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 5

Nicotinic acid–induced binding of β-arrestin to cPLA2 and phosphorylated cPLA2.

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Nicotinic acid–induced binding of β-arrestin to cPLA2 and phosphorylated...
(A and B) GPR109A-expressing HEK-293 cells were stimulated with 10 μM nicotinic acid or control for 10 minutes. Nicotinic acid stimulation increased binding of β-arrestin to cPLA2 (A) and phosphorylated cPLA2 (p-cPLA2) (B). Arrow indicates phosphorylated cPLA2 band. Equivalent amounts of cPLA2 were present in each whole cell lysate (WCL). Equal amounts of β-arrestin were immunoprecipitated in control and nicotinic acid–treated samples. Moreover, β-arrestin was not immunoprecipitated with preimmune serum (not shown). (C and D) Binding of β-arrestin to cPLA2 (C) and phosphorylated cPLA2 (D). *P = 0.0075, **P = 0.015 versus control. Data are mean ± SEM of 5 independent experiments.