Flushing out the role of GPR109A (HM74A)

in the clinical efficacy of nicotinic acid (original) (raw)

In 2003, several groups published studies showing that the orphan receptor GPR109A is activated by nicotinic acid at concentrations consistent with the exposure achieved following therapeutic doses (5–7). Furthermore, additional compounds with a clinical profile similar to that of nicotinic acid (e.g., acipimox and acifran) were also confirmed as full agonists of GPR109A. Importantly, nicotinamide, which does not alter lipoprotein profiles but shares the vitamin-like properties of nicotinic acid, has virtually no GPR109A agonist activity. This pharmacological profile strongly suggests that GPR109A is a molecular target involved in the clinical efficacy of nicotinic acid and therefore offers a potential focus to explore the biological processes involved in the highly desirable therapeutic profile achieved following chronic treatment with this drug (8–9).

The best-described action of nicotinic acid is the inhibition of adipocyte lipolysis. The combination of pharmacology and the use of transgenic mice has confirmed that GPR109A expressed in adipocytes is functionally competent (5–7). A key question is whether the activity of nicotinic acid via GPR109A expressed on the surface of the adipocyte is sufficient to account for the overall clinical efficacy observed. The lowering of circulating nonesterified fatty acid levels via activation of adipocyte GPR109A would be expected to lead to a reduction in hepatic triglyceride synthesis and hence circulating VLDL levels. Due to the inverse relationship between plasma triglycerides and HDL cholesterol, it is likely that HDL levels would be increased if the reduction in VLDL resulted in an inhibition of cholesterol ester transfer protein activity (10).

In addition to expression on adipocytes, GPR109A is known to be most highly expressed in spleen, lung, and lymphoid cells (5). However, the lack of good-quality antibodies has failed to determine whether mRNA expression is always accompanied by functional levels of GPR109A protein. To date, there is very little evidence in the literature for GPR109A-mediated effects outside of adipose tissue. The obvious exception to this is the intense cutaneous vasodilation (flushing) that has been seen clinically with each GPR109A agonist tested to date. In this issue of the JCI, Benyó et al. show that protein upregulated in macrophages by IFN-γ (PUMA-G), the murine ortholog of GPR109A, is responsible for the nicotinic acid–induced flushing response (11). In their murine studies, this group has demonstrated a GPR109A-mediated mobilization of arachidonic acid, which is converted to prostaglandins to result in the characteristic vasodilatory response (Figure 1). This elegant study confirms the proposed mechanism from clinical observation (12) and supports the hypothesis that immune cells in the skin are the most likely source of arachidonic acid and prostaglandins. Clearly, in the mouse, both PGE2, via the type 2 and type 4 PGE2 receptors (EP2 and EP4, respectively), and PGD2, via the PGD2 receptor (DP), are involved in nicotinic acid–induced cutaneous vasodilation. However, in humans, the precise involvement of the prostanoid receptor is yet to be resolved, but based on the analysis of metabolites, DP is likely to be involved (12).

The confirmation that the nicotinic acid–induced flushing response is GPR109A mediated raises several interesting questions. First, will it be possible to produce GPR109A agonists with the beneficial efficacy of nicotinic acid but without the marked flushing response associated with nicotinic acid? Alternative formulations, prodrugs, and different GPR109A ligands (e.g., acipimox and acifran) have been claimed to induce less flushing than crystalline nicotinic acid (13, 14). Therefore, as the chemical diversity of future GPR109A ligands is increased, it is conceivable that compounds that do not compartmentalize into the skin could induce markedly less flushing than that induced by nicotinic acid. Second, the involvement of GPR109A in the flushing response raises the question of whether GPR109A receptors located outside adipose tissue can contribute to the clinical efficacy of nicotinic acid. GPR109A is highly expressed in lymphoid cells. This expression profile, coupled with the observation that in murine macrophages, GPR109A is upregulated by cytokines like IFN-γ (15), may suggest a role for GPR109A in immunity and inflammation. If this is the case, then it is interesting to speculate on whether nicotinic acid achieves any of its clinical efficacy via these cell types (e.g., at the level of the atherosclerotic plaque) and not solely via the normalization of aberrant lipoprotein profiles. Furthermore, one could speculate on a degree of analogy with the mechanism of action that results in the flushing response, for example, the generation of prostaglandins following the liberation of archidonic acid via GPR109A stimulation. If this functionality of GPR109A is indeed involved in the clinical efficacy of nicotinic acid, it raises further areas for investigation, which would include determination of whether the tachyphylaxis observed in the flushing response to nicotinic acid and acipimox is observed in other immune/inflammatory cell types and whether the symptomatic relief from flushing achieved by NSAID administration has detrimental effects on some aspects of the efficacy of GPR109A agonists. It is apparent that the lipoprotein changes achieved with nicotinic acid are not affected by NSAID treatment (16), possibly suggesting the involvement of a direct GPR109A-mediated event.