Inhibition of carnitine acyltransferase activities by bile acids in rat liver peroxisomes.
We recently reported that purified carnitine acetyltransferase is competitively inhibited by bile acids (Sekas, G. and Paul, H.S. (1989) Anal. Biochem. 179, 262-267). In the present study, we initially investigated the effect of bile acids on carnitine acyltransferases in rat hepatic peroxisomes. Activities of carnitine acetyltransferase, carnitine octanoyltransferase, and carnitine palmitoyltransferase were progressively inhibited by increasing concentrations of chenodeoxycholic acid. Kinetic studies revealed that the inhibition by chenodeoxycholic acid was competitive with respect to carnitine with an apparent Ki of 890 microM for carnitine acetyltransferase, 650 microM for carnitine octanoyltransferase and 600 microM for carnitine palmitoyltransferase. We then investigated whether bile acids inhibit the activities of these enzymes ex vivo. The hepatic concentration of bile acids was increased by inducing cholestasis by bile duct ligation. Cholestasis reduced the activity of carnitine acetyltransferase, carnitine octanoyltransferase, and carnitine palmitoyltransferase to 66 +/- 2%, 64 +/- 3%, and 40 +/- 2%, of the control, respectively. The inhibition for each of these enzymes was proportional to the degree of cholestasis. The effect of cholestasis appeared specific for carnitine acyltransferases since the activity of catalase, another peroxisomal enzyme, was not affected by cholestasis. We conclude that bile acids inhibit the activities of carnitine acyltransferases in hepatic peroxisomes. This inhibition by bile acids may be of significance in cholestatic liver disease.
Sekas
G
G
Department of Medicine, University of Pittsburgh School of Medicine, PA.
Paul
H S
HS
D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood / Q000494:pharmacology*; D002333:Carnitine Acyltransferases / Q000037:antagonists & inhibitors*; D002458:Cell Fractionation; D002779:Cholestasis / Q000201:enzymology; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008830:Microbodies / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D011919:Rats, Inbred Strains
D001647:Bile Acids and Salts; D002333:Carnitine Acyltransferases