Secondary bile acids and the biliary epithelia: The good and the bad

Table 1 Some physico-chemical features of the most relevant primary and secondary bile acids in human bile

	Hydroxil groups number and position	Solubility in water (protonated form, µM)1	Critical micellar concentration (sodium salt, mM)1	Hydrophobicity index (taurine conjugated)2
Primary bile acids
Cholic acid	3 (3, 7, 12)	273	13	0
Chenodeoxycholic acid	2 (3, 7)	27	9	0.46
Secondary bile acids
Deoxycholic acid	2 (3, 12)	28	10	0.59
Lithocholic acid	1 (3)	0.05	0.9	1
Ursodeoxycolic acid	2 (3, 7)	0.9	19	-0.47

¹Values assessed in water as reported by Hofmann et al[44].

²Cholic acid and Lithocholic acid were assumed to have (by definition) a value of 0 and 1 respectively[8].

Table 2 Main findings regarding secondary bile acids and biliary epithelia

Model	Administration route	Main results	Main molecular, immunologic findings	Ref.
Ursodeoxycholic acid
BDL rat	Feeding (both the unconjugated and taurine-conjugated form)	Decreased biliary proliferation and secretion. No apoptosis	Decreased H3-histone. PCNA, SR and ASBT expression. No apoptosis. Increased PKC α expression	[38,39]
BDL + vagotomy rat	Feeding (both unconjugated and taurine-conjugated form)	Reversal of duct loss and apoptosis induced by vagotomy	PKCα/Ca2+ dependent mechanism	[41]
Mdr2(-/-) mice	Feeding	Decreased proliferation, inflammation and fibrosis	Inhibition of mast cells activity	[43]
Lithocolic acid
Mouse	Feeding	Destructive cholangitis, bile duct stenosis, bilary infarcts	Damage related to direct toxic effect and not to neutrophil infiltration	[52,53]
In vivo rat and isolated cholagiocytes	Feeding (cholic acid or Lithocholic acid both taurine conjugated)	Similar effect in increasing proliferation and secretion	Effect restricted to large cholangiocytes	[54,55]
In vivo rat and isolated cholagiocytes	Feeding (cholic acid or Lithocholic acid both taurine conjugated)	Cholangiocytes proliferation	Dependent by PKA-mediated ASBT expression	[56]
Deoxycholic acid
Human gallbladder cancer (specimens and cell lines)	In vitro exposure	Increased concentration associated with inhibition of tumor growth	Reduced miR-92b-3p inhibits PI3K/AKT activity	[60]

ASBT: Apical sodium bile acids transporter; BDL: Bile duct ligated; PCNA: Protein cellular nuclear antigen; SR: Secretin receptor.