Low Density Lipoprotein Kinetics Research Articles

Stable Isotope Kinetic Study of ApoM (Apolipoprotein M).

ApoM (apolipoprotein M) binds primarily to high-density lipoprotein before to be exchanged with apoB (apolipoprotein B)-containing lipoproteins. Low-density lipoprotein (LDL) receptor-mediated clearance of apoB-containing particles could influence plasma apoM kinetics and decrease its antiatherogenic properties. In humans, we aimed to describe the interaction of apoM kinetics with other components of lipid metabolism to better define its potential benefit on atherosclerosis. Fourteen male subjects received a primed infusion of 2H3-leucine for 14 hours, and analyses were performed by liquid chromatography-tandem mass spectrometry from the hourly plasma samples. Fractional catabolic rates and production rates within lipoproteins were calculated using compartmental models. ApoM was found not only in high-density lipoprotein (59%) and LDL (4%) but also in a non-lipoprotein-related compartment (37%). The apoM distribution was heterogeneous within LDL and non-lipoprotein-related compartments according to plasma triglycerides (r=0.86; P<0.001). The relationships between sphingosine-1-phosphate and apoM were confirmed in all compartments (r range, 0.55-0.89; P<0.05). ApoM fractional catabolic rates and production rates were 0.16±0.07 pool/d and 0.14±0.06 mg/kg per day in high-density lipoprotein and 0.56±0.10 pool/d and 0.03±0.01 mg/kg per day in LDL, respectively. Fractional catabolic rates of LDL-apoM and LDL-apoB100 were correlated (r=0.55; P=0.042). Significant correlations were found between triglycerides and production rates of LDL-apoM (r=0.73; P<0.004). In humans, LDL kinetics play a key role in apoM turnover. Plasma triglycerides act on both apoM and sphingosine-1-phosphate distributions between lipoproteins. These results confirmed that apoM could be bound to high-density lipoprotein after secretion and then quickly exchanged with a non-lipoprotein-related compartment and to LDL to be slowly catabolized.

Low-dose dexamethasone administration for 3 weeks favorably affects plasma HDL concentration and composition but does not affect very low-density lipoprotein kinetics

Subclinical hypercortisolemia often occurs in subjects with features of the metabolic syndrome, and it has been suggested that it may be, at least in part, responsible for the development of these metabolic abnormalities. However, the metabolic effects of glucocorticoid administration to mimic subclinical glucocorticoid excess have not been evaluated. We used stable isotope-labeled tracer methods in conjunction with magnetic resonance techniques to measure the effect of glucocorticoid excess within the physiological range (~0.7 mg dexamethasone/day for 3 weeks) on glucose and free fatty acid (FFA) rates of appearance (Ra) into plasma, intrahepatic triglyceride (TG) content, very low-density lipoprotein (VLDL)-TG and VLDL-apolipoprotein B-100 (apoB-100) kinetics and plasma lipoprotein subclass concentrations, and particle sizes in nine overweight and obese individuals. Dexamethasone treatment led to a very small but significant increase in body weight (from 87.4±7.1 to 88.6±7.2 kg; P=0.003) and increased HDL-cholesterol (from 45.9±2.8 to 55.1±4.6 mg/dl; P=0.037) and HDL particle (from 33.7±2.2 to 41.4±4.2 nmol/l; P=0.023) concentrations in plasma but had no effect on intrahepatic TG content, glucose and FFA Ra in plasma, hepatic VLDL-TG and VLDL-apoB-100 secretion rates and mean residence times in the circulation, plasma TG and LDL-cholesterol concentrations, and plasma lipoprotein particle sizes. Subclinical hypercortisolemia does not have significant adverse metabolic consequences.

Effect of Fenofibrate and Niacin on Intrahepatic Triglyceride Content, Very Low-Density Lipoprotein Kinetics, and Insulin Action in Obese Subjects with Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease is associated with risk factors for cardiovascular disease, particularly increased plasma triglyceride (TG) concentrations and insulin resistance. Fenofibrate and extended release nicotinic acid (Niaspan) are used to treat hypertriglyceridemia and can affect fatty acid oxidation and plasma free fatty acid concentrations, which influence intrahepatic triglyceride (IHTG) content and metabolic function. The objective of the study was to determine the effects of fenofibrate and nicotinic acid therapy on IHTG content and cardiovascular risk factors. EXPERIMENTAL DESIGN AND MAIN OUTCOME MEASURES: We conducted a randomized, controlled trial to determine the effects of fenofibrate (8 wk, 200 mg/d), Niaspan (16 wk, 2000 mg/d), or placebo (8 wk) on IHTG content, very low-density lipoprotein (VLDL) kinetics, and insulin sensitivity. Twenty-seven obese subjects with nonalcoholic fatty liver disease (body mass index 36 +/- 1 kg/m(2), IHTG 23 +/- 2%) were studied at Washington University. Neither fenofibrate nor Niaspan affected IHTG content, but both decreased plasma TG, VLDL-TG, and VLDL-apolipoprotein B concentrations (P < 0.05). Fenofibrate increased VLDL-TG clearance from plasma (33 to 54 ml/min; P < 0.05) but not VLDL-TG secretion. Niaspan decreased VLDL-TG secretion (27 to 15 micromol/min; P < 0.05) without affecting clearance. Both fenofibrate and Niaspan decreased VLDL-apolipoprotein B secretion (1.6 to 1.2 and 1.3 to 0.9 nmol/min, respectively; P < 0.05). Niaspan reduced hepatic, adipose tissue, and muscle insulin sensitivity (P < 0.05), whereas fenofibrate had no effect on insulin action. Fenofibrate and Niaspan decrease plasma VLDL-TG concentration without altering IHTG content. However, the mechanism responsible for the change in VLDL-TG concentration is different for each drug; fenofibrate increases plasma VLDL-TG clearance, whereas nicotinic acid decreases VLDL-TG secretion.

Effect of 6-month supervised exercise on low-density lipoprotein apolipoprotein B kinetics in patients with type 2 diabetes mellitus

Although low-density lipoprotein (LDL) cholesterol is often normal in patients with type 2 diabetes mellitus, there is evidence for a reduced fractional catabolic rate and consequently an increased mean residence time (MRT), which can increase atherogenic risk. The dyslipidemia and insulin resistance of type 2 diabetes mellitus can be improved by aerobic exercise, but effects on LDL kinetics are unknown. The effect of 6-month supervised exercise on LDL apolipoprotein B kinetics was studied in a group of 17 patients with type 2 diabetes mellitus (mean age, 56.8 years; range, 38-68 years). Patients were randomized into a supervised group, who had a weekly training session, and an unsupervised group. LDL kinetics were measured with an infusion of 1- 13C leucine at baseline in all groups and after 6 months of exercise in the patients. Eight body mass index–matched nondiabetic controls (mean age, 50.3 years; range, 40-67 years) were also studied at baseline only. At baseline, LDL MRT was significantly longer in the diabetic patients, whereas LDL production rate and fractional clearance rates were significantly lower than in controls. Percentage of glycated hemoglobin A 1c, body mass index, insulin sensitivity measured by the homeostasis model assessment, and very low-density lipoprotein triglyceride decreased ( P < .02) in the supervised group, with no change in the unsupervised group. After 6 months, LDL cholesterol did not change in either the supervised or unsupervised group; but there was a significant change in LDL MRT between groups ( P < .05) that correlated positively with very low-density lipoprotein triglyceride ( r = 0.51, P < .04) and negatively with maximal oxygen uptake, a measure of fitness ( r = −0.51, P = .035), in all patients. The LDL production and clearance rates did not change in either group. This study suggests that a supervised exercise program can reduce deleterious changes in LDL MRT.

Development of a novel method to determine very low density lipoprotein kinetics

Isotopic tracer methods of determining triglyceride-rich lipoprotein (TRL) kinetics are costly, time-consuming, and labor-intensive. This study aimed to develop a simpler and cost-effective method of obtaining TRL kinetic data, based on the fact that chylomicrons compete with large VLDL (VLDL(1); S(f) = 60-400) for the same catalytic pathway. Ten healthy subjects [seven men; fasting triglyceride (TG), 44.3-407.6 mg/dl; body mass index, 21-35 kg/m(2)] were given an intravenous infusion of a chylomicron-like TG emulsion (Intralipid; 0.1 g/kg bolus followed by 0.1 g/kg/h infusion) for 75-120 min to prevent the clearance of VLDL(1) by lipoprotein lipase. Multiple blood samples were taken during and after infusion for separation of Intralipid, VLDL(1), and VLDL(2) by ultracentrifugation. VLDL(1)-apolipoprotein B (apoB) and TG production rates were calculated from their linear increases in the VLDL(1) fraction during the infusion. Intralipid-TG clearance rate was determined from its exponential decay after infusion. The production rates of VLDL(1)-apoB and VLDL(1)-TG were (mean +/- SEM) 25.4 +/- 3.9 and 1,076.7 +/- 224.7 mg/h, respectively, and the Intralipid-TG clearance rate was 66.9 +/- 11.7 pools/day. Kinetic data obtained from this method agree with values obtained from stable isotope methods and show the expected relationships with indices of body fatness and insulin resistance (all P < 0.05). The protocol is relatively quick, inexpensive, and transferable to nonspecialist laboratories.

1.P.113 The effects of dietary fish oil on serum lipids and very low density lipoprotein-kinetics in hyperlipidemic apolipoprotein E∗3-Leiden transgenic mice

1.P.113 The effects of dietary fish oil on serum lipids and very low density lipoprotein-kinetics in hyperlipidemic apolipoprotein E∗3-Leiden transgenic mice

Effect of L-carnitine treatment on very low density lipoprotein kinetics in the hyperlipidemic rabbit

This study examined the hypolipidemic effect of 4 weeks of L-carnitine treatment (170 mg/kg b.w./day) in New Zealand White rabbits fed a high fat diet (5% corn oil/0.5% cholesterol). Specifically, [ 3H] glycerol and [ 125I] very low density lipoprotein (VLDL) turnover studies were conducted to examine the effect of treatment on VLDL kinetics. The masses of plasma VLDL-triglycerides (VLDL-TG) and VLDL-apoprotein B (VLDL-apoB) were significantly increased by the high-fat diet. Four weeks of treatment with L-carnitine significantly reduced these masses. Kinetic analysis indicated that fat feeding reduced the fractional catabolic rates (FCRs) of VLDL-TG and VLDL-apoB relative to chow-fed controls. The transport of these VLDL components was not altered by the diet. L.-carnitine treatment had no effect on the FCRs of VLDL-TG and VLDL-apoB or on the transport of VLDL-apoB. Yet, treatment significantly lowered the transport of VLDL-TG. These data indicate that the lipid-lowering effect of L-carnitine in this animal model was due, in part, to a decrease in the transport and not due to an alteration in the fractional catabolic rate of VLDL-TG.

Effects of simvastatin on apoB metabolism and LDL subfraction distribution.

Seven moderately hypercholesterolemic subjects were studied before and after 10 weeks of simvastatin therapy (20 mg/day). Therapy reduced low density lipoprotein (LDL) cholesterol by 39% (p < 0.001), whereas high density lipoprotein and very low density lipoprotein (VLDL) cholesterol were unchanged. Apolipoprotein (apo) B-containing lipoproteins were divided into VLDL1 (Sf 60-400), VLDL2 (Sf 20-60), intermediate density lipoprotein (IDL) (Sf 12-20), and LDL (Sf 0-12), and metabolic changes were sought in dual-tracer VLDL1 and VLDL2 turnover studies. VLDL1 apoB pool size was unaltered by therapy, as were its rates of synthesis, catabolism, and delipidation to VLDL2. Similarly, the VLDL2 apoB pool size was unchanged, but its metabolic fate was altered. The IDL pool size fell significantly (27%, p < 0.01) due entirely to an increased fractional catabolism of the lipoprotein. In our subjects, the circulating mass of LDL apoB decreased (49%, p < 0.01) primarily due to a reduction in its synthesis. Before therapy, 30% of the apoB entering the delipidation cascade in these hyperlipidemic subjects was converted to LDL. On therapy the input remained the same, but direct catabolism from VLDL2 and IDL was increased (p < 0.05), and as a result only 16% eventually appeared in LDL. These kinetic changes were associated with a fall in particle cholesteryl ester content throughout the delipidation cascade. We also observed a link between LDL kinetics and its subfraction distribution. Simvastatin influences the metabolism of LDL, IDL, and VLDL2 but not VLDL1.

Cholesterol absorption, elimination, and synthesis related to LDL kinetics during varying fat intake in men with different apoprotein E phenotypes.

Cholesterol absorption, fecal elimination, and synthesis and low density lipoprotein (LDL) metabolism were measured in 29 middle-aged men while on their normal diet and a diet low in fat and cholesterol, and the obtained values were related to apoprotein (apo) E phenotypes. Basal cholesterol absorption efficiency was positively related to production rate (PR) for LDL apo B and negatively to cholesterol synthesis (measured by fecal steroids and dietary cholesterol), which in turn was negatively associated with the LDL level and positively with the fractional removal (FCR) of LDL apo B. The apo E subscript (e.g., E2/2 = 1, E2/3 = 2, etc.) was positively associated with cholesterol absorption and the LDL apo B and cholesterol levels and negatively with cholesterol synthesis and FCR for LDL apo B. Effective bile acid and cholesterol synthesis, fecal elimination of cholesterol, removal of LDL apo B, and low cholesterol absorption characterized men with the epsilon 2 allele. Reduction of dietary fat and cholesterol intakes lowered LDL cholesterol levels and cholesterol absorption but increased cholesterol synthesis proportionally to the apo E subscript; the FCR and PR for LDL apo B were significantly increased and decreased, respectively. The decrease in absorption was related to enhanced removal of LDL apo B and synthesis of cholesterol. During the modified diet, cholesterol metabolism was poorly related to LDL, apo E phenotypes, and LDL apo B kinetics. A positive correlation of cholesterol absorption with dietary fat intake in combined studies suggests that a dietary fat reduction-associated decrease in LDL cholesterol is at least partly caused by reduced cholesterol absorption.(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of guinea pig plasma low density lipoprotein kinetics by dietary fat saturation.

Dietary fat saturation has been shown to affect hepatic apoB/E receptor expression and to modify low density lipoprotein (LDL) composition and density in guinea pigs. The current studies were designed to investigate the independent and interactive effects of dietary fat saturation alterations in apoB/E receptor expression and LDL composition on in vivo LDL turnover kinetics, both receptor-mediated and receptor-independent. Guinea pigs were fed semi-purified diets containing 15% fat, either polyunsaturated corn oil (CO), monounsaturated olive oil (OL), or saturated lard, and injected with radioiodinated LDL isolated from animals fed the homologous diet. Blood samples were obtained over 33 h to determine apoLDL fractional catabolic rates (FCR) and flux rates. Compared to animals fed OL- or lard-based diets, intake of the CO-based diet resulted in a 50% decrease in LDL apoB pool size associated with a twofold increase in receptor-mediated FCR (P less than 0.001) and a 28% decrease in flux rate (P less than 0.05). Maximal LDL binding capacity of hepatic apoB/E receptors, determined in vitro, was twofold higher for animals fed the CO-based diet compared to guinea pigs fed the OL- and lard-based diets (P less than 0.01). There was a significant correlation between hepatic apoB/E receptor number and in vivo receptor-mediated LDL FCR (r = 0.987). Significant differences in LDL turnover were related to the source of LDL. When injected into animals fed a nonpurified commercial diet, the smaller, cholesteryl ester-depleted LDL isolated from animals fed the CO-based diet had a twofold higher FCR compared to larger LDLs from guinea pigs fed the OL- and lard-based diets, which had similar turnover rates. When LDL from animals fed the commercial diet was radiolabeled and injected into animals fed the three types of dietary fat, significant differences in LDL turnover were observed in the order CO greater than lard greater than OL, suggesting that intravascular processing and tissue uptake of the smaller LDL from animals fed the commercial diet varies depending on the dietary fat saturation fed to the recipient animals. These studies demonstrate that guinea pigs fed polyunsaturated fat diets lower plasma LDL levels in part by an increase in apoB/E receptor-mediated fractional LDL turnover and a decrease in apoLDL flux. In addition, fat saturation alters LDL composition and size which independently affect LDL turnover rates in vivo.

Metabolic basis of primary hypercholesterolemia.

Hypercholesterolemia is a well-established risk factor for coronary heart disease. However, the mechanisms underlying hypercholesterolemia, elevated low density lipoprotein (LDL) in particular, are not well understood. To determine these mechanisms, we studied LDL kinetics in a group of men with primary hypercholesterolemia. LDL kinetics in 134 middle-aged men with high-risk levels of LDL cholesterol (more than 160 mg/dl) were compared with kinetics in 16 men with borderline high-risk levels of LDL cholesterol (120-159 mg/dl) and 14 men with heterozygous familial hypercholesterolemia (FH). Patients with primary hypercholesterolemia (non-FH) were further divided into moderate hypercholesterolemia (LDL cholesterol, 160-210 mg/dl; n = 108) and severe hypercholesterolemia groups (LDL cholesterol, more than 210 mg/dl; n = 26). Four factors contributed to increasing LDL cholesterol concentrations above the borderline range to moderately elevated levels: 37 patients had no increase in LDL apolipoprotein (apo) B levels but had abnormally high LDL cholesterol-to-apo B ratios; 14 patients had very low fractional catabolic rates (FCRs) for LDL, similar to FH patients; 35 patients had FCRs for LDL in the borderline range but high production rates for LDL; and 22 patients had a high flux of LDL (high production rates and high FCRs). In general, patients with severe hypercholesterolemia resembled those with moderate LDL elevations, except that their LDL particles were enriched with cholesterol. Data from the present study reveal that there are several distinct patterns of LDL metabolism responsible for primary hypercholesterolemia. These patterns can serve as the basis for further investigation to determine the molecular defects responsible for each pattern.

Low density lipoprotein kinetics in a family having defective low density lipoprotein receptors in which hypercholesterolemia is suppressed.

Heterozygous familial hypercholesterolemia (FH) usually presents with severe elevations of low density lipoprotein (LDL) cholesterol. Recently, a family with FH was described in which several members heterozygous for a mutation in the LDL receptor gene had normal LDL cholesterol levels. Kinetic studies of LDL apolipoprotein B (apo B) were conducted to determine the metabolic differences between the normolipidemic and hypercholesterolemic FH heterozygotes in the family. Studies were performed in 14 family members including the proband (who has homozygous FH), four FH heterozygotes with high LDL levels, four FH subjects with normolipidemia, and five healthy relatives without FH. The proband had a very low fractional catabolic rate (FCR) for LDL (0.15 pool/day). All the FH and non-FH subjects studied, excluding the FH homozygote, had higher than expected FCRs for LDL. The average FCRs for LDL of hypercholesterolemic and normocholesterolemic subjects were not significantly different (0.39 +/- 0.06 versus 0.37 +/- 0.02 pool/day), and these values were 70-80% of those in unaffected relatives. Compared with hypercholesterolemic FH heterozygotes, normolipidemic heterozygotes had much lower input rates for LDL (17.1 +/- author query macros2.6 versus 8.7 +/- 0.9 pools/day, respectively). These low input rates, together with the higher than usual FCRs for LDL, are responsible for the normal concentrations of LDL cholesterol in some of the FH heterozygotes. The low input of LDL could be due to either a decreased secretion of apo B-containing lipoproteins or an enhanced clearance of LDL precursor lipoproteins.

Genetic epidemiology of differences in low‐density lipoprotein (LDL) cholesterol concentration: Possible involvement of variation at the apolipoprotein B gene locus in LDL kinetics

Circulating levels of low-density lipoprotein (LDL) vary considerably within and between populations, paralleled by differing coronary heart disease (CHD) mortality rates. We have previously shown that variation in the apolipoprotein (apo) B gene as associated with certain restriction fragment length polymorphisms (RFLPs) influences the metabolism of LDL in the U.K. population. To investigate a possible genetic contribution to variation in LDL levels in differing populations we have extended this original study. RFLPs of the apo B gene were determined in samples of individuals from the United Kingdom, Finland, Italy, Spain, and Africa. Significant associations of LDL fractional catabolic rate with the apo B EcoRI and XbaI RFLP genotypes were detected only in the two North European populations. In the African population sample, the XbaI RFLP displayed a significant association with LDL apo B synthesis. The data suggest that variation in the apo B gene influences the metabolism of LDL and that it is different in individuals of different ethnic background.

Effect of dietary fat saturation and cholesterol on LDL composition and metabolism. In vivo studies of receptor and nonreceptor-mediated catabolism of LDL in cebus monkeys.

The mechanism(s) by which polyunsaturated fats reduce low density lipoprotein (LDL) cholesterol and apolipoprotein (apo) B were investigated in 20 cebus monkeys (Cebus albifrons) fed diets containing corn oil or coconut oil as fat (31% of calories) with or without dietary cholesterol (0.1% by weight) for 3 to 10 years. Coconut-oil feeding compared to corn-oil feeding resulted in significant increases in levels of plasma total cholesterol (176%), very low density lipoprotein (VLDL)-LDL cholesterol (236%), high density lipoprotein (HDL) cholesterol (148%), apo B (78%), and apo A-I (112%). The addition of dietary cholesterol to corn oil compared to corn oil alone resulted in smaller, but significant, increases in levels of total cholesterol (44%), HDL cholesterol (40%), and apo A-I (33%). Although the increases in VLDL-LDL cholesterol were of similar magnitude (52%), they barely failed to reach statistical significance (p less than 0.08), while the changes in apo B levels were negligible. The addition of dietary cholesterol to coconut oil, compared to coconut oil alone, resulted in no significant changes in lipoprotein cholesterol or apoproteins, although levels of VLDL-LDL cholesterol and apo B values increased 22% and 16%, respectively. Although hepatic free cholesterol content was not altered by diet, coconut-oil compared to corn-oil feeding resulted in significant increases in hepatic cholesteryl esters (236%) and triglycerides (325%), the latter increasing still further when dietary cholesterol was added to coconut oil (563%). To further assess the effects of these dietary changes on LDL metabolism, radioiodinated normal and glucosylated LDL kinetics were performed. The production rate of LDL apo B was not altered by diet. With corn-oil feeding, 63% of LDL catabolism was via the receptor-mediated pathway. Coconut-oil compared to corn-oil feeding resulted in a 50% decrease in receptor-mediated LDL apo B fractional catabolic rate (FCR) and a 27% reduction in nonreceptor-mediated LDL apo B FCR. The addition of dietary cholesterol to corn oil, compared to corn oil alone, resulted in no significant effect on LDL apo B catabolism. The addition of dietary cholesterol to coconut oil, compared to coconut oil alone, was associated with no significant change in nonreceptor catabolism of LDL apo B but with a 58% decrease in receptor-mediated catabolism of LDL (p less than 0.059). The diet-induced alterations of LDL catabolism were significantly correlated with hepatic lipids, which were enriched in saturated fatty acids.(ABSTRACT TRUNCATED AT 400 WORDS)

Low density lipoprotein kinetics in African Green monkeys showing variable cholesterolaemic responses to diets realistic for westernised people

African Green (vervet) monkeys were fed either an atherogenic Western diet (WD), a prudent diet (PD), or a high carbohydrate diet (HCD) for various lengths of time. Monkeys differed greatly in their response to the WD, and a strong negative correlation was observed between the fractional catabolic rates (FCR) of low density lipoprotein (LDL) and the total plasma cholesterol concentrations ( r = −0.83 P = 0.0029). Similarly the individual synthetic rates (SR) of LDL plotted against the total plasma cholesterol concentrations showed a correlation coefficient of r = 0.94 P = 0.01 for WD animals. There was no correlation for PD or HCD animals for either SR or FCR and the total plasma cholesterol concentrations. The aortic lesion scores correlated with the SRs ( r = 0.66 P = 0.040) but not with the FCRs. LDL turnover was also studied using 125I-labelled native LDL and methylated 131I-labelled LDL in African Green monkeys showing high or low cholesterolaemic response to an atherogenic Western diet. Measurements after 4 weeks and again after 6 months on the diet showed a decrease in both total and non-receptor mediated clearance of LDL. Receptor-mediated catabolism was significantly lowered in the hyperresponding group ( P = 0.0011) and not in the hyporesponding group with a resultant significant difference between the two groups being P = 0.0355 after 6 months. Non-receptor mediated catabolism of LDL was similarly affected in that there was no significant difference between the two groups at 4 weeks but the clearance of methylated LDL was markedly lowered at 6 months, for the hyporesponding group P = 0.0003 and for the hyperresponding group P = 0.0184. Furthermore the hyperresponding group was depressed to a significantly greater extent when compared to the hyporesponding group ( P = 0.0241).

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.

In search of a relationship between physiologically-induced variations in adipose tissue lipoprotein lipase activity and very low density lipoprotein kinetics in normal rats

The relationship between total and heparin-releasable adipose tissue lipoprotein lipase (LPL) activity and very low density lipoprotein (VLDL0-triglyceride (TG) removal rate was studied in normal rats. Significant variation in both total and heparin-releasable adipose tissue LPL activity could be induced by changing diet and/or time of day at which the measurements were made. However, these maneuvers did not seem to modify VLDL-TG kinetics, and substantial variations (both increases and decreases) in LPL activity could be produced without altering VLDL-TG removal. These data indicate that quantitative variations in adipose tissue LPL activity as directly measured do not give rise to useful insights into VLDL-TG kinetics.

Relationship between insulin resistance, insulin secretion, very low density lipoprotein kinetics, and plasma triglyceride levels in normotriglyceridemic man

We have previously postulated that resistance to insulin-mediated glucose uptake was the basic metabolic abnormality in patients with endogenous hypertriglyceridemia. In this situation, glucose tolerance would tend to deteriorate, and could only be maintained by the increased secretion of insulin. Although the ensuing hyperinsulinemia might prevent the development of glucose intolerance, we suggested that it would also lead to increased hepatic very low density (VLDL) triglyceride (TG) synthesis and secretion. In the current study we have quantified these four metabolic variables in 16 nonobese human subjects with plasma TG concentrations < 175 mg/dl. The results demonstrate the following degree of correlation: insulin resistance ▪ insulin response to food ▪ VLDL-TG secretion rate ▪ plasma TG concentration. These data indicate that nonobese subjects with normal TG levels have the same relationship between degree of insulin sensitivity, insulin response to food, VLDL-TG secretion, and TG concentration previously described in patients with endogenous hypertriglyceridemia.