Niacin lipid efficacy is independent of both the niacin receptor GPR109A and free fatty acid suppression.
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 D₂, 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.
Merck Sharp & Dohme Corp., Whitehouse Station, NJ 07065, USA.
Brett
B
Lauring
Andrew K P
AK
Taggart
James R
JR
Tata
Richard
R
Dunbar
Luzelena
L
Caro
Kang
K
Cheng
Jayne
J
Chin
Steven L
SL
Colletti
Josee
J
Cote
Sauzanne
S
Khalilieh
Jiajun
J
Liu
Wen-Lin
WL
Luo
Alexandra A
AA
Maclean
Laurence B
LB
Peterson
Adam B
AB
Polis
Waheeda
W
Sirah
Tsuei-Ju
TJ
Wu
Xuan
X
Liu
Lan
L
Jin
Kenneth
K
Wu
P Douglas
PD
Boatman
Graeme
G
Semple
Dominic P
DP
Behan
Daniel T
DT
Connolly
Eseng
E
Lai
John A
JA
Wagner
Samuel D
SD
Wright
Cynthia
C
Cuffie
Yale B
YB
Mitchel
Daniel J
DJ
Rader
John F
JF
Paolini
M Gerard
MG
Waters
Andrew
A
Plump
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000097:blood / Q000378:metabolism*; D006801:Humans; D008066:Lipolysis / Q000187:drug effects; D008074:Lipoproteins / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009525:Niacin / Q000008:administration & dosage / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism*
C573553:1a,3,5,5a-tetrahydro-1H-2,3-diazacyclopropa(a)pentalene-4-carboxylic acid; D005227:Fatty Acids; C530636:HCAR2 protein, human; C473652:Hcar2 protein, mouse; D008074:Lipoproteins; D011720:Pyrazoles; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D009525:Niacin