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Nicotinic acid and its derivative, Acipimox, have been widely used in the treatment of hyperlipidemia. Pharmacological studies have demonstrated that they exert the beneficial effect through the activation of a Gi-protein-coupled receptor on adipocyte, which has remained elusive to date. Here we show that a novel GPCR, designated HM74b because of its high similarity to HM74, is a receptor for nicotinic acid. HM74b mRNA is found in human, murine, and rat adipose tissues. Nicotinic acid and Acipimox inhibit forskolin-stimulated intracellular cAMP accumulation in human HM74b-expressing cells and activate GTP gamma S binding in a dose-dependent manner. [3H]Nicotinic acid specifically binds to HM74b-expressing membrane and its binding is replaced by Acipimox. This finding will open a new phase of research on the physiological role of nicotinic acid and will be a clue to develop novel antihyperlipidemic drugs.
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Application of nicotinic acid to cell suspension cultures of Petroselinum hortense Hoffm., Daucus carota, Nicotiana tabacum and Nicotiana glauca leads to the formation of the recently isolated[2] nicotinic acid N-alpha-L-arabinoside. In these cell cultures the arabinoside is a metabolically active compound; the nicotinic acid moiety is used for NAD synthesis and nicotinic acid degradation involving decarboxylation and ring fission. N-Methylnicotinic acid (trigonelline) and nicotinic acid N-alpha-L-arabinoside occur alternatively in plant cell suspension cultures, but seem to fulfil the same function as a reserve form for nicotinic acid. Catabolism of nicotinic acid in parsley cell suspension cultures does not involve 6-hydroxynicotinic acid as an intermediate.
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The first two enzymes employed by a Bacillus species for the dissimilation of nicotinic acid are coordinately induced. The inducer of the enzymes appears to be 6-hydroxynicotinic acid, the product of the first enzyme in the pathways. Synthesis of the enzymes is repressed by glucose when ammonium is present in the medium, but not when nicotinic acid is the sole nitrogen source. The possible significance of the coordinate induction and unusual repression is discussed.
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Mechanisms for reduced free fatty acids (FFA) mobilization effected by nicotinic acid (NA) and sodium salicylate (SS) were studied in canine adipose tissue in situ. Both drugs inhibited adipose tissue lipolysis as evidenced by reduced release of glycerol. In addition, although the total amount of FFA re-esterified was not significantly changed, the amount of FFA re-esterified relative to the amount of FFA liberated intracellularly was significantly increased by both drugs. These effects were most pronounced during isoprenaline-stimulated lipolysis. Thus NA and SS reduced mobilization of FFA from canine adipose tissue through a combined effect on re-esterification and lipolysis.
Nicotinic acid phosphoribosyltransferase (NAPRTase; EC 2.4.2.11) forms nicotinic acid mononucleotide (NAMN) and PPi from 5-phosphoribosyl 1-pyrophosphate (PRPP) and nicotinic acid (NA). The Vmax NAMN synthesis activity of the Salmonella typhimurium enzyme is stimulated about 10-fold by ATP, which, when present, is hydrolyzed to ADP and Pi in 1:1 stoichiometry with NAMN formed. The overall NAPRTase reaction involves phosphorylation of a low-affinity form of the enzyme by ATP, followed by generation of a high-affinity form of the enzyme, which then binds substrates and produces NAMN. Hydrolysis of E-P then regenerates the low-affinity form of the enzyme with subsequent release of products. Our earlier studies [Gross, J., Rajavel, M., Segura, E., and Grubmeyer, C. (1996) Biochemistry 35, 3917-3924] have shown that His-219 becomes phosphorylated in the N1 (pi) position by ATP. Here, we have mutated His-219 to glutamate and asparagine and determined the properties of the purified mutant enzymes. The mutant NAPRTases fail to carry out ATPase, autophosphorylation, or ADP/ATP exchanges seen with wild-type (WT) enzyme. The mutants do catalyze the slow formation of NAMN in the absence of ATP with rates and KM values similar to those of WT. In striking contrast to WT, NAMN formation by the mutant enzymes is competitively inhibited by ATP. Thus, the NAMN synthesis reaction may occur at a site overlapping that for ATP. Previous studies suggest that the yeast NAPRTase does not catalyze NAMN synthesis in the absence of ATP. We have cloned, overexpressed, and purified the yeast enzyme and report its kinetic properties, which are similar to those of the bacterial enzyme.
A nonaqueous titration procedure is described for determining aminoacetic acid and nicotinic acid in mixtures and elixirs. The effect of acetylated aminoacetic acid on the potentiometric titration of nicotinic acid is discussed. Above a 2:1 ration of aminoacetic acid to nicotinic acid, the former interferes with titration. The titration curve of nicotinic acid becomes progressively flatter with increasing amounts of the acetylated compound. Above this ratio, nicotinic acid had to be separated from the mixture by dissolving in ethanol for a successful titration.
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A very hydrophilic compound was isolated from parsley cell suspension cultures in high yield after application of nicotinic acid. Using chemical, chromatographic and spectroscopic procedures the structure of this new plant constituent has been elucidated as nicotinic acid N-alpha-L-arabinopyranoside. This structure has been proved by chemical synthesis. An arabinosyltransferase was isolated from parsley cell suspension cultures and purified about 19-fold. The enzyme converted nicotinic acid N-alpha-arabinoside with UDP to nicotinic acid and UDP-arabinose. pH-Optimum (pH 7.0-8.0), Km value for nicotinic acid N-alpha-L-arabinoside (2.2 X 10(-4) mol/l) and mol. wt. (app. 70 000) of the transferase were measured. Function and biosynthesis of the arabinoside in cell cultures are discussed.
D-Glucitol hexanicotinate (sorbinicate), when given orally to fasted rats, depresses the plasma free fatty acids (FFA) and triglycerides. The depression is about equal in intensity and duration to that induced by corresponding doses of nicotinic acid as such, but occurs in the presence of nicotinic acid plasma levels far lower than those obtained with nicotinic acid. In fact, sorbinicate is absorbed more slowly and more smoothly than is the case with nicotinic acid and the bioavailable nicotinic acid after oral sorbinicate administration is thought to be not more than 3--4% of the dose given. At the dose closest to that in clinical use sorbinicate exerts a more lasting effect than nicotinic acid both on FFA and on triglycerides, and at all the doses tested, contrary to nicotinic acid, sorbinicate did not induce plasma FFA rebound. This particular type of bioavailability, which differentiates sorbinicate from nicotinic acid, might explain the better effect on the plasma lipids as well as the absence of the side-effects that occur with nicotinic acid administration.
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