title: The importance of GLUT3 for de novo lipogenesis in hypoxia-induced lipid loading of human macrophages.
abstract: Atherosclerotic lesions are characterized by lipid-loaded macrophages (foam cells) and hypoxic regions. Although it is well established that foam cells are produced by uptake of cholesterol from oxidized LDL, we previously showed that hypoxia also promotes foam cell formation even in the absence of exogenous lipids. The hypoxia-induced lipid accumulation results from increased triglyceride biosynthesis but the exact mechanism is unknown. Our aim was to investigate the importance of glucose in promoting hypoxia-induced de novo lipid synthesis in human macrophages. In the absence of exogenous lipids, extracellular glucose promoted the accumulation of Oil Red O-stained lipid droplets in human monocyte-derived macrophages in a concentration-dependent manner. Lipid droplet accumulation was higher in macrophages exposed to hypoxia at all assessed concentrations of glucose. Importantly, triglyceride synthesis from glucose was increased in hypoxic macrophages. GLUT3 was highly expressed in macrophage-rich and hypoxic regions of human carotid atherosclerotic plaques and in macrophages isolated from these plaques. In human monocyte-derived macrophages, hypoxia increased expression of both GLUT3 mRNA and protein, and knockdown of GLUT3 with siRNA significantly reduced both glucose uptake and lipid droplet accumulation. In conclusion, we have shown that hypoxia-induced increases in glucose uptake through GLUT3 are important for lipid synthesis in macrophages, and may contribute to foam cell formation in hypoxic regions of atherosclerotic lesions.
authors.affiliation: Sahlgrenska Center for Cardiovascular and Metabolic Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Lu
authors.initials: L
authors.lastname: Li
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.forename: Liliana
authors.initials: L
authors.lastname: Håversen
authors.forename: Emma
authors.initials: E
authors.lastname: Lu
authors.forename: Lisa U
authors.initials: LU
authors.lastname: Magnusson
authors.forename: Marcus
authors.initials: M
authors.lastname: Ståhlman
authors.forename: Jan
authors.initials: J
authors.lastname: Borén
authors.forename: Göran
authors.initials: G
authors.lastname: Bergström
authors.forename: Malin C
authors.initials: MC
authors.lastname: Levin
authors.forename: Lillemor Mattsson
authors.initials: LM
authors.lastname: Hultén
mesh_terms: D015687:Cell Hypoxia; D002478:Cells, Cultured; D005487:Foam Cells / Q000378:metabolism*; D020868:Gene Silencing; D005947:Glucose / Q000378:metabolism; D051274:Glucose Transporter Type 3 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism; D050155:Lipogenesis / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference
chemical_list: D051274:Glucose Transporter Type 3; D005947:Glucose