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Niacin Lipid Efficacy Is Independent of Both the Niacin Receptor GPR109A and Free Fatty Acid Suppression.
MedLine Citation:
PMID:  22914621     Owner:  NLM     Status:  In-Data-Review    
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 D(2), 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.
Brett Lauring; Andrew K P Taggart; James R Tata; Richard Dunbar; Luzelena Caro; Kang Cheng; Jayne Chin; Steven L Colletti; Josee Cote; Sauzanne Khalilieh; Jiajun Liu; Wen-Lin Luo; Alexandra A Maclean; Laurence B Peterson; Adam B Polis; Waheeda Sirah; Tsuei-Ju Wu; Xuan Liu; Lan Jin; Kenneth Wu; P Douglas Boatman; Graeme Semple; Dominic P Behan; Daniel T Connolly; Eseng Lai; John A Wagner; Samuel D Wright; Cynthia Cuffie; Yale B Mitchel; Daniel J Rader; John F Paolini; M Gerard Waters; Andrew Plump
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Science translational medicine     Volume:  4     ISSN:  1946-6242     ISO Abbreviation:  Sci Transl Med     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-08-23     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101505086     Medline TA:  Sci Transl Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  148ra115     Citation Subset:  IM    
Merck Sharp & Dohme Corp., Whitehouse Station, NJ 07065, USA.
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