Lb. Nguyen et al., COMPETITIVE-INHIBITION OF HEPATIC STEROL 27-HYDROXYLASE BY SITOSTEROL- DECREASED ACTIVITY IN SITOSTEROLEMIA, Proceedings of the Association of American Physicians, 110(1), 1998, pp. 32-39
We investigated the effect of sitosterol on hepatic sterol 27-hydroxyl
ase activities in subjects with sitosterolemia, a recessive inherited
disease associated with accelerated atherosclerosis and increased leve
ls of sitosterol and other plant sterols and stanols in tissues. Hepat
ic activities of mitochondrial sterol 27-hydroxylase, which catalyzes
the first step in the conversion of cholesterol to bile acids via the
acidic bile acid synthetic pathway, were measured in liver tissues and
related to hepatic microsomal cholesterol 7 alpha-hydroxylase, which
controls the rate of bile acid synthesis via the neutral synthetic pat
hway, These measurements of cholesterol catabolism were correlated to
sterol concentrations and composition in plasma and liver. Sterol 27-h
ydroxylase activities in liver mitochondria of three homozygous sitost
erolemic subjects were 68% lower than in 10 control subjects (p < .05)
and were associated with increased levels of plant sterols in both pl
asma and liver (13% and 16% of total sterols, respectively, compared t
o trace amounts in controls). Analysis of Lineweaver-Burk double recip
rocal plots of sterol 27-hydroxylase activities in control human liver
specimens (where mitochondrial sterol 27-hydroxylase activities were
measured with increasing concentrations of the cholesterol substrate,
in the absence and presence of 100 mu M and 300 mu M sitosterol) revea
led that sitosterol inhibited mitochondrial sterol 27-hydroxylase acti
vity up to 50% by a competitive mechanism. In sitosterolemic subjects,
competitive inhibition of hepatic sterol 27-hydroxylase activity by s
itosterol was associated with competitively inhibited microsomal chole
sterol 7 alpha-hydroxylase activity (averages from 4 sitosterolemic ho
mozygotes and 14 controls were 12.4 +/- 1.9 and 23.6 +/- 2.5 pmol/mg/m
in, respectively). Furthermore, decreased cholesterol catabolism in si
tosterolemic subjects was associated with significantly elevated plasm
a cholesterol concentrations (232 +/- 17 mg/dl, as compared to 180 +/-
13 mg/dl in controls) but with no change in hepatic cholesterol conce
ntrations. In an animal model (rats infused intravenously with sitoste
rol-containing liposomes that increased sitosterol in the liver and pl
asma to levels similar to those found in sitosterolemic subjects), hep
atic mitochondrial sterol 27-hydroxylase and microsomal cholesterol 7
alpha-hydroxylase activities also decreased significantly and were cou
pled to markedly elevated plasma sterol concentrations (120.7 +/- 12.5
mg/dl, as compared to 59.2 +/- 6.3 mg/dl in control animals; p < .05)
but to no change in hepatic cholesterol concentrations. Thus, decreas
ed cholesterol catabolism due to competitive inhibition of both micros
omal cholesterol 7 alpha-hydroxylase and mitochondrial sterol 27-hydro
xylase by elevated hepatic sitosterol concentrations contributes to hy
percholesterolemia and increased risk of atherosclerosis in sitosterol
emia.