Serum lipoprotein-derived fatty acids regulate hypoxia-inducible factor
- 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.
- The Journal of biological chemistry 295(52): 18284-18300 (Journal)
- Registered Authors
- Farber, Steven
- fatty acid, hypoxia-inducible factor (HIF), lipoprotein, low-density lipoprotein (LDL), lysosomal acid lipase, mitochondria
- GEO:GSE129433, GEO:GSE129434
- MeSH Terms
- Fatty Acids/pharmacology*
- Gene Expression Profiling
- Gene Expression Regulation/drug effects*
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism*
- Mice, Inbred C57BL
- Mice, Knockout
- Signal Transduction
- 33109611 Full text @ J. Biol. Chem.
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.
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
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes