Ketone Body 3‐Hydroxybutyrate Ameliorates Atherosclerosis via Receptor Gpr109a‐Mediated Calcium Influx

• Published in: Advanced science 2021-05, Vol.8 (9), p.2003410-n/a
• Main Authors: Zhang, Shu‐jie, Li, Zi‐hua, Zhang, Yu‐dian, Chen, Jin, Li, Yuan, Wu, Fu‐qing, Wang, Wei, Cui, Zong Jie, Chen, Guo‐Qiang
• Format: Article
• Language: English
• Subjects: 3‐HB; Atherosclerosis; calcium influx; Cardiovascular disease; Cell adhesion & migration; Cholesterol; cholesterol efflux; Cytokines; Fatty acids; Lipids; M1 macrophages; Metabolism; NLRP3; PHB; Tumor necrosis factor-TNF; Vitamin B
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202003410

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 (Ca2+) influx. The elevation of intracellular Ca2+ level reduces the release of Ca2+ from the endothelium reticulum (ER) to mitochondria, thus inhibits ER stress triggered by ER Ca2+ 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. This study demonstrates that daily oral administration of ketone body 3‐hydroxybutyrate (3‐HB) attenuates atherosclerosis. Mechanistically, 3‐HB reduces M1 macrophage proportion and promotes cholesterol efflux by acting on macrophages through the Gpr109a–NLRP3 pathway. 3‐HB inhibits ER calcium deletion induced NLRP3 inflammasome activation via 3‐HB–Gpr109a signaling‐mediated extracellular Ca2+ influx in macrophages.