Effects of Different Phenotypes of Hyperlipoproteinemia and of Treatment With Fibric Acid Derivatives on the Rates of Cholesterol 7α-Hydroxylation in Humans

Abstract

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 7α-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 7α-hydroxylation rates were assayed in vivo by tritium release assay after an intravenous injection of [7α- 3 H]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 7α-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.