biological chemistry   295(52): 18284-18300 (Journal)
Registered Authors
Farber, Steven
Keywords
fatty acid, hypoxia-inducible factor (HIF), lipoprotein, low-density lipoprotein (LDL), lysosomal acid lipase, mitochondria
Datasets
GEO:GSE129434, GEO:GSE129433
MeSH Terms
  • Signal Transduction
  • Mice
  • Humans
  • Hydroxylation
  • Lipoproteins/blood
  • Lipoproteins/chemistry*
  • Gene Expression Regulation/drug effects*
  • Mice, Knockout
  • Fatty Acids/pharmacology*
  • Zebrafish
  • Hypoxia-Inducible Factor 1, alpha Subunit/genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit/metabolism*
  • Male
  • Mice, Inbred C57BL
  • Oxygen/metabolism*
  • Animals
  • Gene Expression Profiling
(all 17)
PubMed
33109611 Full text @ J. Biol. Chem.
Abstract
Oxygen regulates hypoxia-inducible factor (HIF) transcription factors to control cell metabolism, erythrogenesis, and angiogenesis. While 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 HIFα subunit of these heterodimeric transcription factors comparable to hypoxia with activation of downstream target genes. Addition of fatty acids to culture media 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 fluorescent reporter 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.
Genes / Markers
Figures
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Phenotype
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Mutations / Transgenics
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Human Disease / Model
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Sequence Targeting Reagents
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Fish
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Antibodies
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Orthology
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Citation
Shao, W., Hwang, J., Liu, C., Mukhopadhyay, D., Zhao, S., Shen, M.C., Alpergin, E.S.S., Wolfgang, M.J., Farber, S.A., Espenshade, P.J. (2020) Serum lipoprotein-derived fatty acids regulate hypoxia-inducible factor. The Journal of biological chemistry. 295(52):18284-18300.