beta-Arrestin1 mediates nicotinic acid-induced flushing, but not its antilipolytic effect, in mice.
Abstract
Nicotinic acid is one of the most effective agents for both lowering triglycerides
and raising HDL. However, the side effect of cutaneous flushing severely limits patient
compliance. As nicotinic acid stimulates the GPCR GPR109A and Gi/Go proteins, here
we dissected the roles of G proteins and the adaptor proteins, beta-arrestins, in
nicotinic acid-induced signaling and physiological responses. In a human cell line-based
signaling assay, nicotinic acid stimulation led to pertussis toxin-sensitive lowering
of cAMP, recruitment of beta-arrestins to the cell membrane, an activating conformational
change in beta-arrestin, and beta-arrestin-dependent signaling to ERK MAPK. In addition,
we found that nicotinic acid promoted the binding of beta-arrestin1 to activated cytosolic
phospholipase A2 as well as beta-arrestin1-dependent activation of cytosolic phospholipase
A2 and release of arachidonate, the precursor of prostaglandin D2 and the vasodilator
responsible for the flushing response. Moreover, beta-arrestin1-null mice displayed
reduced cutaneous flushing in response to nicotinic acid, although the improvement
in serum free fatty acid levels was similar to that observed in wild-type mice. These
data suggest that the adverse side effect of cutaneous flushing is mediated by beta-arrestin1,
but lowering of serum free fatty acid levels is not. Furthermore, G protein-biased
ligands that activate GPR109A in a beta-arrestin-independent fashion may represent
an improved therapeutic option for the treatment of dyslipidemia.
Type
Journal articleSubject
AdipocytesAnimals
Arrestins
Cyclic AMP
Ear
Eicosanoids
Extracellular Signal-Regulated MAP Kinases
Fatty Acids, Nonesterified
Flushing
Humans
Langerhans Cells
Lipolysis
Macrophages
Mice
Mice, Inbred C57BL
Mice, Knockout
Niacin
Nicotinic Agonists
Phospholipases A2, Cytosolic
Phosphorylation
Protein Conformation
Pyrazoles
Receptors, G-Protein-Coupled
Receptors, Nicotinic
Regional Blood Flow
Tetrazoles
beta-Arrestins
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https://hdl.handle.net/10161/5928Published Version (Please cite this version)
10.1172/JCI36806Publication Info
Walters, Robert W; Shukla, Arun K; Kovacs, Jeffrey J; Violin, Jonathan D; DeWire,
Scott M; Lam, Christopher M; ... Lefkowitz, Robert J (2009). beta-Arrestin1 mediates nicotinic acid-induced flushing, but not its antilipolytic
effect, in mice. J Clin Invest, 119(5). pp. 1312-1321. 10.1172/JCI36806. Retrieved from https://hdl.handle.net/10161/5928.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Robert J. Lefkowitz
The Chancellor's Distinguished Professor of Medicine
Dr. Lefkowitz’s memoir, A Funny Thing Happened on the Way to Stockholm, recounts his
early career as a cardiologist and his transition to biochemistry, which led to his
Nobel Prize win.
Robert J. Lefkowitz, M.D. is James B. Duke Professor of Medicine and Professor of
Biochemistry and Chemistry at the Duke University Medical Center. He has been an Investigator
of the

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