Open AccessKetone Body 3‐Hydroxybutyrate Ameliorates Atherosclerosis via Receptor Gpr109a‐Mediated Calcium Influx
Author(s) -
Zhang Shujie,
Li Zihua,
Zhang Yudian,
Chen Jin,
Li Yuan,
Wu Fuqing,
Wang Wei,
Cui Zong Jie,
Chen GuoQiang
Publication year - 2021
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202003410
Subject(s) - inflammasome , inflammation , chemistry , receptor , endocrinology , pyrin domain , efflux , cholesterol , calcium in biology , medicine , calcium , pharmacology , biochemistry
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 2+ ) influx. The elevation of intracellular Ca 2+ level reduces the release of Ca 2+ from the endothelium reticulum (ER) to mitochondria, thus inhibits ER stress triggered by ER Ca 2+ 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.