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.

Association of Serum β-Hydroxybutyrate and Coronary Artery Disease in an Urban Chinese Population

“…A hepatocyte-macrophage “AA shuttle” has been shown to coordinate the fibrogenic response to hepatic injury via mitochondrial metabolism in tissue macrophages after high fat diet-induced fibrosis ( 46 ). Furthermore, BHB has been found to protect the heart from ischemia/reperfusion injury ( 47 ) and attenuate atherosclerosis ( 48 ) in different mice models. Indeed, ketone bodies possess various capabilities and participate in multiple cellular processes ( 49 ), especially in cardiovascular disease, further studies to ascertain the action and specific mechanism of BHB in CAD are warranted.…”

A Polyhydroxyalkanoates-Based Carrier Platform of Bioactive Substances for Therapeutic Applications

“…Other neural benefits from 3HB in different diseases models, such as Alzheimer, Parkinson and other neurodegenerative diseases like epilepsy, are proved in many studies with effective therapy ( Zhang et al, 2013 ; Paoli et al, 2014 ; Napolitano et al, 2020 ). Besides, the maintenance of 3HB level is also reported to resist inflammation and cardiovascular disease, for example, Zhang and her co-workers illustrated that daily nutritional supplementation of 3HB could attenuate atherosclerosis in mice ( Zhang et al, 2021 ).…”

On the nutritional and therapeutic effects of ketone body d-β-hydroxybutyrate

“…At the cellular level, d-3HB markedly increased mitochondrial uncoupling in brown adipose tissue (BAT) which increased mitochondrial respiration and thermogenesis, thereby results in increased resting energy expenditure (REE) in the obese (Deemer et al 2020;Walton et al 2020). More recently, studies revealed that the anti-inflammatory actions of d-3HB on the NOD-like receptor pyrin-domain containing 3 (NLRP3) inflammasome in obese adults can also prevent obesity and associated cardiometabolic complications such as atherosclerosis (Neudorf et al 2020;Zhang et al 2021). The latter study revealed a specific pathway by which d-3HB acts to alleviate atherosclerosis via activation of the GPCR109A, which is known to be key endogenous receptors of d-3HB (Zhang et al 2021).…”

“…More recently, studies revealed that the anti-inflammatory actions of d-3HB on the NOD-like receptor pyrin-domain containing 3 (NLRP3) inflammasome in obese adults can also prevent obesity and associated cardiometabolic complications such as atherosclerosis (Neudorf et al 2020;Zhang et al 2021). The latter study revealed a specific pathway by which d-3HB acts to alleviate atherosclerosis via activation of the GPCR109A, which is known to be key endogenous receptors of d-3HB (Zhang et al 2021).…”