Louise Ménégaut1,2,3,4, Antoine Jalil1,2,3, Thomas Pilot1,2,3, Kevin van Dongen1,2,3,4, Valentin Crespy5, Eric Steinmetz5, Jean Paul Pais de Barros1,2,6, Audrey Geissler7, Wilfried Le Goff8, Nicolas Venteclef9, Laurent Lagrost1,2,3, Thomas Gautier1,2,3, Charles Thomas1,2,3, David Masson1,2,3,4. 1. Univ. Bourgogne Franche-Comté, LNC UMR1231, Dijon, France. 2. INSERM, LNC UMR1231, Dijon, France. 3. FCS Bourgogne-Franche Comté, LipSTIC LabEx, Dijon, France. 4. Laboratory of Clinical Chemistry, CHU Dijon, Dijon, France. 5. Department of Cardiovascular Surgery, CHU Dijon, Dijon, France. 6. Lipidomic Analytic Platform, UBFC, Dijon, France. 7. CellImaP Core Facility, INSERM LNC-UMR1231, Dijon, France. 8. Sorbonne Université, INSERM, Institute of Cardiometabolism and Nutrition (ICAN), UMR_S1166, Hôpital de la Pitié, Paris, France. 9. Cordeliers Research Centre, INSERM, IMMEDIAB, Université de Paris, Université Paris, Paris, France.
Abstract
BACKGROUND AND PURPOSE: Subset of macrophages within the atheroma plaque displays a high glucose uptake activity. Nevertheless, the molecular mechanisms and the pathophysiological significance of this high glucose need remain unclear. While the role for hypoxia and hypoxia inducible factor 1α has been demonstrated, the contribution of lipid micro-environment and more specifically oxysterols is yet to be explored. EXPERIMENTAL APPROACH: Human macrophages were conditioned in the presence of homogenates from human carotid plaques, and expression of genes involved in glucose metabolism was quantified. Correlative analyses between gene expression and the oxysterol composition of plaques were performed. KEY RESULTS: Conditioning of human macrophages by plaque homogenates induces expression of several genes involved in glucose uptake and glycolysis including glucose transporter 1 (SLC2A1) and hexokinases 2 and 3 (HK2 and HK3). This activation is significantly correlated to the oxysterol content of the plaque samples and is associated with a significant increase in the glycolytic activity of the cells. Pharmacological inverse agonist of the oxysterol receptor liver X receptor (LXR) partially reverses the induction of glycolysis genes without affecting macrophage glycolytic activity. Chromatin immunoprecipitation analysis confirms the implication of LXR in the regulation of SLC2A1 and HK2 genes. CONCLUSION AND IMPLICATIONS: While our work supports the role of oxysterols and the LXR in the modulation of macrophage metabolism in atheroma plaques, it also highlights some LXR-independent effects of plaques samples. Finally, this study identifies hexokinase 3 as a promising target in the context of atherosclerosis. LINKED ARTICLES: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.
BACKGROUND AND PURPOSE: Subset of macrophages within the atheroma plaque displays a high glucose uptake activity. Nevertheless, the molecular mechanisms and the pathophysiological significance of this high glucose need remain unclear. While the role for hypoxia and hypoxia inducible factor 1α has been demonstrated, the contribution of lipid micro-environment and more specifically oxysterols is yet to be explored. EXPERIMENTAL APPROACH: Human macrophages were conditioned in the presence of homogenates from human carotid plaques, and expression of genes involved in glucose metabolism was quantified. Correlative analyses between gene expression and the oxysterol composition of plaques were performed. KEY RESULTS: Conditioning of human macrophages by plaque homogenates induces expression of several genes involved in glucose uptake and glycolysis including glucose transporter 1 (SLC2A1) and hexokinases 2 and 3 (HK2 and HK3). This activation is significantly correlated to the oxysterol content of the plaque samples and is associated with a significant increase in the glycolytic activity of the cells. Pharmacological inverse agonist of the oxysterol receptor liver X receptor (LXR) partially reverses the induction of glycolysis genes without affecting macrophage glycolytic activity. Chromatin immunoprecipitation analysis confirms the implication of LXR in the regulation of SLC2A1 and HK2 genes. CONCLUSION AND IMPLICATIONS: While our work supports the role of oxysterols and the LXR in the modulation of macrophage metabolism in atheroma plaques, it also highlights some LXR-independent effects of plaques samples. Finally, this study identifies hexokinase 3 as a promising target in the context of atherosclerosis. LINKED ARTICLES: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.
Authors: Hannes M Findeisen; Vivienne C Voges; Laura C Braun; Jannik Sonnenberg; Dennis Schwarz; Helena Körner; Holger Reinecke; Yahya Sohrabi Journal: Int J Mol Sci Date: 2022-05-31 Impact factor: 6.208
Authors: Mohammed I Y Elmallah; Pablo Ortega-Deballon; Laure Hermite; Jean-Paul Pais-De-Barros; Jessica Gobbo; Carmen Garrido Journal: Mol Oncol Date: 2022-06-14 Impact factor: 7.449