Skip to Content
Merck
  • Serum lipoprotein-derived fatty acids regulate hypoxia-inducible factor.

Serum lipoprotein-derived fatty acids regulate hypoxia-inducible factor.

The Journal of biological chemistry (2020-10-29)
Wei Shao, Jiwon Hwang, Chune Liu, Debaditya Mukhopadhyay, Shan Zhao, Meng-Chieh Shen, Ebru S Selen, Michael J Wolfgang, Steven A Farber, Peter J Espenshade
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
L-Ascorbic acid, BioXtra, ≥99.0%, crystalline
Sigma-Aldrich
Uridine, ≥99%
Sigma-Aldrich
Puromycin dihydrochloride from Streptomyces alboniger, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
Deferoxamine mesylate salt, powder, ≥92.5% (TLC)
Sigma-Aldrich
Cholesterol, from sheep wool, ≥92.5% (GC), powder
Sigma-Aldrich
(±)-Mevalonolactone, ~97% (titration)
Sigma-Aldrich
Lipoprotein Deficient Serum from fetal calf, frozen liquid
Sigma-Aldrich
Bovine Serum Albumin, fatty acid free, low endotoxin, lyophilized powder, BioReagent, suitable for cell culture, ≥96% (agarose gel electrophoresis)
Sigma-Aldrich
Lalistat 2, ≥98% (HPLC)
Sigma-Aldrich
Emetine dihydrochloride
Sigma-Aldrich
Cholesterol-Water Soluble, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
Fetal Bovine Serum, USA origin, sterile-filtered, suitable for cell culture, suitable for hybridoma
Sigma-Aldrich
Ethidium bromide, BioReagent, for molecular biology, powder
Sigma-Aldrich
Lipids Cholesterol Rich from adult bovine serum, liquid, sterile-filtered, BioReagent, suitable for cell culture, suitable for insect cell culture
Sigma-Aldrich
Anti-Thioredoxin antibody produced in rabbit, IgG fraction of antiserum, buffered aqueous solution
Sigma-Aldrich
Ammonium pyrrolidinedithiocarbamate, ~99%
Sigma-Aldrich
Lipoproteins, High Density, Human Plasma
Sigma-Aldrich
Lipoproteins, Very Low Density, Human Plasma
Sigma-Aldrich
Lipoproteins, Low Density, Human Plasma
Roche
DNase I, grade II, from bovine pancreas