Cholesterol and bile acid synthesis in two families with homozygous and heterozygous hypercholesterolemia.

Measurements of cholesterol and bile acid synthesis and of cholesterol precursors were performed in two hypercholesterolemic families with two homozygous girls under basal conditions and during treatment with cholestyramine. The concentrations of serum methyl sterols, squalene, cholesterol, and triglycerides, and the responses to cholestyramine were not consistently different in the two families. However, in both families stimulation of cholesterol synthesis by cholestyramine markedly increased the methyl sterol content of serum lipoproteins both in heterozygotes (with a lowering of serum cholesterol) and in homozygotes (with virtually no lowering of serum cholesterol concentration). The bile acid and cholesterol synthesis rates were modestly low in one family and markedly high in the other both with and without cholestyramine treatment, the baseline production rates being significantly correlated with the increments in the synthesis caused by cholestyramine. The two families apparently represent low and high producing types of familial hypercholesterolemia. Cholesterol synthesis in the two homozygous girls was about twice that of their respective heterozygous parents with and without cholestyramine treatment, suggesting that the double dose of the mutant gene doubled cholesterol production. Furthermore, close child-to-parent correlations for the bile acid and cholesterol synthesis rates point to a genetic control of cholesterol metabolism.