Show simple item record Walters, RW Shukla, AK Kovacs, JJ Violin, JD DeWire, SM Lam, CM Chen, JR Muehlbauer, MJ Whalen, EJ Lefkowitz, RJ
dc.coverage.spatial United States 2012-10-24T18:22:25Z 2009-05
dc.identifier 36806
dc.identifier.citation J Clin Invest, 2009, 119 (5), pp. 1312 - 1321
dc.description.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.
dc.format.extent 1312 - 1321
dc.language eng
dc.relation.ispartof J Clin Invest
dc.relation.isversionof 10.1172/JCI36806
dc.subject Adipocytes
dc.subject Animals
dc.subject Arrestins
dc.subject Cyclic AMP
dc.subject Ear
dc.subject Eicosanoids
dc.subject Extracellular Signal-Regulated MAP Kinases
dc.subject Fatty Acids, Nonesterified
dc.subject Flushing
dc.subject Humans
dc.subject Langerhans Cells
dc.subject Lipolysis
dc.subject Macrophages
dc.subject Mice
dc.subject Mice, Inbred C57BL
dc.subject Mice, Knockout
dc.subject Niacin
dc.subject Nicotinic Agonists
dc.subject Phospholipases A2, Cytosolic
dc.subject Phosphorylation
dc.subject Protein Conformation
dc.subject Pyrazoles
dc.subject Receptors, G-Protein-Coupled
dc.subject Receptors, Nicotinic
dc.subject Regional Blood Flow
dc.subject Tetrazoles
dc.subject beta-Arrestins
dc.title beta-Arrestin1 mediates nicotinic acid-induced flushing, but not its antilipolytic effect, in mice.
dc.type Journal Article
duke.description.endpage 1321 en_US
duke.description.issue 5 en_US
duke.description.startpage 1312 en_US
duke.description.volume 119 en_US
dc.relation.journal Journal of Clinical Investigation en_US
pubs.issue 5
pubs.organisational-group /Duke
pubs.organisational-group /Duke/Faculty
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Biochemistry
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine/Medicine, Cardiology
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Pathology
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Cancer Institute
pubs.organisational-group /Duke/Trinity College of Arts & Sciences
pubs.organisational-group /Duke/Trinity College of Arts & Sciences/Chemistry
pubs.publication-status Published
pubs.volume 119
dc.identifier.eissn 1558-8238

Files in this item

This item appears in the following Collection(s)

Show simple item record