Univ. Bourgogne Franche-Comté, LNC UMR1231, Dijon, France.
INSERM, LNC UMR1231, Dijon, France.
Br J Pharmacol. 2021 Aug;178(16):3124-3139. doi: 10.1111/bph.15358. Epub 2021 Feb 5.
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.
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.
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.
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.
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.
动脉粥样斑块中的巨噬细胞亚群表现出高葡萄糖摄取活性。然而，这种高葡萄糖的分子机制和病理生理学意义仍不清楚。虽然已经证明了缺氧和缺氧诱导因子 1α的作用，但脂质微环境的作用，特别是氧化固醇的作用仍有待探索。
用人类颈动脉斑块的匀浆对人巨噬细胞进行条件处理，并定量检测参与葡萄糖代谢的基因的表达。对基因表达与斑块中氧化固醇组成之间的相关性进行分析。
斑块匀浆对人巨噬细胞的条件处理诱导了包括葡萄糖转运蛋白 1（SLC2A1）和己糖激酶 2 和 3（HK2 和 HK3）在内的几个参与葡萄糖摄取和糖酵解的基因的表达。这种激活与斑块样本中氧化固醇的含量显著相关，并与细胞糖酵解活性的显著增加相关。氧化固醇受体肝 X 受体（LXR）的药理学反向激动剂部分逆转了糖酵解基因的诱导，但不影响巨噬细胞的糖酵解活性。染色质免疫沉淀分析证实了 LXR 对 SLC2A1 和 HK2 基因的调节作用。
虽然我们的工作支持氧化固醇和 LXR 在动脉粥样斑块中调节巨噬细胞代谢的作用，但它也强调了斑块样本的一些 LXR 独立作用。最后，本研究确定了己糖激酶 3 是动脉粥样硬化背景下有前途的靶点。
本文是关于氧化固醇、终身健康和治疗的专题问题的一部分。要查看本部分中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.
