The Effect of Increased Hepatic Sitosterol on the Regulation of 3–Hydroxy–3–Methylglutaryl—Coenzyme A Reductase and Cholesterol 7α–Hydroxylase in the Rat and Sitosterolemic Homozygotes

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Abstract
: We investigated hepatic cholesterol homeostasis in four homozygous sitosterolemic subjects from two unrelated families who showed enhanced absorption, diminished removal and increased tissue and plasma concentrations of sitosterol (24–ethyl cholesterol). Measurements of hepatic 3–hydroxy–3–methylglutaryl coenzyme A reductase activities were correlated with steady state messenger RNA levels and related to cholesterol 7α–hydroxylase activities in the sitosterolemic homozygotes and nine controls. Similar determinations were made in rats infused intravenously with sitosterol so that hepatic and plasma sitosterol concentrations increased to about 10% of total sterols to resemble the human disease sitosterolemia. In the four sitosterolemic homozygotes, hepatic 3–hydroxy–3–methylglutaryl coenzyme A reductase activities were markedly reduced (12% of normal), and steady state 3–hydroxy–3–methylglutaryl coenzyme A reductase messenger RNA levels barely detected. In contrast, hepatic 3–hydroxy–3–methylglutaryl coenzyme A reductase activities and messenger RNA levels were not decreased in rats with similarly elevated hepatic sitosterol concentrations. However, hepatic cholesterol 7α–hydroxylase activity was inhibited 30% in both the sitosterolemic homozygotes and rats with high liver sitosterol concentrations. Plasma cholesterol concentrations increased 120% in the sitosterol–infused rats and 29% in the untreated human homozygotes. These results demonstrate that high–tissue sitosterol concentrations do not inhibit hepatic 3–hydroxy–3–methylglutaryl coenzyme A reductase activity or steady state messenger RNA levels and that they competitively block cholesterol 7α–hydroxylase activity and raise plasma cholesterol levels. Thus the deficiency of 3–hydroxy–3–methylglutaryl coenzyme A reductase in the liver of sitosterolemic homozygotes is inherited and not due to the hepatic accumulation of sitosterol. In distinction, elevated hepatic sitosterol concentrations increase plasma cholesterol levels by competitively suppressing cholesterol 7α–hydroxylase activity. (Hepatology 1994;20:213–219.).

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