Nicotinic acid, also known as niacin or vitamin B3, has long
been used to treat dyslipidemia, and high blood cholesterol and
triglyceride levels. In addition to its lipid-altering effects, niacin
may be involved in modulating inflammation, with a beneficial
effect on adipokine expression and inflammatory markers [1–3].
Despite the long history of the clinical use of niacin, its precise
mechanism of action remains largely unclear. Niacin-targeted
high-affinity NIACR1 and low-affinity NIACR2 G-protein-coupled
receptors (GPCRs) were recently identified [4]. These two niacin
receptor subtypes share greater than 95% sequence homology,
and differ by only 16 amino acids across their sequences. NIACR2
is found only in humans and chimpanzees, and appears to have
arisen from a relatively recent gene duplication [4]. The two
receptors exhibit similar distribution patterns, and are highly restricted
to adipose tissues, spleen, and immune cells [5–7]. Despite
such high homology, they are distinguishable by their
ability to recognize different ligands. Niacin and the endogenous
ligand ketone body b-hydroxybutyrate mediate their beneficial
effects through NIACR1 [8]. NIACR2 serves as a receptor for the
b-oxidation intermediate 3-OH-octanoic acid [9]. Activation of
the niacin receptors in adipose tissue causes a Gi-coupled decrease
in cyclic AMP, which inactivates hormone-sensitive lipase,
thus decreasing triglyceride lipolysis and the release of free fatty
acids [8]. Both receptors have great clinical significance and may
be useful in preventing and regressing atherosclerosis and coronary
diseases.