EFFECTS OF DIFFERENT PHENOTYPES OF HYPERLIPOPROTEINEMIA AND OF TREATMENT WITH FIBRIC ACID-DERIVATIVES ON THE RATES OF CHOLESTEROL 7-ALPHA-HYDROXYLATION IN HUMANS

Little is known about the relationships between hyperlipidemia and bil e acid metabolism. However, hypolipidemic treatment with fibric acid d erivatives has been shown to increase biliary cholesterol secretion, p resumably by reducing bile acid synthesis. To clarify such relationshi ps, we investigated the effects of different hyperlipoproteinemic cond itions and of treatment with fibric acid derivatives on the rates of c holesterol 7 alpha-hydroxylation (the limiting step of bile acid synth esis) in humans. We studied 10 patients (aged 36 to 68 years) with lip oprotein phenotype IIa and with a clinical diagnosis of heterozygous f amilial hypercholesterolemia, a condition of reduced activity of LDL r eceptors, and 11 patients (aged 48 to 70 years) with lipoprotein pheno type IIb or IV and clinical diagnosis of familial combined hyperlipide mia, a condition probably related to increased hepatic lipoprotein syn thesis. Cholesterol 7 alpha-hydroxylation rates were assayed in vivo b y tritium release assay after an intravenous injection of [7 alpha-H-3 ]cholesterol. The results were compared by ANOVA to the values obtaine d 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 we re 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 hyper cholesterolemia group and 1.30 +/- 0.47 mmol/d in the familial combine d hyperlipidemia. group (P < .05 between the two groups and between pa tients with familial combined hyperlipidemia and control subjects; P = NS between patients with familial hypercholesterolemia and control su bjects, as determined by ANOVA). Treatment with both gemfibrozil and b ezafibrate reduced serum cholesterol, slightly increased HDL cholester ol, and significantly reduced serum triglyceride and apo B concentrati ons. Cholesterol 7 alpha-hydroxylation rates were significantly reduce d by nearly 55% both after gemfibrozil and after bezafibrate. Our find ings indirectly suggest that cholesterol degradation to bile acid is i ndependent of receptor-mediated uptake of LDL by the liver. Hydroxylat ion rates seem to parallel serum levels of triglyceride and apo B (par ticularly after fibrate treatment), possibly suggesting a coordinate r eg ulation of bile acid and lipoprotein synthesis.