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Niacin lipid efficacy is independent of both the niacin receptor GPR109A and free fatty acid suppression
- Source :
- Science translational medicine. 4(148)
- Publication Year :
- 2012
-
Abstract
- Nicotinic acid (niacin) induces beneficial changes in serum lipoproteins and has been associated with beneficial cardiovascular effects. Niacin reduces low-density lipoprotein, increases high-density lipoprotein, and decreases triglycerides. It is well established that activation of the seven-transmembrane G(i)-coupled receptor GPR109A on Langerhans cells results in release of prostaglandin Dâ‚‚, which mediates the well-known flushing side effect of niacin. Niacin activation of GPR109A on adipocytes also mediates the transient reduction of plasma free fatty acid (FFA) levels characteristic of niacin, which has been long hypothesized to be the mechanism underlying the changes in the serum lipid profile. We tested this "FFA hypothesis" and the hypothesis that niacin lipid efficacy is mediated via GPR109A by dosing mice lacking GPR109A with niacin and testing two novel, full GPR109A agonists, MK-1903 and SCH900271, in three human clinical trials. In mice, the absence of GPR109A had no effect on niacin's lipid efficacy despite complete abrogation of the anti-lipolytic effect. Both MK-1903 and SCH900271 lowered FFAs acutely in humans; however, neither had the expected effects on serum lipids. Chronic FFA suppression was not sustainable via GPR109A agonism with niacin, MK-1903, or SCH900271. We conclude that the GPR109A receptor does not mediate niacin's lipid efficacy, challenging the long-standing FFA hypothesis.
- Subjects :
- Male
medicine.medical_specialty
Side effect
Lipolysis
Lipoproteins
Blood lipids
Prostaglandin
Biology
Receptors, Nicotinic
Niacin
Receptors, G-Protein-Coupled
chemistry.chemical_compound
Mice
Internal medicine
medicine
Animals
Humans
Receptor
chemistry.chemical_classification
medicine.diagnostic_test
Dose-Response Relationship, Drug
digestive, oral, and skin physiology
Fatty Acids
nutritional and metabolic diseases
food and beverages
Fatty acid
General Medicine
Mice, Inbred C57BL
Endocrinology
chemistry
Pyrazoles
lipids (amino acids, peptides, and proteins)
Lipid profile
Lipoprotein
Subjects
Details
- ISSN :
- 19466242
- Volume :
- 4
- Issue :
- 148
- Database :
- OpenAIRE
- Journal :
- Science translational medicine
- Accession number :
- edsair.doi.dedup.....ebf1aeccbf331668a9796c2e9933ab38