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 |
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GLP-1 release EC50 = 11 µM and 321 nM |
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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 |
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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 |
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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 |
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CA DCA LCA |
50 µM | 6-h incubation | Comparison with matched con. CDCA | 80% of CDCA response 40% 4% |
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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 |
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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).