Abstract 390: Perilipin 1 (plin1) Genotype and Not Gpr109a Associated with Free Fatty Acid Rebound Following Niacin Administration
Niacin has been used for decades as a lipid lowering agent. Stimulation of a G-protein coupled receptor (GPR109A) on adipocytes by niacin results in the anti-lipolytic effect of the drug and reduction in free fatty acids (FFA), a key pharmacodynamic readout of niacin action. Niacin also causes a subsequent rebound increase in FFA which may be linked to adverse glycemic effects. An evoked phenotype genetic study was undertaken to address the hypothesis that variation in GPR109A is associated with the FFA suppression and/or rebound with single-dose niacin.
The study recruited n=294 healthy volunteers (mean age 26 ± 7 years, 51% Female, 35% African-American (AA), 65% Caucasian (Cau)) to an inpatient immediate release 1 gm niacin challenge. The single exon gene GPR109A (1092 bp) was sequenced and genotyping was performed on Affymetrix 6.0 genomewide SNP array. Adipose tissue proteomics was performed for 6 subjects comparing pre-post niacin samples (Applied Biomics, Hayward, CA). Serial plasma samples were collected for FFA, insulin, and glucose determination.
The FFA nadir was 0.09 ± 0.08 meq/L, occurred at 2.2 ± 0.7 hr post niacin, and was lower in Cau (0.09 ± 0.08 vs 0.10 ± 0.07, p=0.003). FFA rebound occurred at 4.9 ± 0.7 hr and was lower in AA (1.7 ± 0.5 vs 2.0 ± 0.5, p<0.0001). Fasting insulin levels and HOMA-IR increased 94 ± 106% (p<0.0001) and 96 ± 149% (p<0.0001), respectively at 5 hr compared to baseline. The two common GPR109A SNPs, C931T (MAF 0.12) and G951A (MAF 0.31), were not associated with FFA nadir nor rebound. Proteomics analysis of adipose tissue samples revealed increased perilpin1 protein expression two hours after niacin. Cau individuals homozygous for the variant allele for PLIN1 (rs894160) had a lower FFA rebound than those with the wild-type allele (p=0.04).
Summary Variation in the niacin receptor GPR109A was not associated with FFA suppression nor rebound. Using an unbiased proteomics screen, we discovered that niacin increased protein expression of perilipin1, a lipid droplet protein that functions to restrict access of lipases to the triglyceride core. A common non-coding variant in PLIN1 was asociated with niacin induced FFA rebound. Pharmacogenomics of niacin may serve to identify patients who may be hyper-reponders to niacin therapy.
- © 2013 by American Heart Association, Inc.