Medium-chain fatty acids as ligands for orphan G protein-coupled receptor GPR84.
Free fatty acids (FFAs) play important physiological roles in many tissues as an energy source and as signaling molecules in various cellular processes. Elevated levels of circulating FFAs are associated with obesity, dyslipidemia, and diabetes. Here we show that GPR84, a previously orphan G protein-coupled receptor, functions as a receptor for medium-chain FFAs with carbon chain lengths of 9-14. Medium-chain FFAs elicit calcium mobilization, inhibit 3',5'-cyclic AMP production, and stimulate [35S]guanosine 5'-O-(3-thiotriphosphate) binding in a GPR84-dependent manner. The activation of GPR84 by medium-chain FFAs couples primarily to a pertussis toxin-sensitive G(i/o) pathway. In addition, we show that GPR84 is selectively expressed in leukocytes and markedly induced in monocytes/macrophages upon activation by lipopolysaccharide. Furthermore, we demonstrate that medium-chain FFAs amplify lipopolysaccharide-stimulated production of the proinflammatory cytokine interleukin-12 p40 through GPR84. Our results indicate a role for GPR84 in directly linking fatty acid metabolism to immunological regulation.
Wang
Jinghong
J
Amgen Inc., South San Francisco, California 94080, USA.
Wu
Xiaosu
X
Simonavicius
Nicole
N
Tian
Hui
H
Ling
Lei
L
D000331:Aequorin / Q000378:metabolism; D000818:Animals; D001853:Bone Marrow; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007107:Immune System / Q000166:cytology / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018076:DNA, Complementary; D005230:Fatty Acids, Nonesterified; C431700:GPR84 protein, human; C507114:Gpr84 protein, mouse; D053762:Interleukin-12 Subunit p40; D008024:Ligands; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000331:Aequorin; D000242:Cyclic AMP; D002118:Calcium