Nicotinic Acid Receptor Agonists Differentially Activate Downstream Effectors

Nicotinic acid remains the most effective therapeutic agent for the treatment and prevention of atherosclerosis resulting from low high density lipoprotein cholesterol. The therapeutic actions of nicotinic acid are mediated by GPR109A, a Gi protein-coupled receptor, expressed primarily on adipocytes...

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Bibliographic Details
Published in:The Journal of biological chemistry 2007-06, Vol.282 (25), p.18028-18036
Main Authors: Richman, Jeremy G., Kanemitsu-Parks, Martha, Gaidarov, Ibragim, Cameron, Jill S., Griffin, Peter, Zheng, Hong, Guerra, Nuvia C., Cham, Linda, Maciejewski-Lenoir, Dominique, Behan, Dominic P., Boatman, Doug, Chen, Ruoping, Skinner, Philip, Ornelas, Pricilla, Waters, M. Gerard, Wright, Samuel D., Semple, Graeme, Connolly, Daniel T.
Format: Article
Language:English
Subjects:
Adipose Tissue - metabolism
Animals
Chlorocebus aethiops
CHO Cells
COS Cells
Cricetinae
Cricetulus
Gene Expression Regulation
Male
Mice
Mice, Inbred C57BL
Mitogen-Activated Protein Kinase 1 - metabolism
Mitogen-Activated Protein Kinase 3 - metabolism
Models, Chemical
Nicotinic Agonists - metabolism
Prostaglandin D2 - metabolism
Rats
Receptors, G-Protein-Coupled - chemistry
Receptors, G-Protein-Coupled - metabolism
Receptors, Nicotinic - chemistry
Receptors, Nicotinic - metabolism
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Summary:Nicotinic acid remains the most effective therapeutic agent for the treatment and prevention of atherosclerosis resulting from low high density lipoprotein cholesterol. The therapeutic actions of nicotinic acid are mediated by GPR109A, a Gi protein-coupled receptor, expressed primarily on adipocytes, Langerhans cells, and macrophage. Unfortunately, a severe, cutaneous flushing side effect limits its use and patient compliance. The mechanism of high density lipoprotein elevation is not clearly established but assumed to be influenced by an inhibition of lipolysis in the adipose. The flushing side effect appears to be mediated by the release of prostaglandin D2 from Langerhans cells in the skin. We hypothesized that the signal transduction pathways mediating the anti-lipolytic and prostaglandin D2/flushing pathways are distinct and that agonists may be identified that are capable of selectively eliciting the therapeutic, anti-lipolytic pathway while avoiding the activation of the parallel flush-inducing pathway. We have identified a number of GPR109A pyrazole agonists that are capable of fully inhibiting lipolysis in vitro and in vivo and not only fail to elicit a flushing response but can antagonize the ability of nicotinic acid to elicit a flush response in vivo. In contrast to flushing agonists, exposure of cells expressing GPR109A to the non-flushing agonists fails to induce internalization of the receptor or to activate ERK 1/2 mitogen-activated protein kinase phosphorylation.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M701866200