title: G Protein-coupled Receptor 40 (GPR40) and Peroxisome Proliferator-activated Receptor γ (PPARγ): AN INTEGRATED TWO-RECEPTOR SIGNALING PATHWAY.
abstract: Peroxisome proliferator-activated receptor γ (PPARγ) ligands have been widely used to treat type 2 diabetes mellitus. However, knowledge of PPARγ signaling remains incomplete. In addition to PPARγ, these drugs also activate G protein-coupled receptor 40 (GPR40), a Gαq-coupled free fatty acid receptor linked to MAPK networks and glucose homeostasis. Notably, p38 MAPK activation has been implicated in PPARγ signaling. Here, rosiglitazone (RGZ) activation of GPR40 and p38 MAPK was found to boost PPARγ-induced gene transcription in human endothelium. Inhibition or knockdown of p38 MAPK or expression of a dominant negative (DN) p38 MAPK mutant blunted RGZ-induced PPARγ DNA binding and reporter activity in EA.hy926 human endothelial cells. GPR40 inhibition or knockdown, or expression of a DN-Gαq mutant likewise blocked activation of both p38 MAPK and PPARγ reporters. Importantly, RGZ induction of PPARγ target genes in primary human pulmonary artery endothelial cells (PAECs) was suppressed by knockdown of either p38 MAPK or GPR40. GPR40/PPARγ signal transduction was dependent on p38 MAPK activation and induction of PPARγ co-activator-1 (PGC1α). Silencing of p38 MAPK or GPR40 abolished the ability of RGZ to induce phosphorylation and expression of PGC1α in PAECs. Knockdown of PGC1α, its essential activator SIRT1, or its binding partner/co-activator EP300 inhibited RGZ induction of PPARγ-regulated genes in PAECs. RGZ/GPR40/p38 MAPK signaling also led to EP300 phosphorylation, an event that enhances PPARγ target gene transcription. Thus, GPR40 and PPARγ can function as an integrated two-receptor signal transduction pathway, a finding with implications for rational drug development.
authors.affiliation: From the Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892 swang@cc.nih.gov.
authors.forename: Shuibang
authors.initials: S
authors.lastname: Wang
authors.affiliation: From the Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Keytam S
authors.initials: KS
authors.lastname: Awad
authors.affiliation: From the Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Elinoff
authors.affiliation: From the Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Dougherty
authors.affiliation: From the Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Gabriela A
authors.initials: GA
authors.lastname: Ferreyra
authors.affiliation: From the Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: Wang
authors.affiliation: From the Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Rongman
authors.initials: R
authors.lastname: Cai
authors.affiliation: From the Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Sun
authors.affiliation: From the Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Anetta
authors.initials: A
authors.lastname: Ptasinska
authors.affiliation: From the Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892 rdanner@nih.gov.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Danner
mesh_terms: D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008024:Ligands; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000077205:Pioglitazone; D061251:Primary Cell Culture; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D020239:Receptor Cross-Talk; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000235:genetics*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C473034:FFAR1 protein, human; D007004:Hypoglycemic Agents; D008024:Ligands; D047495:PPAR gamma; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D004247:DNA; D008156:Luciferases; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D048051:p38 Mitogen-Activated Protein Kinases; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000077205:Pioglitazone
keywords: E1A-binding protein p300 (P300); G protein-coupled receptor (GPCR); G protein-coupled receptor 40 (GPR40); p38 MAPK; peroxisome proliferator-activated receptor (PPAR); peroxisome proliferator-activated receptor gamma (PPARgamma); peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a)(PPARGC1A); sirtuin 1 (SIRT1); thiazolidinedione