© 1995 American Heart Association, Inc.
Articles |
Effects of Different Phenotypes of Hyperlipoproteinemia and of Treatment With Fibric Acid Derivatives on the Rates of Cholesterol 7
-Hydroxylation in Humans
From the Departments of Internal Medicine and Chemistry (A.P.), University of Modena, Italy.
Correspondence to Marco Bertolotti, MD, Istituto di Patologia Medica, Policlinico, Via del Pozzo, 71, 41100 Modena, Italy.
Abstract Little is known about the relationships between
hyperlipidemia and bile acid metabolism.
However, hypolipidemic treatment with fibric acid derivatives has been
shown to increase biliary cholesterol secretion, presumably
by reducing bile acid synthesis. To clarify such relationships, we
investigated the effects of different
hyperlipoproteinemic conditions and of
treatment with fibric acid derivatives on the rates of
cholesterol 7
-hydroxylation (the limiting step of bile
acid synthesis) in humans. We studied 10 patients (aged 36 to 68 years)
with lipoprotein phenotype IIa and with a clinical diagnosis of
heterozygous familial hypercholesterolemia, a condition
of reduced activity of LDL receptors, and 11 patients (aged 48 to 70
years) with lipoprotein phenotype IIb or IV and clinical
diagnosis of familial combined hyperlipidemia, a
condition probably related to increased hepatic lipoprotein synthesis.
Cholesterol 7-hydroxylation rates were assayed in
vivo by tritium release assay after an intravenous
injection of [7-3H]cholesterol. The
results were compared by ANOVA to the values obtained in a group of 28
normolipidemic patients (aged 34 to 83 years), with age as the
covariate. Six patients were also studied after treatment with
gemfibrozil (900 to 1200 mg/d for 6 to 8 weeks) and 5 patients were
studied after treatment with bezafibrate (400 mg/d for 6 to 8 weeks).
Hydroxylation rates were 0.82±0.22 mmol/d in the familial
hypercholesterolemia group and 1.30±0.47 mmol/d in the
familial combined hyperlipidemia group
(P<.05 between the two groups and between patients with
familial combined hyperlipidemia and control subjects;
P=NS between patients with familial
hypercholesterolemia and control subjects, as
determined by ANOVA). Treatment with both gemfibrozil and bezafibrate
reduced serum cholesterol, slightly increased HDL
cholesterol, and significantly reduced serum
triglyceride and apo B concentrations.
Cholesterol 7-hydroxylation rates were significantly
reduced by nearly 55% both after gemfibrozil and after bezafibrate.
Our findings indirectly suggest that cholesterol
degradation to bile acid is independent of receptor-mediated uptake of
LDL by the liver. Hydroxylation rates seem to parallel serum levels of
triglyceride and apo B (particularly after fibrate
treatment), possibly suggesting a coordinate regulation of bile acid
and lipoprotein synthesis.
Key Words: familial hypercholesterolemia • familial combined hyperlipidemia • bile acid synthesis • gemfibrozil • bezafibrate
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