期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 119, 期 5, 页码 1312-1321出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI36806
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资金
- NHLBI NIH HHS [HL16037, HL70631, R01 HL070631, R01 HL016037] Funding Source: Medline
- NIDDK NIH HHS [DK58398, P01 DK058398] Funding Source: Medline
- PHS HHS [5T32 A1007217-25] Funding Source: Medline
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 G(i)/G(o) 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 A(2) as well as beta-arrestin1-dependent activation of cytosolic phospholipase A(2) and release of arachidonate, the precursor of prostaglandin D-2 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.
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