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. 2021 Nov 10;322(2):G201–G222. doi: 10.1152/ajpgi.00125.2021

Table 1.

Effects of BAs on G protein-coupled receptors and nuclear receptors

Receptor Bile Acid Concentration Tissue Preparation  Response Effect Solvent Refs.
G protein-coupled receptors
TGR5 (GPR130, GpBAR1) DCA
OA
1–100 µM
100 µM
Proximal colon from tgr5-WT and KO mice ↑ WT
KO only 100 µM at DCA
5-HT and CGRP from EC cells to stimulate peristaltic reflex 0.1% Ethanol, distilled water (5)
DCA
TLCA
CCDC
100 µM DRG neurons innervating colon (mouse)

Increased intracellular Ca2+ in subpopulations of neurons (%)
DCA ∼20%, TLCA∼ 25%, CCDC∼30%
NA (6)
CCDC 100 µM, 100 µL rectal enema Spinal cord (mouse) Phosphorylated MAP-kinase-ERK-1/2 immunoreactivity (pERK-IR) enhanced in response to colorectal distention Saline
INT-777 10–100 µM Proximal colon (mouse) Increased transepithelial resistance and reduced short circuit current, reduced with TTX or neuron-free preparation DMSO (7)
UDCA 3–60 µM - Weak TGR5 agonist
LCA, DCA 10 and 30 µM Enteroendocrine cell line, STC-1 Promote GLP-1 secretion DMSO (8)
Cells transfected withTGR5 siRNA - Reduced LCA responses at 10 and 30 µM
Cells transfected with TGR5 cDNA Increased LCA responses at 30 µM
Range of conjugated & unconjugated BAs Concentration curve COS-7 monkey kidney cells expressing human or rat TGR5 Increased cAMP production rank order of potency LCA>DCA>CDCA UDCA and CA ∼20% efficacy at 10 µM Modified Krebs-Ringer buffer (9)
UDCA 10 mM -UDCA GLP-1 and PYY release
BA mixture Total BA ∼9 mM, 1 mM each In vivo intraluminal tgr5-WT and KO mice BA mix: ↑ WT
- KO
Isotonic saline
LCA RO5527239 (TGR5 agonist) Concentration curve CHO cells transfected with TGR5 Increased cAMP production
EC50 = 457 and 3.6 nM
EMax∼110% both
NA (10)
DCA RO5527239 Concentration curve STC-1 Increased cAMP production
EC50 = 1.59 µM and 321 nM
GLP-1 release
EC50 = 11 µM and 321 nM
MrgprX4 DCA, UDCA CDCA, CA, OA 2–100 µM HEK293 cells Increased [Ca2]+i Water, DMSO, or 0.1 M NaOHNA (11)
DCA
UDCA
10 µM
100 µM
DRG from +X4 humanized mice ∼5%–6% of +X4 sensory neurons activated by both
DCA, t-DCA, UDCA CDCA 1–2 mM In vivo +X4 humanized mice Increased cholestatic itch
Muscarinic M2 t-CDCA, g-DCA, t-DCA, t-CA 100 µM Ventricular neonatal rat myocytes Reduced contraction (Gi coupled) (role in TGR5 mediated release of cAMP found to be independent of contraction response) L-15 media (12)
TCA 0–100 µM Ventricular neonatal rat myocytes Partial agonist Radioligand binding,
Kd = 17 µM
DMSO HBSS (13)
Reduced cAMP production (30% of carbachol response)
Reduced contraction (0.2 and 1 mM)
Muscarinic M3 CDCA, LCA, g-LCA, t-LCA, g-DCA, t-DCA, UDCA 30 µM Ex vivo, precision-cut lung slices Inhibited acetylcholine contractile responses t-LCA IC50 = 3.2 µM NA (14)
S1PR2 t-CA, t-DCA, g-DCA, g-CA, t-UDCA 50–100 µM Primary rat hepatocytes Activation of ERK1/2 and AKT DMSO (15)
t-CA 100 µM MLE Activation of ERK1/2 and AKT
Cell proliferation and migration
PBS (16)
FPR CDCA 25–400 µM Human monocytes Inhibited monocyte chemotaxis to fMLP IC50 = 100 µM Ethanol (17)
Human monocytes Inhibited monocyte Ca flux by fMLP
EFTR cell Inhibited cell migration by fMLP IC50 = 125 µM
EFTR cell Inhibited Ca2+ flux by fMLP IC50 = 50 µM
Human monocytes EFTR cell Radioligand fMLP binding
IC50 = 140 µM
DCA 25–200 µM Human monocytes and neutrophils Inhibited fMLP induced chemotaxis IC50 = 100 µM PBS (18)
25 µM Inhibited fMLP induced Ca2+ mobilization
5–200 µM Radioligand fMLP binding
Nuclear receptors
FXR CDCA>DCA and LCA 50 µM concentration curve for CDCA CV-1 cells with rat FXR
HepG2 cells with human FXR
Transactivation of FXR with luciferase reporter
CDCA EC50 = 50 µM and 10 µM rat and human FXR
Ethanol (19)
CDCA>DCA and LCA 100 µM CV-1 cells Reporter gene assay.
Increased CAT activity
NA (20)
CDCA, g-CDCA, t-CDCA FRET ligand sensing assay
Increased relative fluorescence
CDCA EC50 = 4.5 µM
g- and t-CDCA
EC50 = 10 µM
CA GW4062 (FXR agonist) 200 mg/kg
100 mg/kg
Mice treated in vivo 72 h before to tissue harvest Ileum, jejunum and duodenum ↑
Liver-
FGF-15 mRNA present in ileum, jejunum and duodenum NA (21, 22)
CDCA Concentration curve Human ileum and colon mucosal biopsies Ileum ↑
Colon–
FGF19 expression
EC50 = 20 µM
CA


DCA
LCA
50 µM 6-h incubation Comparison with matched con. CDCA 80% of CDCA response


40%
4%
OCA 20 µM 5 times greater than CDCA response
PXR LCA
3-keto-LCA
Concentration curve CV-1 cells with human PXR
Scintillation proximity binding assay
IC50 = 9 and 15 µM
NA (23)
LCA 100 µM CV-1 cells with human or mouse PXR and reporter plasmid ↑ (Human) Reporter gene assay. Increased CAT activity
3-keto-LCA (Cyp3a23)2-tk-CAT
CDCA -
CA -
DCA -
CDCA
DCA
LCA
100 µM CV-1 cells with human and rodent PXR and reporter plasmids

Reporter gene activity and CYP3A4 reporter gene activity NA (24)
LCA 8 mg/day for 4 days, oral gavage PXR-WT and KO mice in vivo ↑ WT
-KO
Northern blot analysis CYP3A11 mRNA
VDR LCA
3-keto-LCA
Concentration curve HEK293 cells transfected with VDR GAL4-receptor luciferase assay
EC50 = 8 and 3 µM
NA (25)
LCA
3-keto-LCA
Monkey kidney COS-7 Competitive binding assay [3H]1,25(OH)2D3
Ki = 29 and 8 µM
CA, CDCA
LCA 0.8 mmol/kg, oral gavage Ileum tissue of Vdr WT and KO ↑ WT
-KO
Induces mRNA expression of Cyp24a1 Ethanol and corn oil (26)

CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; LCA, lithocholic acid. 3-Keto-LCA is the major metabolite of LCA in rats. UDCA, ursodeoxycholic acid; t-, tauro-conjugated; g-, glyco-conjugated bile acid. Cell lines: rat basophil leukemia cell line transfected with FPR EFTR cell; mouse large cholangiocytes MLE; monkey kidney CV-1 cells; human hepatoma HepG2; enteroendocrine cell line, STC-1. Responses: activation, ↑; inhibition, ↓; no change, -. Solvents: NA, no information available; DMSO stock, dimethyl sulfoxide (DMSO).