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Clearance from plasma of triacylglycerol and cholesteryl ester after intravenous injection of chylomicron-like lipid emulsions in rats and man.

ABSTRACT: Chylomicrons transport fat and cholesterol via lymphatic vessels from the intestine into the bloodstream. The understanding of the metabolism of chylomicrons in man has been slowed by the difficulty of obtaining lymph chylomicrons for experimental studies. Acceptable methods for the study of chylomicron clearance in man are required, because the metabolism of chylomicrons may be abnormal in diseases such as diabetes mellitus. Metabolism of chylomicrons may also play a role in the development of atherosclerosis. In the present work, lipid emulsions were used as a physical model of chylomicrons. Triacylglycerol-rich lipid emulsions labelled with tracer amounts of radioactive triolein and cholesteryl oleate were prepared by sonication and purified by density gradient ultracentrifugation, then injected into unanaesthetized rats and normal human subjects. Plasma radioactivities were measured for 30 min in rats and 90 min in human subjects. Rat lymph chylomicrons were also injected into rats for comparison with the clearance of the lipid emulsions. The plasma clearance data for triacylglycerols and cholesteryl esters were fitted with a kinetic model using the SAAM/CONSAM programs. Multiple studies analysis of the individual studies in each group was used to obtain estimates of the parameter average values and variabilities. The plasma residence times of the lipid labels were obtained from the fitted clearance data. Our results suggest that information about chylomicron metabolism in man can be obtained by analysis of the plasma clearance data following the injection of suitably labelled chylomicron-like lipid emulsions. Our data provide a baseline for comparisons with individuals having abnormalities of lipid metabolism or risk factors for arteriosclerosis.

SUBMITTER: Redgrave TG

PROVIDER: S-EPMC1132358 | biostudies-other | 1993 Mar

REPOSITORIES: biostudies-other

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Project description:Context:Glucagon-like peptide-1 (GLP-1) agonists control postprandial glucose and lipid excursion in type 2 diabetes; however, the mechanisms are unclear. Objective:To determine the mechanisms of postprandial lipid and glucose control with lixisenatide (GLP-1 analog) in type 2 diabetes. Design:Randomized, double-blind, cross-over study. Setting:Centre for Diabetes, Endocrinology, and Research, Royal Surrey County Hospital, Guildford, United Kingdom. Patients:Eight obese men with type 2 diabetes [age, 57.3 ± 1.9 years; body mass index, 30.3 ± 1.0 kg/m2; glycosylated hemoglobin, 66.5 ± 2.6 mmol/mol (8.2% ± 0.3%)]. Interventions:Two metabolic studies, 4 weeks after lixisenatide or placebo, with cross-over and repetition of studies. Main Outcome Measures:Study one: very-low-density lipoprotein (VLDL) and chylomicron (CM) triacylglycerol (TAG) kinetics were measured with an IV bolus of [2H5]glycerol in a 12-hour study, with hourly feeding. Oral [13C]triolein, in a single meal, labeled enterally derived TAG. Study two: glucose kinetics were measured with [U-13C]glucose in a mixed-meal (plus acetaminophen to measure gastric emptying) and variable IV [6,6-2H2]glucose infusion. Results:Study one: CM-TAG (but not VLDL-TAG) pool-size was lower with lixisenatide (P = 0.046). Lixisenatide reduced CM [13C]oleate area under the curve (AUC)60-480min concentration (P = 0.048) and increased CM-TAG clearance, with no effect on CM-TAG production rate. Study two: postprandial glucose and insulin AUC0-240min were reduced with lixisenatide (P = 0.0051; P < 0.05). Total glucose production (P = 0.015), rate of glucose appearance from the meal (P = 0.0098), and acetaminophen AUC0-360min (P = 0.006) were lower with lixisenatide than with placebo. Conclusions:Lixisenatide reduced [13C]oleate concentrations, derived from a single meal in CM-TAG and glucose rate of appearance from the meal through delayed gastric emptying. However, day-long CM production, measured with repeated meal feeding, was not reduced by lixisenatide and decreased CM-TAG concentration resulted from increased CM-TAG clearance.

Project description:1. The cholesteryl ester of isolated chylomicron-remnant particles was efficiently degraded by hepatocyte monolayers. The degradation was sensitive to metabolic inhibitors. 2. With increasing amounts of remnant cholesteryl ester the rate of uptake approached saturation and conformed to a linear double-reciprocal plot. The V(max.) was determined as 80ng of cholesteryl ester/h per mg of protein and the apparent K(m) as 1.4mug of cholesteryl ester per mg of protein. The time course for the uptake and hydrolysis suggested that binding of particles to the cell surface preceded the degradation. 3. Cholesteryl esters of native chylomicrons were degraded to a much smaller extent and their presence had only a small inhibitory effect on the degradation of chylomicron remnants. Intestinal very-low-density lipoproteins were degraded somewhat faster than chylomicrons, and caused more inhibition of remnant degradation. Rat high-density lipoproteins inhibited the hydrolysis of remnant cholesteryl ester by up to 50%, but had less influence on the amount of cholesteryl ester that was bound to the cells. Serum decreased both the uptake and hydrolysis, whereas d=1.21 infranatant had no effect. 4. The cholesteryl ester hydrolysis after the uptake by the cells was inhibited by chloroquine and by colchicine. Only 28-36% of the unhydrolysed cholesteryl ester could be released from these cells by trypsin treatment, indicating that the major portion was truly intracellular. The particles that could be released from the cell surface by trypsin and those remaining in the medium had the same triacylglycerol/cholesteryl ester ratio as the added remnant particles. Significant amounts of denser particles were thus not formed during contact with the cell surface. 5. The presence of heparin, as well as preincubation of the cells with heparin, increased the uptake of chylomicron remnants. This effect was most marked in the presence of serum. A much smaller proportion of the other serum lipoproteins was taken up, and this proportion was not increased by heparin.

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Clearance from plasma of triacylglycerol and cholesteryl ester after intravenous injection of chylomicron-like lipid emulsions in rats and man.

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