Table 1.
Ligands and localization of GPCRs associated with NAFLD
| GPCR | Endogenous Ligands | Select Synthetic Ligands | G Protein Coupling | Localization |
|---|---|---|---|---|
| GPR91 (SUCNR1) | Succinate (13) | cESA (20); cCPDA (20); CMPD131 (21) | Gα (13, 22,23)ERK1/2, c-JUN | Kidney (mRNA, protein) (17, 23,24), Liver (mRNA, protein) (19, 25), Retina (mRNA, protein) (26), Adipose (mRNA, protein) (27), Heart (mRNA, protein) (28), Dendritic cells (mRNA, protein) (29), Breast (mRNA) (19), Blood vessels (mRNA) (30) |
| GPR55 (LPIR1) | Cannabinoids (31–35), LPI (36), OEA (37) | AM251 (37), AM281 (37), SR141716A (37), HU210 (38), JWH015 (39), CP55940 (37), O1602 (37), Abnormal cannabidiol (35), ML‐193 (40), O‐1918 (40), CID16020046 (40) | Gα12 (41)RhoAGαq (42)PKCβIIG13 (35)RhoA, CDC42, RAC1β-Arrestin (43)ERK 1/2 | CNS (mRNA) (35, 39, 44), Neutrophils (mRNA) (45), Gastrointestinal tract (mRNA) (35), Adipose (mRNA, protein) (46,47), Liver (mRNA, protein) (46,47), Skeletal muscle (mRNA) (46), Pancreas (protein) (48) |
| GPR119 (GPCR2) | OEA (49, 50), LEA (49, 51, 150), 2OG (51,52), LPC (38), LPEA (53), 1-Oleoyl-LPEA (53), LPI (53), LPS (53), LPA (53), SPC (53), Oleic acid (53), Oleamide (53), PEA (53), Anandamide (53), ODA (53), NADA (53), N-Oleoyl-tyrosine (53), 2-Linoleoyl glycerol (53), 2-Palmitoyl glycerol (53), 2-AG (53), 1-Oleoyl glycerol (53), 1-LG(53) | PSN632408 (38), AR231453 (38), APD668 (53), APD597 (53), GSK-1292263 (53), MBX-2982 (53), PSN632408 (54), Sitagliptin (41), Linagliptin (41), Tenegliptin (41) | Gαs (55), Gαi (55), Gαq (55), β-Arrestin (55) | Pancreas (mRNA) (52), Small intestine (mRNA) (52), Stomach (mRNA) (52), Colon (mRNA) (52), Liver (mRNA) (51), Hepatocytes (mRNA) (51), Small intestine (mRNA) (56,57), Macrophages (58,59) |
| GPR109a (HCA2, MB74b) | Butyrate (60–62), β-Hydroxybutyrate (63) | Niacin (64), Monomethylfumarate (65), Dimethylfumarate (66) | Gαi (64) | Adipose (mRNA) (64), Lung (mRNA) (64), Spleen (mRNA) (64), Kidney (protein) (60), Macrophages (protein) (60), Liver (mRNA, protein) (67), Colon (mRNA) (68), Pancreas (mRNA, protein) (69), Brain (mRNA) (70) |
| GPR142 (GPRg1b, PGR2) | Tryptophan (71,72), Phenylalanine (71) | CLP-3094 (37), CpdA (73), Benzo-[1,2,4]-triazolo-[1,4]-oxazepine (74), LY3325656 (75) | Gαs (76), Gαi (73), Gαq (71) | Brain (mRNA) (72, 77), Hypothalamus (mRNA) (72), Pancreas (mRNA) (72, 78), Pituitary (mRNA) (72), Lung (mRNA) (72), Spleen (mRNA) (77), Liver (mRNA) (72, 77), Kidneys (mRNA) (72, 77), Stomach (mRNA) (72), Small intestine (mRNA) (72), Colon (mRNA) (72), Adipose (mRNA) (72), Heart (mRNA) (72), Testis (mRNA) (77) |
| GPR41 (FFAR3, Gm478) | Propionate (79), Butyrate (79), Pentanoate (79), Acetate (79), Formate (79) | AR420626 (80) | Gαi/o (81), p38JNKGβγ (82), PLCb, MAPK, p38, JNK | White adipose (mRNA) (79, 83), Small intestine (mRNA) (16), Pancreas (mRNA) (79, 84), Spleen (mRNA, protein) (79, 85,86), PBMCs (mRNA) (79), Placenta (mRNA) (79), Lung (mRNA, protein) (79, 85), Pituitary (mRNA) (79)v Brain (mRNA) (79), Liver (mRNA, protein) (79, 85), Stomach (mRNA) (79), Kidney (mRNA) (79, 86), Bone marrow (mRNA) (79), Prostate (mRNA) (79, 85), Colon (mRNA, protein) (87) |
| GPR43 (FFAR2) | Acetate (79), Propionate (79), Butyrate (79), Pentanoate (79), Hexanoate (79), Formate (79) | Compound 1 (80), Compound 2 (80), Compound 3 (80), GLPG0974 (80), CATPB (80), Cmp71 (80), MeCmp71 (80), BTI-A-404 (80), BTI-A-292 (80), 4-CMTB (80), AZ1729 (80) | Gαi/o (80), Gαq/11(80), Gβγ(80), p38 (87), JNK (87), β-Arrestin (80), NF-κB | Immune cells (mRNA, protein) (79, 85), Pancreas (mRNA) (88), Liver (protein) (85), Small intestine (Protein) (89), Mucosal mast cells (protein) (89), Adipose (mRNA) (86, 90), Colon (mRNA, protein) (86, 89), Spleen (mRNA, protein) (85,86), Stomach (mRNA) (86), Lung (mRNA, protein) (85,86), Heart (mRNA) (140) Muscle (mRNA) (140) Bone marrow (mRNA) (90) |
| GPR40 (FFAR1) | Medium-/long-chain FFAs (91–93) | Fasiglifam (40), RLA-8 (88), SCO-267 (94), Fezagepras (95) | Gαq (96) | Pancreas (mRNA, protein) (91, 97,98), Brain (mRNA) (91), Hepatocytes (mRNA) (99), Immune cells (mRNA) (91), Small intestine (mRNA, protein) (57, 100), Taste buds (protein) (101) |
cCPDA, cis-1,2-cyclopropanedicarboxylic acid; cESA, cis-epoxysuccinic acid; Compound 1, 3-benzyl-4-(cyclopropyl-(4-(2,5-dichlorophenyl)thiazol-2-yl)amino)-4-oxobutanoic acid; Compound 2, (R)-3-(cyclopentylmethyl)-4-(cyclopropyl-(4-(2,6-dichlorophenyl)thiazol-2-yl)amino)-4-oxobutanoic acid; Compound 3, (2S,5R)-5-(2-chlorophenyl)-1-1(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid; LEA, linoleoyl ethanolamide; LPA, lysophosphatidic acid; LPEA, lysophosphatidylethanolamine; LPC, lysophosphatidylcholines; LPI, lysophosphatidylinositol; LPS, lysophosphatidylserine; OEA, oleoylethanolamide; 2OG, 2-oleoylglycerol; PEA, palmitoylethanolamide; ODA, N-oleoyl-dopamine; NADA, N-arachidonoyl-dopamine; 2-AG, 2-arachidonoyl glycerol; 1-LG, 1-linoleoyl glycerol; AM251, 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide; AM281, 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide; SR141716, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-pyrazole-3-carboxamide; HU210, (−) 11-OH-8-tetrahydrocannabinol-dimethylheptyl; JWH015, (2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone; CP55940, (−)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol; O1602, 5-methyl-4-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-1,3-benzenediol; ML‐193, N-[4-[[(3,4-dimethyl-5-isoxazolyl)amino]sulfonyl]phenyl]-6,8-dimethyl-2-(2-pyridinyl)-4-quinolinecarboxamide; O‐1918, 1,3-dimethoxy-5-methyl-2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]benzene; CID16020046, 4-[4,6-dihydro-4-(3-hydroxyphenyl)-3-(4-methylphenyl)-6-oxopyrrolo[3,4-c]pyrazol-5(1H)-yl]benzoic acid; PSN632408, tert-butyl 4-((3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)piperidine-1-carboxylate; AR231453, (2-fluoro-4-methanesulfonylphenyl)-(6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitropyrimidin-4-yl)amine, AR-231,453, AR231453, N-(2-fluoro-4-(methylsulfonyl)phenyl)-6-(4-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-5-nitropyrimidin-4-amine; APD668, isopropyl 4-(1-(2-fluoro-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)piperidine-1-carboxylate; APD597, 4-[[5-methoxy-6-[[2-methyl-6-(methylsulfonyl)-3-pyridinyl]amino]-4-pyrimidinyl]oxy]-1-piperidinecarboxylic acid, 1-methylethyl ester; GSK-1292263, 3-isopropyl-5-(4-(((6-(4-(methylsulfonyl)phenyl)pyridin-3-yl)oxy)methyl)piperidin-1-yl)-1,2,4-oxadiazole; MBX-2982, 2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]-4-[[4-(tetrazol-1-yl)phenoxy]methyl]-1,3-thiazole; PSN632408, 4-[[3-(4-pyridinyl)-1,2,4-oxadiazol-5-yl]methoxy]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester; CpdA; N-[(3-methylimidazol-4-yl)methyl]-1-[5-methyl-4-(2-thienyl)pyrimidin-2-yl]-5-propyl-pyrazole-4-carboxamide); LY3325656, N-((2S,4R)-2-(5-(1,4-dimethyl-1H-imidazol-5-yl)-4H-1,2,4-triazol-3-yl)tetrahydro-2H-pyran-4-yl)-N-methyl-3-(trifluoromethyl)benzamide; AR420626, N-(2,5-dichlorophenyl)-4-(furan-2-yl)-2-methyl-5-oxo-1,4,5,6,7,8-hexahydro-quinoline-3-carboxamide; GLPG0974; CATPB, (s)-3-(2-(3-chlorophenyl)acetamido)-4-(4-(trifluoromethyl)phenyl)butanoic acid; Cmp71, (4-(1-(benzo[b]thiophene-3-carbonyl)-2-methyl-N-(4-trifluoromethylbenzyl)azetidine-2-carboxamido)butanoic acid); MeCmp71, (methyl 4-(1-(benzo[b]thiophene-3-carbonyl)-2-methyl-N-(4-trifluoromethylbenzyl)azetidine-2-carboxamido)butanoate); BTI-A-404, [4-[4-(dimethylamino)phenyl]-N-(3,5-dimethylphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxamide]; BTI-A-292, [4-[4-(dimethylamino) phenyl]-N-(4,5-dimethylphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxamide]; 4-CMTB, 4-Chloro-α-(1-methylethyl)-N-2-thiazolyl-benzeneacetamide; AZ1729, 4-fluoro-N-[3-[2-[(aminoiminomethyl)amino]-4-methyl-5-thiazolyl]phenyl]benzamide; RLA-8, (E)-8-(3-methoxy-5-(4-methoxystyryl)phenoxy)octanoic acid; SCO-267, (3S)-3-cyclopropyl-3-{2-[(1-{2-[(2,2-dimethylpropyl)(6-methylpyridin-2-yl)carbamoyl]-5-methoxyphenyl}piperidin-4-yl)methoxy]pyridin-4-yl}propanoic acid; CLP-3094, 2-((2-(4-chlorophenoxy)ethyl)thio)-1H-benzo[d]imidazole; SPC, sphingosylphosphorylcholine.