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The rate at which radioactivity appeared in cholesteryl esters (CE) in whole serum and in very low density lipoproteins (VLDL) and low density lipoproteins (LDL) when radioactively labelled free cholesterol (FC) was incubated with serum was investigated. At 4 degrees C equilibration of radioactive FC with native FC occurred, but there was no conversion to CE. At 37 degrees C CE mass increased in parallel with radioactivity in CE both in whole serum and VLDL/LDL. Incubation at 37 degrees C with an inhibitor of lecithin cholesterol acyl transferase (LCAT) abolished the increase in the total CE radioactivity and mass in serum. Transfer of CE from high density lipoprotein (HDL) to VLDL/LDL, however, continued to occur. An assay for LCAT and for cholesteryl ester transfer protein (CETP) was developed, which employed the increases in radioactive CE in whole serum and VLDL/LDL during a single incubation as indices of LCAT and CETP activity, respectively. Determination of the initial serum FC concentration allowed the expression of these activities in nmol/ml per h. References ranges were established in 62 fasting normolipidaemic men and women and increases in both LCAT and CETP were found following a fatty meal. The experiments thus provided further information about the carrier-mediated transfer of CE from its site of esterification on HDL to VLDL/LDL and formed the basis of a relatively simple assay, which has advantages over previously published methods and which may be used in clinical and epidemiological studies to elucidate the role of CETP and LCAT in atherosclerosis.

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This report describes the metabolism of apolipoprotein B-containing lipoproteins in seven familial hypercholesterolemic (FH) homozygotes and compares the results to the values obtained from five healthy control subjects. The concentration, composition, and metabolism of large, triglyceride-rich very low density lipoproteins (VLDL1, Sf 60-400) were the same in the control and FH groups, indicating that this component of the VLDL delipidation cascade ws unaffected by the absence of receptors. In contrast, familial hypercholesterolemic small VLDL2 (Sf 20-60) was enriched with cholesterol and depleted in triglyceride. Moreover, its plasma concentration was elevated as a result of an increase in its synthesis and a defect in the removal of a remnant population within this density interval. The latter accounted for up to 50% of the total mass of the fraction. Onward transfer of apolipoprotein B (apoB) from small VLDL through intermediate density lipoprotein (IDL) to low density lipoprotein (LDL) was retarded, suggesting that receptors were involved in this supposedly lipase-mediated event. IDL and LDL concentrations increased up to fourfold above normal in the plasma of the FH patients due partly to the delay in maturation and partly to defective direct catabolism. We conclude that the LDL receptor plays multiple and important roles in the metabolism and transformation of apoB-containing particles in the Sf 0-400 flotation interval.

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A protein factor has been found in serum which converts the M form of placental alkaline phosphatase (PLAP) to the A and B forms. The identity of the conversion products has been confirmed by analysis of their dimers and polypeptides. Proteolysis is not implicated in this phenomenon. This report establishes microvillous M-PLAP as the precursor of the A and B forms.

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This study was designed to investigate the response of Type III hyperlipoproteinemic subjects to bezafibrate therapy. The metabolism of apolipoprotein B was examined in four lipoprotein subclasses of Sf 60-400 (large very low density lipoprotein (VLDL)), Sf 20-60 (small VLDL), Sf 12-20 (intermediate density lipoprotein (IDL)), and Sf 0-12 (low density lipoprotein (LDL)) before and during bezafibrate therapy. Treatment reduced the plasma concentration of VLDL and raised high density lipoprotein (HDL) cholesterol. There was no net change in LDL cholesterol or its associated apolipoprotein B. The decrease in plasma VLDL derived mainly from an inhibition of synthesis of both large and small subfractions which reduced the number of particles in the circulation without normalizing their lipid composition. Catabolism of the larger VLDL also increased, presumably as a result of lipoprotein lipase activation. Although the plasma concentration of LDL was unchanged, both its synthesis and catabolism were perturbed. Its fractional catabolic rate fell by 50%, but the impact that this would have had on its steady state level in the circulation was apparently blunted by a decrease in its synthesis from Sf 12-20 IDL. In the control phase of the study, most IDL apolipoprotein B was converted to LDL. Bezafibrate therapy channelled this material towards direct catabolism.

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The chemical trimethylcyclohexanol (TMC) is closely related to menthol, the major component of a terpene preparation with known choleretic and cholelitholytic activity. Its effects on hepatic cholesterol synthesis and bile secretion were examined in the rat. In both acute and long-term dosing experiments TMC significantly inhibited hepatic S-3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase. TMC was a potent choleretic, with detectable effects on bile flow at low doses, which also reduced coupling of cholesterol secretion to bile salt secretion. Single large doses tended to lower biliary cholesterol output and caused significant reduction in cholesterol saturation index after biliary diversion for 1 h. TMC and its widely prescribed ester cyclandelate, which is rapidly degraded to TMC after ingestion, should be investigated further as potential cholelitholytic treatments in man.

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Seventeen hours after a single oral dose of the cyclic monoterpenes cineole or menthol, rat liver 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity was inhibited by up to 70%. The transient nature of this effect (no inhibition 41 h after dosing) was compatible with the rapid metabolism and excretion of these terpenes. Neither menthol, and its major metabolite, menthylglucuronide, nor cineole acted as direct inhibitors of HMG-CoA reductase activity in vitro, although menthol was found to bind to liver microsomes Ks approximately 0.1 mM). Unlike the short term effects of dietary cholesterol, terpene administration did not affect HMG-CoA reductase activity by modulation of the lipid microenvironment of the enzyme. Thus, following menthol or cineole treatment, we found no deviations from the normal kinetic responses to changes in temperature or in concentration of HMG-CoA. Furthermore, the inhibitory effect was still seen after solubilization of the enzyme from microsomes. The loss of HMG-CoA reductase activity was not associated with increased phosphorylation of the enzyme. Immunotitration of HMG-CoA reductase from terpene-treated rats showed that activity loss was due to less enzyme molecules (together with some possibly "cripple" enzyme), indicating that rates of enzyme synthesis or degradation had been altered. Since menthol inhibition of reductase was still observed in rats deprived of foods, we conclude that the effect is not mediated by those hormones whose concentration is changed during fasting (insulin, glucagon, and adrenaline).

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