Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells

Abstract

Nicotinic acid (niacin) is a drug used to reduce the progression of atherosclerosis. Its antiatherosclerotic activity is believed to result from lipid-modifying effects, including its ability to decrease LDL cholesterol and increase HDL cholesterol levels in plasma. Here, we report that in a mouse model of atherosclerosis, we found that nicotinic acid inhibited disease progression under conditions that left total cholesterol and HDL cholesterol plasma levels unaffected. The antiatherosclerotic effect was not seen in mice lacking the receptor for nicotinic acid GPR109A. Surprisingly, transplantation of bone marrow from GPR109A-deficient mice into atherosclerosis-prone animals also abrogated the beneficial effect of nicotinic acid. We detected expression of GPR109A in macrophages in atherosclerotic plaques. In macrophages from WT mice, but not from GPR109A-deficient animals, nicotinic acid induced expression of the cholesterol transporter ABCG1 and promoted cholesterol efflux. Furthermore, activation of GPR109A by nicotinic acid inhibited MCP-1-induced recruitment of macrophages into the peritoneal cavity and impaired macrophage recruitment to atherosclerotic plaques. In contrast with current models, our data show that nicotinic acid can reduce the progression of atherosclerosis independently of its lipid-modifying effects through the activation of GPR109A on immune cells. We conclude therefore that GPR109A mediates antiinflammatory effects, which may be useful for treating atherosclerosis and other diseases.

The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages

“…Furthermore, it has been reported that 15d-PGJ 2 can stimulate angiogenesis 49 . Similar mechanisms may underlie the anti-atherogenic effect of HCA 2 activation 50 . In vascular macrophages, HCA 2 activation upregulated genes with an anti-inflammatory and anti-atherogenic function 50 .…”

“…Similar mechanisms may underlie the anti-atherogenic effect of HCA 2 activation 50 . In vascular macrophages, HCA 2 activation upregulated genes with an anti-inflammatory and anti-atherogenic function 50 . Collectively, these data suggest that HCA 2 provides the pharmacological basis to modulate monocyte/macrophage function and to redirect these cells into a salutary pathway.…”

The Effect of Multiple Micronutrient Supplementation on Mortality and Morbidity of HIV-Infected Adults: A Meta-Analysis of Randomized Controlled Trials

“…Many previous and ongoing preclinical studies have demonstrated that micronutrient supplementation can enhance the immune function and decrease oxidative damage, and thus can retard or inhibit the progression of some infectious and oxidative injury-related diseases (18)(19)(20)(21). When evaluating in an epidemic view, however, the effects of micronutrient supplementation on immune function and oxidative damage were disappointing, and even conflicting (22)(23)(24).…”

Induction of regulatory T cells: A role for probiotics and prebiotics to suppress autoimmunity

“…However, in colonic lumen, butyrate is generated at high concentrations (10 20 mM) by gut microbiota and serves as an endogenous agonist for GPR109A [166,167]. Interestingly, Gpr109a in immune cells plays a nonredundant function in niacin-mediated suppression of inflammation and atherosclerosis [168]. Gut microbiota also produce niacin.…”