taurochenodeoxycholic-acid and Hepatitis

Biliary atresia (BA) is a severe chronic cholestasis disorder of infants that leads to death if not treated on time. Neonatal hepatitis syndrome (NHS) is another leading cause of neonatal cholestasis confounding the diagnosis of BA. Recent studies indicate that altered bile acid metabolism is closely associated with liver injury and cholestasis. In this study, we systematically measured the bile acid metabolome in plasma of BA, NHS, and healthy controls. Liver bile acids were also measured using biopsy samples from 48 BA and 16 NHS infants undergoing operative cholangiography as well as 5 normal adjacent nontumor liver tissues taken from hepatoblastoma patients as controls. Both BA and NHS samples had significantly elevated bile acid levels in plasma compared to normal controls. BA patients showed a distinct bile acid profile characterized by the higher taurochenodeoxycholic acid (TCDCA) level and lower chenodeoxycholic acid (CDCA) level than those in NHS patients. The ratio of TCDCA to CDCA in plasma was significantly higher in BA compared to healthy infants (p < 0.001) or NHS (p < 0.001). The area under receiver operating characteristic curve for TCDCA/CDCA to differentiate BA from NHS was 0.923 (95% CI: 0.862-0.984). These findings were supported by significantly altered expression levels of bile acid transporters and nuclear receptors in liver including farnesoid X receptor (FXR), small heterodimer partner (SHP), bile salt export pump (BSEP), and multidrug resistant protein 3 (MDR3) in BA compared to NHS. Taken together, the plasma bile acid profiles are distinct in BA, NHS, and normal infants, as characterized by the ratio of TCDCA/CDCA differentially distributed among the three groups of infants.

Topics: Alanine Transaminase; Area Under Curve; Aspartate Aminotransferases; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Bile Acids and Salts; Biliary Atresia; Case-Control Studies; Chenodeoxycholic Acid; Cholangiography; Cholestasis; Female; gamma-Glutamyltransferase; Gene Expression Regulation; Hepatitis; Humans; Infant; Infant, Newborn; Male; Metabolome; Receptors, Cytoplasmic and Nuclear; Taurochenodeoxycholic Acid

Accumulating bile acids (BA) trigger cholangiocyte proliferation in chronic cholestasis. The aim of this study was to determine if ursodeoxycholate (UDCA) or tauroursodeoxycholate (TUDCA) chronic feeding prevents the increased cholangiocyte growth and secretion in bile duct-ligated (BDL) rats, if UDCA and TUDCA effects are associated with increased cholangiocyte apoptosis, and to determine if this inhibition is dependent on increased intracellular Ca(2+) ([Ca(2+)](i)) and activation of protein kinase C (PKC) alpha. Immediately after BDL, rats were fed UDCA or TUDCA (both 275 micromol/d) for 1 week. We determined the number of bile ducts in liver sections, cholangiocyte proliferation (by measurement of H(3) histone and proliferating cellular nuclear antigen in isolated cholangiocytes), and ductal secretion. In purified cholangiocytes from 1-week BDL rats, we evaluated if UDCA and TUDCA directly inhibit cholangiocyte proliferation and secretin-stimulated adenosine 3', 5'-monophosphate levels. We determined if UDCA and TUDCA activate PKC, increase [Ca(2+)](i), and alter the apical BA transporter (ABAT) expression in cholangiocytes. UDCA and TUDCA inhibited in vivo the cholangiocyte proliferation, secretion, and ABAT expression. In vitro UDCA and TUDCA inhibition of cholangiocyte growth and secretion required increased [Ca(2+)](i) and PKC alpha. In conclusion, activation of Ca(2+)-dependent PKC alpha is required for UDCA and TUDCA inhibition of cholangiocyte growth and secretion. Reduced cholangiocyte ABAT may decrease endogenous BA stimulation of cholangiocyte growth and secretion.

Topics: Animals; Apoptosis; Bile Acids and Salts; Bile Ducts; Calcium; Carrier Proteins; Cell Division; Cholagogues and Choleretics; Cholestasis; Down-Regulation; Hepatitis; Hydroxysteroid Dehydrogenases; Isoenzymes; Ligation; Liver; Male; Membrane Glycoproteins; Organ Size; Protein Kinase C; Protein Kinase C-alpha; Rats; Rats, Inbred F344; Taurochenodeoxycholic Acid; Ursodeoxycholic Acid