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.