Interrelations in the oxidative metabolism of free fatty acids, glucose, and glycerol in normal and hyperlipemic patients. A compartmental model.

Palmitate, glucose, and glycerol oxidation to CO(2) have been investigated in the fasted state in ten normal subjects and nine patients (six hyperlipoproteinemias, one xanthomatosis, and two glycogenosis) after intravenous injection of [1-(14)C]palmitate, [1-(14)C]glucose, or [1-(14)C]glycerol in tracer amounts. The specific activities and concentrations of plasma palmitate, glycerol, or glucose and expired CO(2) were measured at various intervals after the injection for a period of 24 h. All the studies were analyzed in terms of a multicompartment model describing the structure for each of the subsystems, the transfer of carbon label between subsystems, and the oxidation to CO(2). A bicarbonate subsystem was also included in the model to account for its role in shaping the CO(2) curves. All the CO(2) activity following a palmitate injection could be accounted for by a direct oxidative pathway from plasm FFA with the addition of a 20-min delay compartment. The same also applied to glucose, except that the delay compartment had a mean time of about 150 min. Only about a third of the injected glycerol was directly oxidized to CO(2) from plasma; the delay time was about 4 min. Most of the remainder was converted to glucose. In normals about 45% of the FFA is oxidized to CO(2) directly. This constitutes about 30% of the total CO(2) output. In hyperlipemia the CO(2) output is nearly unchanged and the contribution from FFA is nearly the same. There is a considerable increase (factor of 2), however, in FFA mobilization, most of which is probably diverted to triglyceride synthesis. The glucose and glycerol subsystems are roughly the same in normals and hyperlipemics. About 50% of glucose is oxidized by the direct pathways which accounts for about 35% of the CO(2) output. Glycerol accounts for only 1.5% of the CO(2) produced. Major changes occurred in the glycerol and glucose subsystems in glycogenosis. The changes are consistent with the known deficiency in glucose-6-phosphatase in this disorder. There is a considerable reduction (factor of 2 or more) in the release of glucose to plasma (gluconeogenesis) and in the conversion of glycerol to glucose. Despite the integration of the kinetics of the glucose, glycerol, and FFA subsystems over a 24-h period, 36% of the CO(2) production was still unaccounted for in normals and 50% in hyperlipemics. Thus, some of the carbon must wind up in very slowly turning-over pools which supply CO(2) through subsystems not covered in these studies (triglycerides, glycogen, amino acids, etc.). All the modeling was carried out with the aid of the SAAM25 computer program.

Metabolism of adrenal cholesterol in man. I. In vivo studies.

The kinetics of plasma and adrenal cholesteral equilibration were analyzed in patients undergoing bilateral adrenalectomy for generalized mammary carcinoma. A biological model is proposed to help in the understanding of adrenal cholesterol physiology. It comprises two intracellular compartments: (1) A compartment of free adrenal cholesterol which is small (of the order of 17 mg) but turns over very fast; it is renewed approximately 8 times per day: 3 times by the inflow of free plasma cholesterol, and 5 times by the hydrolysis of esterified adrenal cholesterol, the contribution of adrenal cholesterol synthesis appearing to be relatively small. (2) A compartment of esterified adrenal cholesterol which is 20 times larger; it is constantly renewed by in situ esterification and hydrolysis with a daily fractional turnover rate of the order of 0.25. The direct and selective accumulation of plasma cholesteryl esters is practically absent. Only free adrenal cholesterol returns to plasma, mostly after conversion into steroid "hormones."However small the synthesis of adrenal cholesterol may be, it seems more important in the zona "reticularis." On the other hand, the inflow of plasma cholesterol and the turnover of the free adrenal compartment tend to be faster in the zona "fasciculata." The equilibration of plasma and adrenal cholesterol can proceed unmodified under conditions of ACTH suppression. In one patient with Cushing's disease the size of the two adrenal compartments was clearly increased but their equilibration with plasma cholesterol proceeded normally. In another patient the kinetics of hydrocortisone corresponded to those of free adrenal cholesterol in the control studies.

Metabolism of adrenal cholesterol in man. II. In vitro studies including a comparison of adrenal cholesterol synthesis with the synthesis of the clucocorticosteroid hormones.

The synthesis of adrenal cholesterol, its esterification and the synthesis of the glucocorticosteroid hormones were studied in vitro on human adrenal tissue. It was found that the synthesis of adrenal cholesterol may normally be small in the zona "fasciculata," particularly when compared with the synthesis of the glucocorticosteroid hormones, that it is several times higher in the zona "reticularis" where esterified cholesterol is less abundant, and that under ACTH stimulation it increases strikingly and proportionally to the degree of esterified adrenal cholesterol depletion. ON THE OTHER HAND, THE RELATIVE RATE OF ESTERIFICATION AS WELL AS THE CONCENTRATION OF FREE ADRENAL CHOLESTEROL ARE REMARKABLY STABLE: they do not differ according to the adrenal zonation and are unaffected by ACTH. Furthermore, from a qualitative point of view, the relative proportions of Delta(1) and Delta(2) cholesteryl esters formed in situ are similar to those anticipated from their relative concentrations, suggesting that the characteristic fatty acid distribution of the adrenal cholesteryl esters results from an in situ esterification rather than from a selective uptake of the plasma cholesteryl esters. Besides, the in vitro esterification reveals a propensity to the formation of the most unsaturated cholesteryl esters. Regarding hydrocortisone and corticosterone, their synthesis tends to be more elevated in the zona "fasciculata." Despite its higher cholesterol concentration the zona "fasciculata" should not therefore be viewed as a quiescent functional complement to the zona "reticularis" and the cortical distribution of glucocorticosteroid hormone synthesis is quite distinct from that of adrenal cholesterol synthesis.

Blood cholesterol and hydrocortisone production in man: quantitative aspects of the utilization of circulating cholesterol by the adrenals at rest and under adrenocorticotropin stimulation.

A kinetic study of the conversion of blood cholesterol into hydrocortisone was carried out in two patients through prolonged infusions of cholesterol-4-(14)C. The following points appear to be established by our observations:1) The infused tracer behaved metabolically like endogenous cholesterol; it could therefore serve as a means of labeling plasma cholesterol for investigating its utilization by the adrenal cortex.2) At rest, about 80% of hydrocortisone derived from plasma cholesterol, the other 20% thus being synthesized in situ from acetate and other unlabeled precursors.3) Under ACTH stimulation the participation of plasma cholesterol in the synthesis of hydrocortisone was the same as at rest; the conversion of plasma cholesterol into hydrocortisone was thus proportional to the production of glucocorticosteroids by the adrenal glands.4) The specific activities of hydrocortisone allowed us to trace its adrenal precursors including adrenal cholesterol. The kinetics of the replacement of adrenal cholesterol by plasma cholesterol underlined the functional heterogeneity of the former. The experimental data were compatible with the following model: A fraction of plasma cholesterol entering the adrenal cell is immediately available for metabolism and conversion into steroid hormones, and another fraction turns over slowly, representing some form of storage.

Prevalence and clinical features of celiac disease in 950 children with type 1 diabetes in France.

UNLABELLED: The prevalence of celiac disease is higher in children with type 1 diabetes mellitus (DM) than in the general pediatric population, but may vary widely across countries. Sensitive and specific antibody tests are available for detecting celiac disease. AIMS: To evaluate the prevalence in France of histologically documented celiac disease in a vast cohort of children with type 1 DM, and to describe the features of celiac disease and treatment response. METHODS: Retrospective cohort study of 950 children with type 1 diabetes seen between 1994 and 2001. Antibodies to gliadin, reticulin, endomysium and transglutaminase were looked for one to seven times in each patient. RESULTS: Fifteen patients (1.6%) had biopsy-confirmed celiac disease. Symptoms led to the diagnosis in six patients (mean age, 7 years) and screening tests in nine patients (mean age, 11 years). Anti-endomysium antibodies were consistently positive. Tests for HLA-DQB1 0201 and/or 0302 were positive. Anti-endomysium antibody seroconversion was seen in two patients, 2 and 6 years, respectively, after the diagnosis of diabetes. In another patient, the biopsy became abnormal 6 years after the first positive anti-endomysium antibody test (latent form). After a mean of 3 years on a gluten-free diet, significant increases were noted in body weight (P=0.04) and insulin dose (P=0.05); clinical symptoms completely resolved in five of the six symptomatic patients. CONCLUSIONS: The prevalence of celiac disease is higher in children with type 1 DM than in the general pediatric population. Serological screening is useful for diagnosing asymptomatic celiac disease, detecting seroconversion and monitoring latent forms of disease.

Advantages to using capillary blood beta-hydroxybutyrate determination for the detection and treatment of diabetic ketosis.

Ketone body determination is indicated in all diabetic patients when the risk of ketotic decompensation exists. New methods of screening for ketosis, in particular capillary blood ketone body determination, provide analytical, technical and clinical advantages compared to the conventional ketonuria. It is proposed that a diabetic patient with hyperglycaemia (capillary blood glucose > 2.50 g.l(-1)) and capillary blood ketone bodies exceeding 0.5 mmol.l(-1) requires therapeutic management. For values greater than 3 mmol.l(-1) or in case of more serious clinical symptoms, hospitalisation is indicated, considering the high probability of ketoacidotic decompensation. The advantages of capillary blood ketone body determination including easy use, and rapid and objective results may improve management of the diabetic patient, especially in emergency situations. However, prescription by a physician of capillary blood ketone body determination should be offered to targeted populations that have a high risk of ketoacidotic decompensation, after providing education to patients that is above all aimed at preventing this metabolic complication. In this context of determining ketone bodies in capillary blood, the term "capillary blood ketone bodies" is therefore preferable to the term "capillary blood beta-hydroxybutyrate determination". Indeed, it appears more appropriate, simple, descriptive and significant both for health-care staff and for patients.

Effects of fenofibrate on high and low density lipoprotein metabolism in heterozygous familial hypercholesterolemia.

This study investigates the influence of pharmacological doses of fenofibrate on HDL and LDL metabolism in 5 familial hypercholesterolemia heterozygotes. Fenofibrate lowered plasma low density lipoprotein cholesterol (20%, P less than 0.025), triglycerides (37%: P less than 0.005) and apolipoprotein B (14%: P less than 0.05) but increased apo A-I (20%; P = 0.01). Kinetic studies showed that the drug markedly increased the fractional catabolic rate of LDL-apo B by 59% and its synthetic rate by 36%. Fractional catabolic rate of apo A-I was also increased by 26% but accompanied by a much greater increase of its synthetic rate (49%). Thus the change in balance between catabolism and synthesis of both apoproteins affected by fenofibrate accounts for the observed plasma concentration changes, which may be considered as favourable with regard to the management of atherosclerosis.

Effect of sialic acid removal on human low density lipoprotein catabolism in vivo.

This study was undertaken to determine whether sialic acid removal alters the catabolism of low density lipoprotein in humans. Human low density lipoproteins labeled in vitro with 125I were incubated in the presence (termed desialylated) or absence (sialylated) of neuraminidase. The treatment with neuraminidase from Clostridium perfringens removed 90% of the sialic acid residues which did not change the chemical composition of the lipoproteins. Sialylated or desialylated LDL were injected intravenously into normal human subjects. The mathematical analysis of the plasma radioactivity decay curves (followed for 220 h) of desialylated low density lipoproteins, when compared with sialylated LDL, showed a shorter mean transit time (51 h vs 60 h), a 52% faster metabolic catabolic rate and an increased volume of distribution. The data are consistent with a proposed metabolism of low density lipoproteins: in humans, desialylation appears to accelerate the first step of the low density lipoprotein conversion but not to alter its final catabolism.

Kinetics of a heterogeneous population of particles in low density lipoprotein apolipoprotein B.

This paper examines the kinetics of low density lipoprotein (LDL) metabolism following the in vivo injection of native and chemically-modified lipoproteins in an attempt to assess the relative importance of receptor-dependent and receptor-independent catabolic pathways. The shape of the urinary/plasma ratio curve suggested heterogeneity of the LDL-apolipoprotein B pool and excluded homogeneity. This heterogeneity required the building of a more complex model that allowed the simultaneous fitting of plasma and urinary data. This new model permits the precise quantification of both receptor and non-receptor pathways.

Metabolism of apolipoprotein C-III in normolipemic human subjects.

Radioiodinated apolipoprotein C-III labeled either by the iodine monochloride procedure or by the Bolton-Hunter reagent were incubated in vitro with normal HDL. The labeled HDL-apo C-III, after ultracentrifugation and dialysis, was injected intravenously in 8 normolipidemic subjects. The label was followed in VLDL, IDL + LDL, HDL, d = 1.225 g/ml infranate as well as in total plasma and urine for the first time over a period of 2 weeks. Apolipoprotein C-III distributes readily between the different lipoprotein classes, only a small amount being present in the non-lipoprotein fraction. The percent distribution of apo C-III radioactivity and mass was found similar in VLDL, IDL and HDL using 3 different separation methods. Residence time in the whole system was 2.45 +/- 0.33 days. Fractional catabolic rates calculated from the urine/plasma radioactivity ratios or from the plasma curve were 0.731 +/- 0.096 and 0.767 +/- 0.125 pools/day. Synthetic rate was 2.28 +/- 0.32 mg/day/kg. The parameters seem not affected by the labeling procedure. The shapes of the plasma curve and of the urine/plasma ratio curve suggest a kinetic heterogeneity in the metabolism of apo C-III-containing particles.

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.

Metabolism of apolipoprotein C-I in normolipoproteinemic human subjects.

Labeling of apolipoprotein C-I by the Bolton and Hunter reagent allowed a study of the kinetics of this peptide in normolipidemic human volunteers. After its intravenous injection the appearance of radioactivity of the labeled apoprotein was followed in plasma, lipoprotein fractions, and urine for 15 days. Apolipoprotein C-I was quickly associated with HDL and to a smaller extent with VLDL in in vitro and in vivo incubation. Kinetic parameters of apolipoprotein C-I were compared with those of apo A-I. Fractional catabolic rates are respectively 0.422 +/- 0.044 vs 0.240 +/- 0.003 pools/day, residence times through the whole system 3.24 +/- 0.27 vs 6.31 +/- 0.27 days and production rates 1.79 +/- 0.18 vs 13.2 +/- 2.1 mg/kg X day. Two explanations for these differences are proposed.

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.

Comparing outcomes in renal replacement therapy: how should we correct for case mix?

The need to evaluate the effectiveness of clinical practice to justify expensive therapy in the face of financial constraints in all areas of health care delivery makes it necessary to identify groups of patients who are likely to benefit most from treatment. Various risk stratification methods have been used for analyzing survival probabilities for patients receiving renal replacement therapy. Complicated risk stratification methods produce large numbers of risk groups of small sizes, which makes comparison between individual centers difficult. We compared three simple methods of risk stratification, that divided patients into low-, medium-, and high-risk groups, in a cohort of 1,407 patients who commenced renal replacement therapy in five European countries during a 7-year period. Method 1 considered age (>55 years) and diabetes alone; method 2 used a higher age limit (>70 years) and comorbid illnesses, including those other than diabetes; and method 3 used only the number of comorbidities (none, 1, or > or =2) for stratification. Kaplan-Meier survival curves were constructed for comparison between risk groups and Cox's regression model used to assess strength of relationship with mortality. Although patient survival was significantly different between the low-, medium-, and high-risk groups using all three methods, Cox's regression analysis showed that method 2 provided the greatest discrimination between risk groups. In predicting mortality, method 2 (based on comorbidities and age) showed the highest sensitivity and specificity (84% and 80%, respectively) compared with method 1 (80% and 74%) and method 3 (64% and 82%). Validation of this approach in other populations in a prospective study is required before this method, which takes into account the influences of both age and comorbidity for risk stratification, can be used for comparing survival data and for presenting results of renal replacement therapy.

Regulation of calcium fluxes in the thyroid.

Calcium (Ca2+) exchanges were studied in dog thyroid slices incubated in vitro. With 45Ca2+-prelabeled slices, carbamylcholine 10(-7)-10(-5) M (Cchol) induced an important transitory spike efflux, inhibited by procaine and atropine while the stimulated efflux obtained with high concentrations of TSH (10 mU/ml) was progressive and sustained over time. The effects observed with both agents did not require extracellular Ca2+ and were insensitive to verapamil 10(-6)-10(-4) M. Neither dibutyryl (Bu2)-cAMP, nor any agent raising intracellular cAMP (prostaglandin E2, choleratoxin, inhibitors of phosphodiesterases with low concentrations of TSH) were able to reproduce the action of TSH 10 mU/ml, forskolin 10(-5) M being the only exception. Replacement of sodium by choline (+ atropine) in the incubation medium decreased the basal efflux and inhibited the TSH effect. Ouabain 10(-3) M also abolished the TSH-induced Ca2+ efflux, while having no influence on carbamylcholine action. TSH 10 mU/ml and 1 mU/ml, Bu2-cAMP 10(-3) M, choleratoxin and prostaglandin E2 with inhibitors of phosphodiesterase decreased the total 45Ca2+ uptake of the slices, while no effect of Cchol could be detected on this parameter. The results obtained suggest that (1) Cchol and TSH stimulate 45Ca2+ efflux from dog thyroid slices with different kinetics, by mobilization of intracellular Ca2+ stores; (2) this effect of TSH is not mediated by cAMP; (3) independently TSH at low concentrations (1 mU/ml), through cAMP, decreased 45Ca2+ uptake; this suggests that increased 45Ca2+ efflux and decreased uptake result from different mechanisms, as has been described for iodide exchange in FRTL-5 cells.

Apolipoprotein C-II and C-III metabolism in a kindred of familial hypobetalipoproteinemia.

Three affected members of a kindred with asymptomatic hypobetalipoproteinemia (HBL) showed low levels of triglycerides, low-density lipoprotein (LDL)-cholesterol, and apolipoproteins (apo) B, C-II, and C-III. Turnover of iodine-labeled apo C-II and apo C-III associated in vitro to plasma lipoproteins was studied after intravenous injection. Radioactivity in plasma and lipoproteins (95% recovered in high-density lipoprotein [HDL] density range) and in 24-hour urine samples was observed for 16 days. A parallelism of the slowest slopes of plasma decay curves was observed between apo C-II and apo C-III, indicating a partial common catabolic route. Urine/plasma radioactivity ratio (U/P) varied with time, suggesting heterogeneity of metabolic pathways. A new compartmental model using the SAAM program was built, not only fitting simultaneously plasma and urine data, but also taking into account the partial common metabolism of lipoprotein particles (LP) containing apo C-II and apo C-III. The low apo C-II and C-III plasma concentrations observed in HBL compared with normal resulted from both an increased catabolism and a reduced synthesis, these changes being more marked for apo C-III. The modifications in the rate constants of the different pathways calculated from the new model are in favor of an increased direct removal of particles following the fast pathway, likely in the very-low-density lipoprotein (VLDL) density range.

Receptor-dependent and -independent catabolism of low-density lipoprotein in a kindred with familial hypobetalipoproteinemia.

Three affected members of a kindred with asymptomatic hypobetalipoproteinemia (HBL) were injected intravenously with 125I-labeled native low-density lipoproteins (LDL) and 131I-labeled cyclohexanedione (CHD)-treated LDL. Plasma and urine radioactivity data were collected for 15 days at regular intervals. A compartmental model using the SAAM program was built to fit simultaneously 125I and 131I plasma radioactivity decay and urine excretion data. This model allows precise calculation of the kinetic parameters of both receptor-independent (NR) and receptor-dependent (R) pathways. Compared with normal subjects, HBL patients show a 90% increased fractional catabolic rate (FCR) of LDL by both routes, more marked for the R pathway (215% increase), and an approximately 50% reduced production rate (PR). Structural analysis did not show significant abnormalities of apolipoprotein (apo) B in HBL patients compared with normal. These data suggest that the very reduced, LDL-apo B plasma levels result from a combination of two processes: (1) an increased activity of all catabolic routes, and (2) a reduced "synthesis" rate. The latter may result from a decreased conversion of very-low-density lipoprotein (VLDL) to LDL secondary to an increased direct removal of large VLDL, suggested by apo C-II and C-III turnover studies previously reported.

A long-term study of the efficacy of oxandrolone in hyperlipoproteinemias.

Oxandrolone, an anabolic steroid, significantly reduced serum triglycerides in type III, IV, and V hyperlipoproteinemia, with a concomitant decrease in pre-beta lipoproteins. Its slightly enhancing effect on serum cholesterol and absolute increase in beta lipoproteins might eventually discourage its administration in type II patients. Alpha lipoproteins always remained at low levels. In addition to its hypotriglyceridemic action,, oxandrolone induced a slight reduction in uric acid and alkaline phosphatases. Untoward side effects were not observed even after prolonger therapy. Therefore, oxandrolone might deserve a place among the few available triglyceride-reducing therapies.

Effect of alcohol intake on high and low density lipoprotein metabolism in healthy volunteers.

To determine the effect of moderate doses of ethanol on lipoprotein metabolism, the kinetics of [125I]high density apolipoprotein (Apo) A-I and [131I]low density Apo B were examined in 9 normal volunteers before and after regular intake of 60-70 g of ethanol/day. Plasma levels of Apo B and Apo A-I were significantly increased but remained in the normal range. Mean synthesis of Apo A-I and B were increased, respectively, from 12.6 and 13.7 mg/kg per day in the absence of ethanol to 18.8 and 17.1 mg/kg/day after 2 wk of ethanol intake. Fractional catabolic rates for Apo A-I and B increased respectively from 0.204 and 0.340 in the period without ethanol to 0.266 and 0.372 after ethanol. These findings indicate that despite rather moderate increase in both Apo plasma levels, ethanol produced profound alterations in their metabolism, namely increased turnovers.

The effect of combined fenofibrate and cholestyramine therapy on low-density lipoprotein kinetics in familial hypercholesterolemia patients.

The effects of combined drug treatment (fenofibrate and cholestyramine) have been investigated in vivo by simultaneously determining total and receptor-independent LDL catabolism with 125I-labelled LDL and 131I-labelled LDL coupled with cyclohexanedione. Receptor-mediated catabolism of LDL determined as the difference between the turnover of 125I and 131I, was found to be reduced in heterozygotes with familial hypercholesterolemia. Treatment with combined fenofibrate and cholestyramine markedly stimulated both receptor-mediated (by more than 2-fold) and receptor-independent catabolism. LDL-Apo B and LDL-cholesterol levels were reduced by 38% and 36%, respectively. The combined treatment also reduced the absolute synthetic rate of LDL-Apo B (by 9%). The mechanisms responsible for these kinetic effects are discussed.