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).