Metabolism of Squalene in Triglyceride-rich Lipoproteins in Humans

8 ABBREVIATIONS ACAT Acylcoenzyme A:cholesterol acyltransferase ANOVA Analysis of variance Apo Apolipoprotein AUC Area under curve AUIC Area under incremental curve BMI Body mass index CETP Cholesteryl ester transfer protein d Density GLC Gas-liquid chromatography HDL High-density lipoprotein HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A HPLC High-pressure liquid chromatography HSPG Heparan sulphate proteoglycan IDL Intermediate-density lipoprotein LCAT Lecithin:cholesterol acyltransferase LDL Low-density lipoprotein LPL Lipoprotein lipase LRP LDL receptor-related protein PLTP Phospholipid transfer protein SR-BI Scavenger receptor class B type I VLDL Very low-density lipoprotein 9 LIST OF ORIGINAL PUBLICATIONS This thesis is based on the following original articles, which are referred to in the text by their Roman numerals. In addition, some unpublished data are presented. and squalene metabolism is age dependent. Dietary squalene increases cholesterol synthesis measured with serum non-cholesterol sterols after a single oral dose in humans. Fate of intravenously administered squalene and plant sterols in human subjects. A and squalene clearances and cholesterol synthesis off and on lovastatin treatment in type III hyper-lipoproteinemia. ABSTRACT Squalene, a non-steroid obligate precursor of cholesterol, is derived from both de novo synthesis from acetyl coenzyme A and from diet. Little is known of the postprandial metabolism of squalene. However, recent evidence exists that squalene may play a role in the development of atherosclerosis such that the removal of postprandial squalene was retarded in women with coronary artery disease. Accordingly, the kinetics and metabolism of squalene in the postprandial state and after intravenous administration in humans were studied. An oral fat load test with 0.5 g of squalene was performed in six young (22-25 years) and eight old (78-79 years) males to learn whether postprandial squalene metabolism is affected by age. The acute effects of a single dose of squalene on cholesterol synthesis as measured by cholesterol precursor sterols in postprandial lipoproteins were studied in 16 subjects who underwent two oral fat challenges in random order, one with 0.5 g of squalene supplement and the other without. Removal of squalene from chylomicrons was investigated in six subjects by giving an intravenous bolus injection of artificial chylomicron-like lipid emulsion (Intralipid R) enriched with squalene. To learn whether inhibition of cholesterol absorption with a subsequent increase in cholesterol synthesis reduces postprandial squalene concentrations, three oral fat challenges with 0.5 g of squalene in each were performed in 11 mildly hypercholesterolemic subjects before and during stanol ester (3g/day) consumption. The latter two tests were performed during stanol ester …