Serum Lipoproteins Regulate Hypoxia‐Inducible Factors Under Normoxia

Abstract

Hypoxia‐inducible factor (HIF) transcription factors are central regulators of oxygen homeostasis, controlling energy utilization, erythrogenesis, angiogenesis and cancer metabolism. Oxygen negatively regulates HIF activity by promoting HIFα prolyl hydroxylation and proteasome‐dependent degradation. Using human pancreatic adenocarcinoma cells, we demonstrate that serum lipoproteins are an independent regulator of HIF under normoxia. Decreasing extracellular lipid supply inhibited HIF prolyl hydroxylation, leading to accumulation of HIFα comparable to hypoxia with activation of downstream target genes. Addition of unsaturated fatty acids suppressed this signal, which required an intact mitochondrial respiratory chain. A survey of different cell lines showed that this signaling pathway functions in a wide range of tissues. These studies show that lipoprotein and oxygen supply are distinct signals integrated to control HIF activity and identify serum lipids as a potential modulator of HIF pathway activity.Support or Funding InformationNational Institutes of Health, HL077588 and GM126088This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.