Abstract

Nicotinic acid is a lipid-lowering agent widely used to treat hypertriglyceridemia and to elevate low high density lipoprotein levels. However, the underlying mechanisms are poorly understood. In this study, G protein activation by nicotinic acid and derivatives was assessed as stimulation of guanosine 5′-(γ-[³⁵S]-thio)triphosphate ([³⁵S]GTPγS) binding, and [³H]nicotinic acid was used for specific labeling of binding sites. Nicotinic acid (EC₅₀ ∼1 μM) stimulated [³⁵S]GTPγS binding in membranes from rat adipocytes and spleen, but not from other tissues. G protein activation in adipocyte membranes in the presence of maximally activating concentrations of the selective A₁adenosine receptor agonist 2-chloro-N ⁶-cyclopentyladenosine and nicotinic acid was almost additive, indicating that G proteins of mostly distinct pools were activated by these agonists. G protein activation by nicotinic acid and related substances in spleen and adipocytes revealed identical pharmacological profiles. [³H]Nicotinic acid specifically detected guanine nucleotide-sensitive binding sites of identical pharmacology in adipocyte and spleen membranes. The site of action of nicotinic acid is distinct from other G protein-coupled receptors. These data indicate that nicotinic acid most probably acts on a specific G protein-coupled receptor.