To determine the acute and long-term effects of
low density lipoprotein (
LDL) reduction on
cholesterol biosynthesis, we studied changes in the
cholesterol precursors
mevalonic acid (MVA) and
lathosterol in patients with heterozygous
familial hypercholesterolemia undergoing
LDL-
apheresis. Long-term
LDL-
apheresis in eight patients resulted in slight but insignificant increases in plasma MVA levels and
lathosterol/
cholesterol (L/C) ratios over 18 months. In short-term studies, six patients not on drugs and six patients treated with
lovastatin or
pravastatin had blood taken immediately before and after
LDL-
apheresis, and afterwards on days 1, 2, 3, 5, and 7. Plasma L/C ratios and MVA concentration did not change significantly on the first day after
LDL-
apheresis in those not on
statin therapy (1.11 +/- 0.08 vs. 1.40 +/- 0.18, and 9.2 +/- 1.3 vs. 9.1 +/- 0.6 ng/ml, respectively) but increased in the
statin-treated group (from 0.78 +/- 0.09 to 1.55 +/- 0.21, P = 0.003 and from 5.0 +/- 0.7 to 11.0 +/- 1.6 ng/ml, P = 0.008, respectively). There was no clear correlation between the changes in either of these precursors and the extent of reduction of total
cholesterol by
LDL-
apheresis, but there was a strong inverse correlation with the post-
apheresis LDL-cholesterol level (r = -0.77, P = 0.002 for L/C ratio; r = -0.75, P = 0.003 for MVA). Post-
apheresis changes in L/C ratio and MVA were mutually correlated (r = 0.68. P = 0.01). We conclude that
LDL-
apheresis stimulates
cholesterol biosynthesis transiently despite concomitant
therapy with an
HMG-CoA reductase inhibitor, the degree of stimulation being inversely related to the level to which the
LDL-cholesterol was reduced.