THE EFFECT OF INCREASED HEPATIC SITOSTEROL ON THE REGULATION OF 3-HYDROXY-3-METHYLGLUTARYL-COENZYME-A REDUCTASE AND CHOLESTEROL 7-ALPHA-HYDROXYLASE IN THE RAT AND SITOSTEROLEMIC HOMOZYGOTES
S. Shefer et al., THE EFFECT OF INCREASED HEPATIC SITOSTEROL ON THE REGULATION OF 3-HYDROXY-3-METHYLGLUTARYL-COENZYME-A REDUCTASE AND CHOLESTEROL 7-ALPHA-HYDROXYLASE IN THE RAT AND SITOSTEROLEMIC HOMOZYGOTES, Hepatology, 20(1), 1994, pp. 213-219
We investigated hepatic cholesterol homeostasis in four homozygous sit
osterolemic subjects from two unrelated families who showed enhanced a
bsorption, diminished removal and increased tissue and plasma concentr
ations of sitosterol (24-ethyl cholesterol). Measurements of hepatic 3
-hydroxy-3-methylglutaryl coenzyme A reductase activities were correla
ted with steady state messenger RNA levels and related to cholesterol
7 alpha-hydroxylase activities in the sitosterolemic homozygotes and n
ine controls. Similar determinations were made in rats infused intrave
nously with sitosterol so that hepatic and plasma sitosterol concentra
tions increased to about 10% of total sterols to resemble the human di
sease sitosterolemia. In the four sitosterolemic homozygotes, hepatic
3-hydroxy-3-methylglutaryl coenzyme A reductase activities were marked
ly reduced (12% of normal), and steady state 3-hydroxy-3-methylglutary
l coenzyme A reductase messenger RNA levels barely detected. In contra
st, hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activities
and messenger RNA levels were not decreased in rats with similarly el
evated hepatic sitosterol concentrations. However, hepatic cholesterol
7 alpha-hydroxylase activity was inhibited 30% in both the sitosterol
emic homozygotes and rats with high liver sitosterol concentrations. P
lasma cholesterol concentrations increased 120% in the sitosterol-infu
sed rats and 29% in the untreated human homozygotes. These results dem
onstrate that high-tissue sitosterol concentrations do not inhibit hep
atic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity or stead
y state messenger RNA levels and that they competitively block cholest
erol 7 alpha-hydroxylase activity and raise plasma cholesterol levels.
Thus the deficiency of 3-hydroxy-3-methylglutaryl coenzyme A reductas
e in the liver of sitosterolemic homozygotes is inherited and not due
to the hepatic accumulation of sitosterol. In distinction, elevated he
patic sitosterol concentrations increase plasma cholesterol levels by
competitively suppressing cholesterol 7 alpha-hydroxylase activity.