β-Arrestin1 mediates nicotinic acid–induced flushing, but not its antilipolytic effect, in mice
Robert W. Walters, … , Erin J. Whalen, Robert J. Lefkowitz
Robert W. Walters, … , Erin J. Whalen, Robert J. Lefkowitz
Published April 6, 2009
Citation Information: J Clin Invest. 2009;119(5):1312-1321. https://doi.org/10.1172/JCI36806.
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Research Article Cardiology

β-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, β-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 β-arrestins to the cell membrane, an activating conformational change in β-arrestin, and β-arrestin–dependent signaling to ERK MAPK. In addition, we found that nicotinic acid promoted the binding of β-arrestin1 to activated cytosolic phospholipase A2 as well as β-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, β-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 β-arrestin1, but lowering of serum free fatty acid levels is not. Furthermore, G protein–biased ligands that activate GPR109A in a β-arrestin–independent fashion may represent an improved therapeutic option for the treatment of dyslipidemia.

Authors

Robert W. Walters, Arun K. Shukla, Jeffrey J. Kovacs, Jonathan D. Violin, Scott M. DeWire, Christopher M. Lam, J. Ruthie Chen, Michael J. Muehlbauer, Erin J. Whalen, Robert J. Lefkowitz

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Figure 8

Nicotinic acid–induced cutaneous flushing and activity of cPLA2 is attenuated in β-arrestin1–deficient mice.

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Nicotinic acid–induced cutaneous flushing and activity of cPLA2 is atten...
(A) Perfusion of the ventral ear in wild-type, β-arrestin1–deficient, or β-arrestin2–deficient mice was measured with laser Doppler. Baseline perfusion was measured for 150 seconds, then mice were given i.p. injections of 100 mg/kg nicotinic acid. Data are mean ± SEM for change in perfusion as a function of time. (B) Total response to nicotinic acid, plotted as mean ± SEM area under the curve. (C) Maximum response to nicotinic acid, plotted as mean ± SEM. *P < 0.0001 versus wild type. (D) Maximum response to PGD2, plotted as mean ± SEM (n = 15–25 per condition). (E) Nicotinic acid–stimulated release of eicosanoids was measured in peritoneal macrophages. Thioglycollate-elicited peritoneal macrophages were loaded with H3-arachidonic acid (H3-AA) for 24 hours, and then rinsed to remove arachidonic acid not incorporated into cell membrane lipids. Macrophages were stimulated for 10 minutes with 200 μM nicotinic acid, and radioactivity released into the media was measured. Data are mean ± SEM (n = 4 per condition) for change in radioactivity, plotted as a percentage of the maximum response. **P = 0.0001 versus nicotinic acid–treated wild type.