School of Life Sciences Tsinghua University Beijing 100084 P. R. China.
Institute of Cell Biology Beijing Normal University Beijing 100875 P. R. China.
Adv Sci (Weinh). 2021 Mar 1;8(9):2003410. doi: 10.1002/advs.202003410. eCollection 2021 May.
Atherosclerosis is a chronic inflammatory disease that can cause acute cardiovascular events. Activation of the NOD-like receptor family, pyrin domain containing protein 3 (NLRP3) inflammasome enhances atherogenesis, which links lipid metabolism to sterile inflammation. This study examines the impact of an endogenous metabolite, namely ketone body 3-hydroxybutyrate (3-HB), on a mouse model of atherosclerosis. It is found that daily oral administration of 3-HB can significantly ameliorate atherosclerosis. Mechanistically, 3-HB is found to reduce the M1 macrophage proportion and promote cholesterol efflux by acting on macrophages through its receptor G-protein-coupled receptor 109a (Gpr109a). 3-HB-Gpr109a signaling promotes extracellular calcium (Ca) influx. The elevation of intracellular Ca level reduces the release of Ca from the endothelium reticulum (ER) to mitochondria, thus inhibits ER stress triggered by ER Ca store depletion. As NLRP3 inflammasome can be activated by ER stress, 3-HB can inhibit the activation of NLRP3 inflammasome, which triggers the increase of M1 macrophage proportion and the inhibition of cholesterol efflux. It is concluded that daily nutritional supplementation of 3-HB attenuates atherosclerosis in mice.
动脉粥样硬化是一种慢性炎症性疾病，可导致急性心血管事件。NOD 样受体家族、含吡喃结构域蛋白 3（NLRP3）炎性小体的激活增强了动脉粥样硬化的发生，将脂质代谢与无菌炎症联系起来。本研究探讨了内源性代谢物酮体 3-羟基丁酸（3-HB）对动脉粥样硬化小鼠模型的影响。结果发现，每日口服 3-HB 可显著改善动脉粥样硬化。其作用机制是，3-HB 通过其受体 G 蛋白偶联受体 109a（Gpr109a）作用于巨噬细胞，降低 M1 巨噬细胞比例并促进胆固醇流出。3-HB-Gpr109a 信号促进细胞外钙（Ca）内流。细胞内 Ca 水平的升高减少了内质网（ER）中 Ca 从 ER 到线粒体的释放，从而抑制了 ER 钙库耗竭引发的 ER 应激。由于 NLRP3 炎性小体可被 ER 应激激活，因此 3-HB 可抑制 NLRP3 炎性小体的激活，从而增加 M1 巨噬细胞比例并抑制胆固醇流出。综上所述，每日营养补充 3-HB 可减轻小鼠的动脉粥样硬化。
