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

Abstract

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.

• Authors: Shu-Jie Zhang, Zi-Hua Li, Yu-Dian Zhang, Jin Chen, Yuan Li, Fu-Qing Wu, Wei Wang, Zong Jie Cui, Guo-Qiang Chen
• Journal: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (Adv Sci (Weinh)) Vol. 8 Issue 9 Pg. 2003410 (05 2021) ISSN: 2198-3844 [Electronic] Germany
• PMID: 33977048 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Advanced Science published by Wiley‐VCH GmbH.

Chemical References

• Hcar2 protein, mouse
• Ketone Bodies
• Receptors, G-Protein-Coupled
• Calcium
• 3-Hydroxybutyric Acid

Topics

• 3-Hydroxybutyric Acid (therapeutic use)
• Animals
• Atherosclerosis (drug therapy)
• Calcium (metabolism)
• Disease Models, Animal
• Ketone Bodies (therapeutic use)
• Mice
• Receptors, G-Protein-Coupled (drug effects)
• Signal Transduction (drug effects)