Presence of choloyl- and chenodeoxycholoyl-coenzyme A thioesterase activity in human liver

In human liver homogenate the formation of bile acid-CoA thioesters is loca lized both to the microsomal fraction catalysed by an ATP-dependent synthet ase and to the peroxisomal fraction catalysed by the thiolase in the last s tep of the P-oxidative cleavage of the 5 beta-cholestanoyl side chain. The cytosolic bile acid-Coa:amino acid N-acyltransferase catalyse the conjugati on of the CoA-activated bile acids with taurine or glycine prior to secreti on into bile. The formation of bile acid-CoA esters is considered the rate- limiting step in bile acid amidation. So far, a bile acid-CoA cleaving acti vity has not been assessed in the research of bile acid amidation in human liver. In this work, a bile acid-CoA cleaving activity has been demonstrate d at a rate that may influence the concentration of bile acid-CoA thioester s, free bile acids and amidated bile acids within the hepatocyte. Recently, it was shown that free chenodeoxycholic acid, formed by the thioesterase, is the physiological ligand of the farnesoid X receptor. A multiorganelle distribution of the bile acid-CoA hydrolytic activity was found. In the postnuclear fraction of human liver homogenate, apparent K-m and V-max for the cleavage of choloyl-CoA were 7.7 x 10-5 mol/L and 3.6 nmo l x mg(-1) x min(-1), respectively. The corresponding values for chenodeoxy choloyl-CoA cleavage were 7.1x10(-5) mol/L and 4.8 nmol x mg(-1) x min(-1). Hydrolytic activities were detected in the microsomal and the peroxisomal fractions where the bile acid-CoA esters are formed as well as in cytosol h ousing the N-acyltransferase activity. Compared to the bile acid-CoA synthe tase activities, the hydrolytic activities were considerably higher, both i n the postnuclear fraction and in the microsomal fraction. The thioesterase activities were in the same range as detected for the N-acyltransferase ac tivities both in the postnuclear fraction and in the cytosolic fraction. Th e mere presence of thioesterase in microsomes, peroxisomes and cytosol seem s counterproductive to bile acid amidation. The thioesterases may have an i ndirect regulatory function on the bile acid synthesis and are important fo r the regulation of bile acid synthesis by providing free chenodeoxycholic acid, the most potent activator of the farnesoid X receptor.