HCAR1

Summary

HCAR1 (hydroxycarboxylic acid receptor 1, HGNC:4532) is a protein-coding gene on chromosome 12q24.31, encoding Hydroxycarboxylic acid receptor 1 (Q9BXC0). Acts as a receptor for L-lactate and mediates its anti-lipolytic effect through a G(i)-protein-mediated pathway.

G protein-coupled receptors (GPCRs, or GPRs), such as GPR81, contain 7 transmembrane domains and transduce extracellular signals through heterotrimeric G proteins.

Source: NCBI Gene 27198 — RefSeq curated summary.

At a glance

• GWAS associations: 53
• Clinical variants (ClinVar): 70 total
• Druggable target: yes
• MANE Select transcript: NM_032554

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4532
Approved symbol	HCAR1
Name	hydroxycarboxylic acid receptor 1
Location	12q24.31
Locus type	gene with protein product
Status	Approved
Aliases	HCA1, FKSG80, TA-GPCR, LACR1
Ensembl gene	ENSG00000196917
Ensembl biotype	protein_coding
OMIM	606923
Entrez	27198

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000432564

RefSeq mRNA: 1 — MANE Select: NM_032554 NM_032554

CCDS: CCDS9236

Canonical transcript exons

ENST00000432564 — 1 exons

Exon	Start	End
ENSE00001618531	122726076	122730844

Expression profiles

Bgee: expression breadth broad, 98 present calls, max score 77.85.

FANTOM5 (CAGE): breadth broad, TPM avg 0.5853 / max 23.6896, expressed in 221 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
133841	0.4569	201
133842	0.0738	42
133843	0.0546	14

Top tissues by expression

214 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	77.85	gold quality
omental fat pad	UBERON:0010414	68.93	gold quality
peritoneum	UBERON:0002358	68.85	gold quality
adipose tissue of abdominal region	UBERON:0007808	67.38	gold quality
spleen	UBERON:0002106	61.91	gold quality
minor salivary gland	UBERON:0001830	59.84	gold quality
body of stomach	UBERON:0001161	59.71	gold quality
subcutaneous adipose tissue	UBERON:0002190	59.21	gold quality
stromal cell of endometrium	CL:0002255	58.76	gold quality
metanephros cortex	UBERON:0010533	58.34	gold quality
right lobe of thyroid gland	UBERON:0001119	58.31	gold quality
adipose tissue	UBERON:0001013	58.19	gold quality
saliva-secreting gland	UBERON:0001044	58.19	gold quality
stomach	UBERON:0000945	57.42	gold quality
mouth mucosa	UBERON:0003729	57.30	gold quality
left lobe of thyroid gland	UBERON:0001120	55.47	gold quality
thyroid gland	UBERON:0002046	55.24	gold quality
colonic epithelium	UBERON:0000397	54.59	gold quality
ganglionic eminence	UBERON:0004023	53.46	gold quality
adult mammalian kidney	UBERON:0000082	53.31	gold quality
cortex of kidney	UBERON:0001225	53.24	gold quality
endocervix	UBERON:0000458	53.07	gold quality
metanephros	UBERON:0000081	52.99	gold quality
kidney	UBERON:0002113	51.13	gold quality
fundus of stomach	UBERON:0001160	50.69	gold quality
ectocervix	UBERON:0012249	50.65	gold quality
cortical plate	UBERON:0005343	50.57	gold quality
fallopian tube	UBERON:0003889	50.48	gold quality
hindlimb stylopod muscle	UBERON:0004252	50.30	gold quality
uterine cervix	UBERON:0000002	50.27	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.93

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PPARG

miRNA regulators (miRDB)

56 targeting HCAR1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-548M	99.70	68.87	1749
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-141-5P	99.57	67.86	897
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-5683	99.36	68.59	2083
HSA-MIR-4652-3P	99.33	70.02	2742
HSA-MIR-2116-5P	99.32	69.34	1273
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-4520-2-3P	99.14	69.28	1009
HSA-MIR-6809-5P	99.13	68.45	1223
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-6770-5P	98.97	66.76	1853

Literature-anchored findings (GeneRIF, showing 31)

• GPR81 with relatively restricted expression in the adipose tissues functions as a receptor for lactate and can mediate an anti-lipolytic effect of lactate. (PMID:18952058)
• Data show that the coordinated PPARgamma-mediated regulation of the GPR81, GPR109A and GPR109B presents a novel mechanism by which TZDs may reduce circulating free fatty acid levels and perhaps ameliorate insulin resistance in obese patients. (PMID:19633298)
• demonstrated that the C165-E166-S167-F168 motif at the second extracellular loop is critical for GPR81 function, and the conserved six Cys residues at the extracellular regions are necessary for GPR81 function (PMID:21862690)
• Description of a GPR81 selective agonist with in vivo efficacy, inhibiting lipolysis without flushing. (PMID:24486398)
• Lactate negatively regulates TLR induction of the NLRP3 inflammasome and production of IL1beta, via ARRB2 and GPR81 in liver and pancreatic injury. (PMID:24657625)
• Data support that GPR81 is important for cancer cell regulation of lactate transport mechanisms. (PMID:24928781)
• HCA1/3 are necessary for breast cancer cells to balance lipid/fatty acid metabolism. (PMID:25839160)
• HCAR1 and monocarboxylate transporters activity is required for the L- and D-lactate-mediated enhancement of DNA repair and of HeLa cell survival. (PMID:26208712)
• Findings identify GPR81 as a tumor-promoting receptor in breast cancer progression and suggest a novel mechanism that regulates GPR81-dependent activation of the PI3K/Akt signaling axis in tumor microenvironment. (PMID:27765922)
• Lactate receptor/HCAR1 expression in cervical carcinoma cells may contribute to the modulation of cellular DNA repair mechanisms. (PMID:28258841)
• Activation of GPR81 decreases intracellular cAMP levels and inhibits PKA activity, leading to activation of TAZ and upregulation of PD-L1. This study reveals a critical role for lactate in the immune checkpoint pathway and an unexpected function of TAZ in tumor evasion of the T-cell-mediated immune response. (PMID:28604752)
• The novel role of HCAR1 in development of chemoresistance in cervical carcinoma HeLa cells via ABCB1 transporter up-regulation. (PMID:29151072)
• Monocarboxylate transporters in cancer. (PMID:31395464)
• Activation of GPR81 can rescue oscillatory shear stress -induced reduced expression of the key atheroprotective transcription factor KLF2. (PMID:31444899)
• The transcriptional response of GPR81 to lactate is mediated by Signal transducer and activator of transcription 3 (STAT3). (PMID:31666207)
• The lactate receptor GPR81 promotes breast cancer growth via a paracrine mechanism involving antigen-presenting cells in the tumor microenvironment. (PMID:32071396)
• Effects of GPR81 silencing combined with cisplatin stimulation on biological function in hypopharyngeal squamous cell carcinoma. (PMID:32582969)
• Heterogeneous ozone effects on the DNA methylome of bronchial cells observed in a crossover study. (PMID:32978449)
• HCAR1/MCT1 Regulates Tumor Ferroptosis through the Lactate-Mediated AMPK-SCD1 Activity and Its Therapeutic Implications. (PMID:33296645)
• Rare and potentially pathogenic variants in hydroxycarboxylic acid receptor genes identified in breast cancer cases. (PMID:34852802)
• Transcriptomic and functional studies reveal miR-431-5p as a tumour suppressor in pancreatic ductal adenocarcinoma cells. (PMID:35182679)
• Activation of lactate receptor HCAR1 down-modulates neuronal activity in rodent and human brain tissue. (PMID:35240875)
• The lactate sensor GPR81 regulates glycolysis and tumor growth of breast cancer. (PMID:35428832)
• Lactate receptor HCAR1 regulates cell growth, metastasis and maintenance of cancerspecific energy metabolism in breast cancer cells. (PMID:35775372)
• Insights into the regulation of podocyte and glomerular function by lactate and its metabolic sensor G-protein-coupled receptor 81. (PMID:36084306)
• The lactate receptor GPR81 is predominantly expressed in type II human skeletal muscle fibers: potential for lactate autocrine signaling. (PMID:36622074)
• History and Function of the Lactate Receptor GPR81/HCAR1 in the Brain: A Putative Therapeutic Target for the Treatment of Cerebral Ischemia. (PMID:37391123)
• Activation of GPR81 aggravated intestinal ischemia/reperfusion injury-induced acute lung injury via HMGB1-mediated neutrophil extracellular traps formation. (PMID:37698122)
• High Glucose Levels Promote Switch to Synthetic Vascular Smooth Muscle Cells via Lactate/GPR81. (PMID:38334628)
• Lactate/Hydroxycarboxylic Acid Receptor 1 in Alzheimer’s Disease: Mechanisms and Therapeutic Implications-Exercise Perspective. (PMID:38427215)
• Immunohistochemical localization of HCA1 receptor in placenta in presence of fetal growth restriction. (PMID:38909565)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hcar1	ENSMUSG00000049241
rattus_norvegicus	Hcar1	ENSRNOG00000026661

Paralogs (15): GPR31 (ENSG00000120436), GPR42 (ENSG00000126251), FFAR2 (ENSG00000126262), FFAR1 (ENSG00000126266), OXER1 (ENSG00000162881), OXGR1 (ENSG00000165621), P2RY1 (ENSG00000169860), P2RY6 (ENSG00000171631), GPR82 (ENSG00000171657), P2RY2 (ENSG00000175591), HCAR2 (ENSG00000182782), FFAR3 (ENSG00000185897), P2RY4 (ENSG00000186912), SUCNR1 (ENSG00000198829), HCAR3 (ENSG00000255398)

Protein

Protein identifiers

Hydroxycarboxylic acid receptor 1 — Q9BXC0 (reviewed: Q9BXC0)

Alternative names: G-protein coupled receptor 104, G-protein coupled receptor 81

All UniProt accessions (2): A0A4Y1JWP1, Q9BXC0

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a receptor for L-lactate and mediates its anti-lipolytic effect through a G(i)-protein-mediated pathway.

Subcellular location. Cell membrane.

Tissue specificity. Expressed abundantly in brown and white fat. It also detectable at lower levels in liver, kidney, skeletal muscle, brain and pituitary. Not detected in frontal, temporal and occipital lobes of the cortex, basal forebrain, caudate nucleus, nucleus accumbens and hippocampus.

Similarity. Belongs to the G-protein coupled receptor 1 family.

RefSeq proteins (1): NP_115943* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain
IPR051893	HCARs	Family

Pfam: PF00001

UniProt features (37 total): mutagenesis site 9, topological domain 8, transmembrane region 7, sequence conflict 5, disulfide bond 3, sequence variant 3, chain 1, glycosylation site 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
8Z8B	ELECTRON MICROSCOPY	2.65
9KT9	ELECTRON MICROSCOPY	2.7
8Z87	ELECTRON MICROSCOPY	2.73
8Z8A	ELECTRON MICROSCOPY	2.82
9IZD	ELECTRON MICROSCOPY	3.16
9J8Z	ELECTRON MICROSCOPY	3.36

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BXC0-F1	80.83	0.50

Antibody-complex structures (SAbDab): 4 — 8Z8A, 8Z8B, 9J8Z, 9KT9

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (3): 6–157, 7–252, 88–165

Glycosylation sites (1): 3

Mutagenesis-validated functional residues (9):

Position	Phenotype
71	greatly impairs the agonistic activity of chba.
99	diminishes the response to l-lactate. abolishes the agonistic activity of chba.
166	greatly impairs the agonistic activity of chba.
168	reduction in agonistic activity of chba.
233	diminishes the response to l-lactate.
240	diminishes the response to l-lactate.
261	greatly impairs the agonistic activity of chba.
264	reduction in agonistic activity of chba.
267	diminishes the response to l-lactate.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-3296197	Hydroxycarboxylic acid-binding receptors
R-HSA-418594	G alpha (i) signalling events

MSigDB gene sets: 62 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, MODULE_571, GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, BHATI_G2M_ARREST_BY_2METHOXYESTRADIOL_DN, MODULE_453, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_LIPID_METABOLIC_PROCESS, RYTTCCTG_ETS2_B, GOBP_ADENYLATE_CYCLASE_INHIBITING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_LIPID_CATABOLIC_PROCESS, GOBP_LIPID_CATABOLIC_PROCESS, GOBP_REGULATION_OF_LIPID_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CATABOLIC_PROCESS

GO Biological Process (4): G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193), negative regulation of lipid catabolic process (GO:0050995), signal transduction (GO:0007165)

GO Molecular Function (1): G protein-coupled receptor activity (GO:0004930)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Class A/1 (Rhodopsin-like receptors)	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor activity	1
signal transduction	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase inhibitor activity	1
negative regulation of catabolic process	1
lipid catabolic process	1
negative regulation of lipid metabolic process	1
regulation of lipid catabolic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
transmembrane signaling receptor activity	1
G protein-coupled receptor signaling pathway	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

526 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HCAR1	DENR	O43583	839
HCAR1	SLC16A3	O15427	602
HCAR1	FFAR4	Q5NUL3	599
HCAR1	SLC16A4	O15374	598
HCAR1	ARRB2	P32121	573
HCAR1	SLC16A7	O60669	569
HCAR1	GPR84	Q9NQS5	527
HCAR1	SLC16A1	P53985	514
HCAR1	GPR148	Q8TDV2	507
HCAR1	FFAR2	O15552	442
HCAR1	LDHA	P00338	416
HCAR1	OXGR1	Q96P68	381
HCAR1	SLC16A14	Q7RTX9	380
HCAR1	RPL27A	P46776	367
HCAR1	SLC5A12	Q1EHB4	367

IntAct

9 interactions, top by confidence:

A	B	Type	Score
HCAR1	RAMP1	psi-mi:“MI:0915”(physical association)	0.400
RAMP2	HCAR1	psi-mi:“MI:0915”(physical association)	0.400
HCAR1	RAMP2	psi-mi:“MI:0915”(physical association)	0.400
RAMP3	HCAR1	psi-mi:“MI:0915”(physical association)	0.400
HCAR1		psi-mi:“MI:0915”(physical association)	0.370
ATG16L1		psi-mi:“MI:0914”(association)	0.350
HCAR1	ATP2B4	psi-mi:“MI:0914”(association)	0.350

BioGRID (6): HCAR1 (Synthetic Lethality), HCAR1 (Reconstituted Complex), CERS5 (Affinity Capture-MS), ATP2B4 (Affinity Capture-MS), SLC7A3 (Affinity Capture-MS), HCAR1 (Affinity Capture-RNA)

ESM2 similar proteins: A0A4W3GG95, A7YY44, B0F9W3, B0UXR0, B2GV46, B3G515, B5X337, E7FEL0, O00398, O46685, O70526, P21556, P25023, P25105, P25116, P26824, P30411, P30558, P32299, P43657, P46002, P46093, P49019, P50132, P56488, Q00991, Q15743, Q1JQB3, Q28642, Q3UFD7, Q4G072, Q4KLH9, Q61038, Q62035, Q80Z39, Q8BFQ3, Q8BFU7, Q8BLG2, Q8BMC0, Q8BUD0

Diamond homologs: A0A6I8PUB9, E9QJ73, F8VQN3, O00270, O09047, O42179, O55197, P21109, P25024, P25025, P35344, P35383, P41231, P41232, P46092, P49019, P55920, P97266, Q15722, Q16581, Q28003, Q28422, Q28519, Q28807, Q2KI97, Q2YEG0, Q5REI5, Q5YA25, Q6TAC8, Q80Z39, Q8C131, Q8CIM5, Q8SQ54, Q8TDS4, Q8TDS5, Q96G91, Q99PE3, Q9BXC0, Q9EP66, Q9JL21

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

70 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	69
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

79 predictions. Top by Δscore:

Variant	Effect	Δscore
12:122729667:C:CT	donor_gain	0.9600
12:122729668:C:CT	donor_gain	0.9200
12:122729274:T:TA	donor_gain	0.6600
12:122729664:C:CT	donor_gain	0.6600
12:122729666:A:AC	donor_gain	0.5800
12:122730426:CCCAG:C	donor_gain	0.5800
12:122729665:C:CT	donor_gain	0.5700
12:122729102:T:C	donor_gain	0.5200
12:122730425:A:AC	donor_gain	0.5200
12:122730426:C:CC	donor_gain	0.5200
12:122730448:TCATC:T	donor_gain	0.5200
12:122730418:AGCAC:A	donor_loss	0.5000
12:122730419:GCACT:G	donor_loss	0.5000
12:122730420:CACT:C	donor_loss	0.5000
12:122730421:AC:A	donor_loss	0.5000
12:122730422:C:G	donor_loss	0.5000
12:122730423:T:TA	donor_loss	0.5000
12:122730424:C:CC	donor_loss	0.5000
12:122730425:ACCCA:A	donor_loss	0.5000
12:122730426:C:A	donor_loss	0.5000
12:122729100:A:AC	donor_gain	0.4800
12:122729101:C:CC	donor_gain	0.4800
12:122729101:CTT:C	donor_gain	0.4500
12:122730425:AC:A	donor_gain	0.4400
12:122730426:CC:C	donor_gain	0.4400
12:122729259:G:C	donor_gain	0.4300
12:122730430:G:C	donor_gain	0.4100
12:122729829:C:CA	donor_gain	0.4000
12:122730417:TAGCA:T	donor_loss	0.3900
12:122729604:T:TA	donor_gain	0.3600

AlphaMissense

2295 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:122729653:G:C	F229L	0.993
12:122729653:G:T	F229L	0.993
12:122729655:A:G	F229L	0.993
12:122729785:G:C	F185L	0.993
12:122729785:G:T	F185L	0.993
12:122729787:A:G	F185L	0.993
12:122730034:G:C	S102R	0.993
12:122730034:G:T	S102R	0.993
12:122730036:T:G	S102R	0.993
12:122729527:G:C	S271R	0.992
12:122729527:G:T	S271R	0.992
12:122729529:T:G	S271R	0.992
12:122729545:G:C	S265R	0.991
12:122729545:G:T	S265R	0.991
12:122729547:T:G	S265R	0.991
12:122729922:A:G	W140R	0.991
12:122729922:A:T	W140R	0.991
12:122730157:A:C	D61E	0.990
12:122730157:A:T	D61E	0.990
12:122730172:A:C	N56K	0.990
12:122730172:A:T	N56K	0.990
12:122729632:G:C	S236R	0.989
12:122729632:G:T	S236R	0.989
12:122729634:T:G	S236R	0.989
12:122729636:G:C	P235R	0.989
12:122729636:G:T	P235H	0.988
12:122730255:C:G	G29R	0.986
12:122729757:A:G	C195R	0.985
12:122730000:A:C	Y114D	0.984
12:122730159:C:G	D61H	0.984

dbSNP variants (sampled 300 via entrez): RS1000666869 (12:122730925 G>A), RS1000884509 (12:122731204 A>T), RS1001340487 (12:122728228 C>A,T), RS1001520368 (12:122730748 C>A,T), RS1001559176 (12:122728508 C>T), RS1001629583 (12:122732816 CT>C), RS1002212309 (12:122727242 C>T), RS1002451399 (12:122731702 G>A), RS1003561918 (12:122732721 A>C), RS1004500399 (12:122730419 G>A,C), RS1004928477 (12:122727122 T>A), RS1005245133 (12:122731794 A>C,G), RS1005924464 (12:122728368 T>G), RS1007804591 (12:122727521 G>T), RS1008710711 (12:122730555 G>A)

Disease associations

OMIM: gene MIM:606923 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

53 associations (top):

Study	Trait	p-value
GCST005412_5	Thrombin-activatable fibrinolysis inhibitor levels	7.000000e-07
GCST010173_78	Triglyceride levels	4.000000e-13
GCST010242_447	HDL cholesterol levels	4.000000e-11
GCST010242_518	HDL cholesterol levels	1.000000e-58
GCST010244_222	Triglyceride levels	3.000000e-19
GCST012227_564	Hip circumference adjusted for BMI	3.000000e-08
GCST90002391_253	Mean corpuscular hemoglobin concentration	2.000000e-10
GCST90002397_222	Mean spheric corpuscular volume	2.000000e-12
GCST90002404_147	Red cell distribution width	1.000000e-16
GCST90002406_403	Reticulocyte fraction of red cells	1.000000e-10
GCST90020024_240	A body shape index	4.000000e-09
GCST90020024_246	A body shape index	4.000000e-25
GCST90020024_247	A body shape index	5.000000e-17
GCST90020024_248	A body shape index	5.000000e-14
GCST90020024_250	A body shape index	2.000000e-11
GCST90020024_424	A body shape index	3.000000e-20
GCST90020024_425	A body shape index	5.000000e-11
GCST90020024_426	A body shape index	9.000000e-11
GCST90020025_119	Waist-to-hip ratio adjusted for BMI	3.000000e-09
GCST90020025_121	Waist-to-hip ratio adjusted for BMI	7.000000e-13
GCST90020025_125	Waist-to-hip ratio adjusted for BMI	8.000000e-12
GCST90020025_27	Waist-to-hip ratio adjusted for BMI	1.000000e-09
GCST90020025_28	Waist-to-hip ratio adjusted for BMI	5.000000e-14
GCST90020025_29	Waist-to-hip ratio adjusted for BMI	6.000000e-38
GCST90020025_30	Waist-to-hip ratio adjusted for BMI	3.000000e-21
GCST90020025_32	Waist-to-hip ratio adjusted for BMI	3.000000e-17
GCST90020025_35	Waist-to-hip ratio adjusted for BMI	5.000000e-29
GCST90020025_36	Waist-to-hip ratio adjusted for BMI	2.000000e-18
GCST90020025_37	Waist-to-hip ratio adjusted for BMI	4.000000e-20
GCST90020026_31	Hip index	1.000000e-08

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0009188	Red cell distribution width
EFO:0007789	BMI-adjusted waist circumference
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1075101 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: gpcr — Hydroxycarboxylic acid receptors

Most potent curated ligand interactions (6 total), top 6:

Ligand	Action	Affinity	Parameter
compound 2 [PMID: 24486398]	Agonist	7.24	pEC50
compound 2 [PMID: 31932225]	Agonist	7.13	pEC50
3,5-dihydroxybenzoic acid	Full agonist	3.72	pEC50
L-lactic acid	Full agonist	2.89	pEC50
D-lactic acid	Partial agonist	2.52	pEC50
γ-hydroxybutyrate	Full agonist	1.82	pEC50

ChEMBL bioactivities

319 potent at pChembl≥5 of 322 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.30	EC50	5	nM	CHEMBL4642043
7.89	EC50	13	nM	CHEMBL4632482
7.85	EC50	14	nM	CHEMBL3717084
7.85	EC50	14	nM	CHEMBL3717773
7.85	EC50	14	nM	CHEMBL3718324
7.85	EC50	14	nM	CHEMBL3715748
7.85	EC50	14	nM	CHEMBL3716940
7.85	EC50	14	nM	CHEMBL3716494
7.85	EC50	14	nM	CHEMBL3718239
7.85	EC50	14	nM	CHEMBL3716479
7.85	EC50	14	nM	CHEMBL3715359
7.85	EC50	14	nM	CHEMBL3717920
7.85	EC50	14	nM	CHEMBL3715599
7.85	EC50	14	nM	CHEMBL3715673
7.85	EC50	14	nM	CHEMBL3716637
7.85	EC50	14	nM	CHEMBL3718637
7.85	EC50	14	nM	CHEMBL3719308
7.85	EC50	14	nM	CHEMBL3718131
7.85	EC50	14	nM	CHEMBL3718227
7.85	EC50	14	nM	CHEMBL3717420
7.85	EC50	14	nM	CHEMBL3717482
7.85	EC50	14	nM	CHEMBL3717636
7.85	EC50	14	nM	CHEMBL3716302
7.85	EC50	14	nM	CHEMBL3715478
7.85	EC50	14	nM	CHEMBL3717852
7.85	EC50	14	nM	CHEMBL3718085
7.85	EC50	14	nM	CHEMBL3717252
7.85	EC50	14	nM	CHEMBL3717608
7.85	EC50	14	nM	CHEMBL3717582
7.85	EC50	14	nM	CHEMBL3718240
7.85	EC50	14	nM	CHEMBL3715890
7.85	EC50	14	nM	CHEMBL3717797
7.85	EC50	14	nM	CHEMBL3717469
7.85	EC50	14	nM	CHEMBL3719226
7.85	EC50	14	nM	CHEMBL3719094
7.85	EC50	14	nM	CHEMBL3718624
7.85	EC50	14	nM	CHEMBL3717555
7.85	EC50	14	nM	CHEMBL3719235
7.85	EC50	14	nM	CHEMBL3718861
7.85	EC50	14	nM	CHEMBL3716500
7.85	EC50	14	nM	CHEMBL3717347
7.85	EC50	14	nM	CHEMBL3716263
7.85	EC50	14	nM	CHEMBL3718374
7.85	EC50	14	nM	CHEMBL3714909
7.85	EC50	14	nM	CHEMBL3717689
7.85	EC50	14	nM	CHEMBL3715394
7.85	EC50	14	nM	CHEMBL3715218
7.85	EC50	14	nM	CHEMBL3718175
7.85	EC50	14	nM	CHEMBL3716993
7.85	EC50	14	nM	CHEMBL3716914

PubChem BioAssay actives

35 with measured affinity, of 105 total; 35 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
6-(2-chloro-4-ethoxy-5-morpholin-4-ylphenyl)-3-[6-(1-methylpiperidin-4-yl)sulfonyl-1,3-benzothiazol-2-yl]-1H-pyridin-2-one	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.0050	uM
2-chloro-4-ethoxy-N-[[6-[(4-methylpiperazin-1-yl)methyl]-1,3-benzothiazol-2-yl]carbamoyl]-5-pyrrolidin-1-ylbenzamide	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.0130	uM
2-chloro-4-ethoxy-N-[[6-[(4-methylpiperazin-1-yl)methyl]-1,3-benzothiazol-2-yl]carbamoyl]-5-pyrazol-1-ylbenzamide	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.0190	uM
3-(1,3-benzothiazol-2-yl)-6-(2-chloro-4-ethoxy-5-morpholin-4-ylphenyl)-1H-pyridin-2-one	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.0210	uM
6-(2-chloro-4-ethoxy-5-morpholin-4-ylphenyl)-3-[5-(2-hydroxyacetyl)-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridin-2-yl]-1H-pyridin-2-one	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.0220	uM
2-chloro-4-ethoxy-N-[[6-[(4-methylpiperazin-1-yl)methyl]-1,3-benzothiazol-2-yl]carbamoyl]-5-pyrrol-1-ylbenzamide	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.0220	uM
2-chloro-4-ethoxy-N-[[6-(1-methylpiperidin-4-yl)sulfonyl-1,3-benzothiazol-2-yl]carbamoyl]-5-pyrazol-1-ylbenzamide	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.0230	uM
2-chloro-4-ethoxy-5-[(2R)-2-methylmorpholin-4-yl]-N-[[6-[(4-methylpiperazin-1-yl)methyl]-1,3-benzothiazol-2-yl]carbamoyl]benzamide	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.0320	uM
2-chloro-5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-4-ethoxy-N-[6-[3-(4-methylpiperazin-1-yl)propylsulfonyl]-1,3-benzothiazol-2-yl]benzamide	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.0540	uM
2-chloro-4-ethoxy-N-[[6-[(4-methylpiperazin-1-yl)methyl]-1,3-benzothiazol-2-yl]carbamoyl]-5-morpholin-4-ylbenzamide	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.0740	uM
6-(2-chloro-4-ethoxy-5-morpholin-4-ylphenyl)-3-[5-(2-methoxyacetyl)-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridin-2-yl]-1H-pyridin-2-one	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.0750	uM
2-chloro-4-ethoxy-5-morpholin-4-yl-N-[(5-phenyl-1,3-thiazol-2-yl)carbamoyl]benzamide	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.1030	uM
2-chloro-4-ethoxy-N-[6-(1-methylpiperidin-4-yl)oxy-1,3-benzothiazol-2-yl]-5-morpholin-4-ylbenzamide	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.1100	uM
2-chloro-4-ethoxy-5-morpholin-4-yl-N-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-ylcarbamoyl)benzamide	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.1200	uM
2-chloro-4-ethoxy-5-[(2R)-2-methylmorpholin-4-yl]-N-[6-[3-(4-methylpiperazin-1-yl)propylsulfonyl]-1,3-benzothiazol-2-yl]benzamide	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.1600	uM
2-chloro-4-ethoxy-N-[[6-(1-methylpiperidin-4-yl)sulfonyl-1,3-benzothiazol-2-yl]carbamoyl]-5-morpholin-4-ylbenzamide	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.1660	uM
2-(2-chloro-4-ethoxy-5-morpholin-4-ylphenyl)-5-[6-(1-methylpiperidin-4-yl)sulfonyl-1,3-benzothiazol-2-yl]-1H-pyrimidin-6-one	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.2400	uM
N-(1-benzothiophen-2-ylcarbamoyl)-2-chloro-4-ethoxy-5-morpholin-4-ylbenzamide	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.2600	uM
2-chloro-5-[(2S,6S)-2,6-dimethylmorpholin-4-yl]-4-ethoxy-N-[6-[3-(4-methylpiperazin-1-yl)propylsulfonyl]-1,3-benzothiazol-2-yl]benzamide	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.2700	uM
N-(1,3-benzothiazol-2-ylcarbamoyl)-2-chloro-4-ethoxy-5-morpholin-4-ylbenzamide	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.2990	uM
2-chloro-4-ethoxy-N-[[6-[(4-methylpiperazin-1-yl)methyl]-1,3-benzothiazol-2-yl]carbamoyl]-5-(1H-pyrazol-5-yl)benzamide	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.3600	uM
2-chloro-4-ethoxy-N-[6-[(4-methylpiperazin-1-yl)methyl]-1,3-benzothiazol-2-yl]-5-morpholin-4-ylbenzamide	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.4100	uM
5-(1,3-benzothiazol-2-yl)-2-(2-chloro-4-ethoxy-5-morpholin-4-ylphenyl)-1H-pyrimidin-6-one	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.4900	uM
2-chloro-4-ethoxy-N-[[6-[(4-methylpiperazin-1-yl)methyl]-1,3-benzothiazol-2-yl]carbamoyl]benzamide	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.5600	uM
2-chloro-4-ethoxy-N-[6-[3-(4-methylpiperazin-1-yl)propylsulfonyl]-1,3-benzothiazol-2-yl]-5-morpholin-4-ylbenzamide	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.6000	uM
N-[(5-acetyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridin-2-yl)carbamoyl]-2-chloro-4-ethoxy-5-morpholin-4-ylbenzamide	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.7190	uM
2-chloro-4-ethoxy-N-[6-(1-methylpiperidin-4-yl)sulfonyl-1,3-benzothiazol-2-yl]-5-morpholin-4-ylbenzamide	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.7400	uM
4-ethoxy-N-[[6-[(4-methylpiperazin-1-yl)methyl]-1,3-benzothiazol-2-yl]carbamoyl]-3-morpholin-4-ylbenzamide	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.7400	uM
2-chloro-4-ethoxy-N-[(5-methyl-1,3-thiazol-2-yl)carbamoyl]-5-morpholin-4-ylbenzamide	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.7690	uM
2-chloro-4-ethoxy-N-[[5-(2-hydroxyacetyl)-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridin-2-yl]carbamoyl]-5-morpholin-4-ylbenzamide	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.8950	uM
4-ethoxy-N-[[6-[(4-methylpiperazin-1-yl)methyl]-1,3-benzothiazol-2-yl]carbamoyl]-5-morpholin-4-yl-2-(trifluoromethyl)benzamide	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	1.4000	uM
N-(1,3-benzothiazol-2-yl)-2-chloro-4-ethoxy-5-morpholin-4-ylbenzamide	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	1.9000	uM
2-chloro-4-fluoro-N-[[6-(1-methylpiperidin-4-yl)sulfonyl-1,3-benzothiazol-2-yl]carbamoyl]-5-pyrazol-1-ylbenzamide	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	3.6000	uM
2-chloro-4-methyl-N-[[6-(1-methylpiperidin-4-yl)sulfonyl-1,3-benzothiazol-2-yl]carbamoyl]-5-pyrazol-1-ylbenzamide	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	6.1000	uM
2-chloro-N-[[6-(1-methylpiperidin-4-yl)sulfonyl-1,3-benzothiazol-2-yl]carbamoyl]-5-pyrazol-1-ylbenzamide	1651440: Agonist activity at human GPR81 overexpressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	7.0000	uM

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
OTX015	decreases expression	1
bisphenol A	affects cotreatment, increases methylation	1
tris(2-butoxyethyl) phosphate	affects expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
2-palmitoylglycerol	increases expression	1
bisphenol S	increases expression	1
(+)-JQ1 compound	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Dimethyl Sulfoxide	affects expression	1
Estradiol	decreases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	affects expression	1
Aflatoxin B1	decreases expression	1
Copper Sulfate	increases expression	1
Vitamin K 3	affects expression	1

ChEMBL screening assays

28 unique, capped per target: 16 binding, 12 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1105990	Binding	Binding affinity to GPR81	Discovery of a biaryl cyclohexene carboxylic acid (MK-6892): a potent and selective high affinity niacin receptor full agonist with reduced flushing profiles in animals as a preclinical candidate. — J Med Chem
CHEMBL2150703	Functional	Agonist activity at human recombinant GPR81 transfected in african green monkey COS-7 cells after 20 mins by [35S]GTPgammaS binding assay	Identification of Hydroxybenzoic Acids as Selective Lactate Receptor (GPR81) Agonists with Antilipolytic Effects. — ACS Med Chem Lett

Cellosaurus cell lines

2 cell lines: 2 spontaneously immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C3MM	CHO-GPR81	Spontaneously immortalized cell line	Female
CVCL_KV30	cAMP Hunter CHO-K1 GPR81 Gi	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.