Effects of different phenotypes of hyperlipoproteinemia and of treatment with fibric acid derivatives on the rates of cholesterol 7α-hydroxylation in humans

Marco Bertolotti, Mauro Concari, Paola Loria, Nicola Abate, Adriano Pinetti, M. Eugenia Guicciardi, Nicola Carulli

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Little is known about the relationship 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 the 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-1H]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 or receptor-mediated uptake of LDL by the liver. Hydroxylaton 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.

Original languageEnglish (US)
Pages (from-to)1064-1069
Number of pages6
JournalArteriosclerosis, thrombosis, and vascular biology
Volume15
Issue number8
DOIs
StatePublished - Aug 1995

Keywords

  • bezafibrate
  • bile acid synthesis
  • familial combined hyperlipidemia
  • familial hypercholesterolemia
  • gemfibrozil

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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