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

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.