T. Magot

Apolipoproteins C-II and C-III metabolism in hypertriglyceridemic patients Effect of a drastic triglyceride reduction by combined diet restriction and fenofibrate administration

Four hypertriglyceridemic patients, who had received an equilibrated high calorie diet and no lipid lowering drug for 1 month, were injected intravenously with 125I-apo C-II and 131I-apo C-III labeled homologous lipoproteins. Plasma and urine radioactivity, lipid and apolipoprotein levels were followed at regular intervals for 15 days. At the end of this first kinetic study the patients were advised to adhere for 1 month to a more restricted diet, limited in fat, and were given additionally 300 mg fenofibrate daily. After this treatment, a new kinetic study involving intravenous injection (similar to the first one) was performed. The protocols of both studies were identical. Treatment (diet plus drug) (1) reduced total cholesterol by 26 +/- 8%, triglycerides by 56 +/- 15%, apo C-II by 36 +/- 14%, and apo C-III by 48 +/- 10%; (2) modified the distribution of radioactivity between lipoproteins proportionally to the change in their mass ratio (decrease in VLDL and increase in HDL); (3) changed the kinetics of both apoproteins by rising the fractional removal rate, shortening residence time and decreasing the synthesis rate of both apolipoproteins C-II and C-III. The treatment was, however, unable to reduce the synthesis rate of apo C-III to normal, suggesting a major role of the apoprotein overproduction in the triggering of hypertriglyceridemia.

Effect of simvastatin on receptor-dependent low density lipoprotein catabolism in normocholesterolemic human volunteers

Simvastatin, an inhibitor of HMG-CoA reductase was given to 7 normolipidemic healthy volunteers for 1 month at a dose of 20 mg/day. Measurements of turnover of low density lipoprotein apolipoprotein B (LDL-apo B) were determined before and after drug treatment using intravenous injection of 125I-labeled LDL and 131I-labeled cyclohexanedione-treated LDL to quantify the receptor pathway. In addition to a 13% increase in HDL cholesterol and apolipoprotein A-I concentrations, plasma cholesterol was reduced by 20%, LDL-cholesterol by 32%, and apolipoprotein B by 23%. Assuming a heterogeneous pool of LDL, the new model presented in the companion paper was built to calculate the contribution of the receptor-dependent and the receptor-independent pathways and the corresponding fractional catabolic rates. Simvastatin did not modify constantly the synthetic rate of LDL-apo B but increased the fractional catabolic rate of the receptor-dependent pathway and the contribution of this pathway in the catabolism. The fall in LDL plasma levels observed in normocholesterolemic subjects can be then entirely explained by an enhanced fractional removal of LDL from the circulation by the receptor route.

Origin and Fate of Cholesterol in Rat Plasma Lipoproteins in vivo

After a single ingestion of a diet containing 14C-cholesterol, cholesterol radioactivity in the stomachal and intestinal contents, in the different organs and in the very low density lipopr

In vivo effect of simvastatin on lipoprotein cholesteryl ester metabolism in normocholesterolemic volunteers

A kinetic study on lipoprotein cholesteryl ester metabolism was carried out in 4 normolipidemic volunteers before and after treatment with simvastatin. They received LDL labelled with 3H-cholesteryl linoleate. A lipoprotein cholesteryl ester model was developed that fit the radioactivity in LDL, HDL and VLDL cholesteryl ester during 24 hours following injection. Before treatment, the model is consistent with previously reported data. Moreover our results suggest that, in normal fasting subjects, the efflux of plasma cholesteryl ester is almost exclusively derived from LDL. Administration of drug decreased LDL cholesteryl ester concentration by 35%. After treatment, the rate constant concerning LDL catabolism was increased by 25% and the model required the existence of a direct removal of VLDL cholesteryl ester (40% of total VLDL turnover). Our results suggest that the reduction in the LDL cholesteryl ester concentration induced by treatment with simvastatin is due to an increase in the uptake of LDL and LDL precursors (VLDL, VLDL remnants) by LDL receptors.

Origin and fate of rat plasma cholesterol in vivo. Modelling of cholesterol movements between plasma and organs

A cholesterol system model was developed in the rat following a single injection of red cells containing free (unesterified) [3H]cholesterol. The radioactivity of free and esterified cholesterol in the different parts of the system was measured during the 48 h following tracer introduction. The model consisted of seven compartments (red cell free cholesterol, plasma and liver free and esterified cholesterol, total cholesterol in the rapidly and slowly exchangeable carcass pools). The model was validated by the similarity between simulated and experimental values during the 48 h following tracer introduction. Both the fractional rate of cholesterol esterification in the plasma (0.44 h-1) and liver (0.01 h-1) and the fractional exchange rate of free cholesterol from the plasma towards the various organs (particularly 3 h-1 towards the liver for a total of 7 h-1) can be estimated with this model. The results show that cholesterol movements between the plasma and the different organs take place mainly through intense free cholesterol exchanges, resulting in a low net flux.

Effect of portacaval or mesentericocaval anastomosis on cholesterol metabolism in rats

Portacaval anastomosis (PCA) lowered by 50% the cholesterol concentration in the plasma of rats. The free and esterified cholesterol contents in the lipoproteins were decreased with the very low density lipoproteins most affected (-85%). Cholesterol concentration as total content in the liver was reduced. The major change in the cholesterol metabolism, as studied with an isotopic equilibrium method, was the decrease in the intestinal absorption coefficient of dietary cholesterol (56.0 +/- 2.7% instead of 73.3 +/- 1.9% in controls). The rate of cholesterol transformation into bile acids was decreased (10.5 +/- 0.3 vs 14.5 +/- 0.5 mg/day/rat in controls). The rate of internal secretion of cholesterol was slightly reduced while the rate of fecal external secretion was increased, suggesting that the synthesis of cholesterol by extra-digestive tissues (including liver) was reduced after PCA. The effects of PCA on cholesterol metabolism were similar to those described for glucagon administration. Since this shunt results in hyperglucagonemia, it is suggested that this hormonal perturbation was the main factor involved in the modifications of cholesterol metabolism after PCA. Moreover, mesentericocaval anastomosis, which shunts only the intestinal blood and allows the pancreatic hormones a normal transport through the liver, did not significantly modify cholesterol metabolism. Only cholesterolemia (-28%) and the absorption coefficient of dietary cholesterol (66.0 +/- 2.3%) were slightly reduced.

In Vivo Metabolism of Apolipoproteins C-II Aid C-IIII in Normal and Hypertriglyceridemic Subjects

Two papers on apo C-II and apo C-III metabolism have been published in 1981 and 1982 (1,2), only one comparing normal and hypeirlipoproteinemic subjects (1). The kinetic analysis of 1 2 5l labeled VLDL was followed in plasma for 48 h only and there were no urine data. The essential limitation of these early studies was their short duration due to the low specific activity of each individual C peptide obtained after whole VLDL-apoprotein labeling (apo B, C, E) necessitating tedious and error-prone separation procedures.

Influence des acides gras à chaîne courte ou moyenne sur la dynamique du cholestérol chez le rat

The effects of a diet consisting of 10% medium-chain triglycerides (C8:0, C10:0) or 10% homogeneous triglycerides of 6- to 14-carbon chain saturated fatty acids on cholesterol turnover processes were studied in rats using the isotope equilibrium method. Cholesterol absorption was not significantly affected by the type of dietary fatty acid ingested. In contrast, lengthening of the fatty acid chain caused a moderate increase in the rates of cholesterol secretion (internal and external) and of transformation into bile acids. Thus, cholesterol synthesis was 80% higher in rats fed trimyristin (25.7 mg/day) than in those receiving tricaproin (14.6 mg/day). This increase seems essentially due to stimulated liver cholesterogenesis, as shown by in vivo incorporation of 14C-acetate.

Origine et devenir du cholestérol des lipoprotéines plasmatiques du rat in vivo. III: Mise en évidence et mesure du flux de cholestérol estérifié des HDL vers les chylomicrons

A study has been carried out to measure the transfer rate of esterified cholesterol from the HDL into the chylomicrons, as previously suggested. Rats were intravenously injected with cholesterol-labelA study has been carried out to measure the transfer rate of esterified cholesterol from the HDL into the chylomicrons, as previously suggested. Rats were intravenously injected with cholesterol-labelled plasma or red cells. The specific activity of esterified cholesterol of HDL and chylomicrons was measured during 12 h following injection. Results were treated by compartmental analysis. The transfer rate was 0.21-0.22 h-1 with an uptake rate of chylomicrons by the liver of 8 h-1 (t1/2 5 min). This represents a 0.8 mg h-1 flux of esterified cholesterol from HDL into chylomicrons, i.e., in our conditions, 75% of the total input into the chylomicrons esterified cholesterol. This process could be the major way for the disappearance of HDL esterified cholesterol.