The effect of the
acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor
HL-004 on
bile acid production was studied during the regression phase of pre-established
hypercholesterolemia in
stroke-prone spontaneously hypertensive rats (SHRSP). These rats were fed a hypercholesterolemic diet containing 5%
cholesterol, 2%
cholic acid, and 20% suet for 30 days to induce
hypercholesterolemia. The regression phase was started by switching the diet to normal chow, followed by another 30 days of the diet. The decrease in serum
cholesterol level was accelerated by treatment with 0.09%
HL-004. At the end of regression, hepatic ACAT activity was significantly lower in the
HL-004 treated animals, an event concomitant with the significant decrease in
cholesteryl ester content in the liver. In contrast hepatic
cholesterol 7 alpha-hydroxylase activity was maintained at a higher level in the
HL-004 treated animals.
HL-004 increased the secretion of
bile acid and biliary
lipids in bile duct-cannulated SHRSP. In HepG2:cells,
HL-004 at 1-30 microM dose-dependently stimulated
bile acid synthesis from [3H]
cholesterol. When
cholesterol 7 alpha-hydroxylase activity of the liver was compared ex vivo in the presence and in the absence of exogenous
cholesterol, it was suggested that the higher
7 alpha-hydroxylase activity of the
HL-004 group could be attributed not only to expansion of the endogenous
cholesterol pool, which may be the result of hepatic ACAT inhibition by
HL-004 but to the direct effect of
HL-004 on
bile acid production. Thus,
HL-004 accelerates the regression of
hypercholesterolemia, an event which may be related to the stimulation of
bile acid production in the liver.