LDL-apoB Fractional Catabolic Rate Research Articles

Lipoprotein (a) and Low-density lipoprotein apolipoprotein B metabolism following apheresis in patients with elevated lipoprotein(a) and coronary artery disease.

Lipoprotein apheresis effectively lowers lipoprotein(a) [Lp(a)] and low-density lipoprotein (LDL) by approximately 60%-70%. The rebound of LDL and Lp(a) particle concentrations following lipoprotein apheresis allows the determination of fractional catabolic rate (FCR) and hence production rate (PR) during non-steady state conditions. We aimed to investigate the kinetics of Lp(a) and LDL apolipoprotein B-100 (apoB) particles in patients with elevated Lp(a) and coronary artery disease undergoing regular apheresis. A cross-sectional study was carried out in 13 patients with elevated Lp(a) concentration (>500mg/L) and coronary artery disease. Lp(a) and LDL-apoB metabolic parameters, including FCR and PR were derived by the fit of a compartment model to the Lp(a) and LDL-apoB concentration data following lipoprotein apheresis. The FCR of Lp(a) was significantly lower than that of LDL-apoB (0.39 [0.31, 0.49] vs 0.57 [0.46, 0.71] pools/day, P=0.03) with no significant differences in the corresponding PR (14.80 [11.34, 19.32] vs 15.73 [11.93, 20.75] mg/kg/day, P=0.80). No significant associations were observed between the FCR and PR of Lp(a) and LDL-apoB. In patients with elevated Lp(a), the fractional catabolism of Lp(a) is slower than that of LDL-apoB particles, implying that different metabolic pathways are involved in the catabolism of these lipoproteins. These findings have implications for new therapies for lowering apolipoprotein(a) and apoB to prevent atherosclerotic cardiovascular disease.

Lipoprotein Metabolism in APOB L343V Familial Hypobetalipoproteinemia.

Familial hypobetalipoproteinemia (FHBL) is a codominant disorder of lipoprotein metabolism characterized by decreased plasma concentrations of low-density lipoprotein (LDL)-cholesterol and apolipoprotein B (apoB). The objective was to examine the effect of heterozygous APOB L343V FHBL on postprandial triglyceride-rich lipoprotein (TRL) and fasting lipoprotein metabolism. Plasma incremental area under the curve apoB-48 and apoB-48 kinetics were determined after ingestion of a standardized oral fat load using compartmental modeling. Very low-density lipoprotein (VLDL)-, intermediate-density lipoprotein (IDL)-, and LDL-apoB kinetics were determined in the fasting state using stable isotope methods and compartmental modeling. The postprandial incremental area under the curve (0-10 h) in FHBL subjects (n = 3) was lower for large TRL-triglyceride (-77%; P < .0001), small TRL-cholesterol (-83%; P < .001), small TRL-triglyceride (-88%; P < .001), and for plasma triglyceride (-70%; P < .01) and apoB (-63%; P < .0001) compared with controls. Compartmental analysis showed that apoB-48 production was lower (-91%; P < .05) compared with controls. VLDL-apoB concentrations in FHBL subjects (n = 2) were lower by more than 75% compared with healthy, normolipidemic control subjects (P < .01). The VLDL-apoB fractional catabolic rate (FCR) was more than 5-fold higher in the FHBL subjects (P = .07). ApoB production rates and IDL- and LDL-apoB FCRs were not different between FHBL subjects and controls. We conclude that when compared to controls, APOB L343V FHBL heterozygotes show lower TRL production with normal postprandial TRL particle clearance. In contrast, VLDL-apoB production was normal, whereas the FCR was higher in heterozygotes compared with lean control subjects. These mechanisms account for the marked hypolipidemic state observed in these FHBL subjects.

Abstract 236: Lipoprotein Metabolism in APOB L343V Familial Hypobetalipoproteinemia

Familial hypobetalipoproteinemia (FHBL) is a codominant disorder of lipoprotein metabolism characterized by decreased plasma concentrations of LDL-cholesterol and apolipoprotein (apo) B. We examined the effect of heterozygous APOB L343V FHBL on fasting and postprandial lipoprotein metabolism. VLDL, IDL-, and LDL-apoB kinetics were determined in the fasting state using stable isotope methods and compartmental modeling. VLDL-apoB concentrations in FHBL subjects (n=2) were reduced by more than 75% compared to healthy, normolipidemic control subjects ( P &lt;0.01). VLDL-apoB fractional catabolic rate (FCR) was more than 5-fold higher in the FHBL subjects ( P =0.07). ApoB production rates and IDL- and LDL-apoB FCRs were not different between FHBL subjects and controls. To assess postprandial lipoprotein metabolism, a standardized oral fat load was given after a 12 h fast to heterozygous APOB L343V FHBL subjects (n=3) and normolipidemic controls. The postprandial incremental area under the curve (0-10 h) in FHBL subjects was decreased for large TRL-triglyceride (-77%; P &lt;0.0001), small TRL-cholesterol (-83%; P &lt;0.001), small TRL-triglyceride (-88%; P &lt;0.0.001) and plasma apoB (-63%; P &lt;0.0001) compared with controls. Compartmental modeling analysis showed that apoB-48 production was decreased (-91%; P &lt;0.05) compared with controls. We conclude that when compared to controls, APOB L343V FHBL heterozygotes show decreased TRL production with normal postprandial TRL particle clearance. In contrast, VLDL-apoB production was normal, while the FCR was higher in heterozygotes compared with lean control subjects. These mechanisms account for the marked hypolipidemic state observed in these FHBL subjects.

Abstract 127: The Mediterranean Diet With and Without Weight Loss Improves Several Features of Low-Density Lipoprotein Metabolism in Men With Metabolic Syndrome

Objective To assess the impact of a Mediterranean type diet (MedDiet), without weight loss (-WL) and with weight loss (+WL), on features of LDL and LDL- apolipoprotein (apo) B metabolism in men with metabolic syndrome (MetS). Methods and Results The diet of 19 men with MetS (NCEP-ATP III, age 24-62 years) was first standardized to a typical North American control diet that they consumed for 5 weeks under isoenergetic feeding conditions (all foods and beverages provided). Subjects were then fed a MedDiet for 5 weeks also under isoenergetic conditions (MedDiet-WL), after which they underwent a 20-week weight loss period in free-living conditions (average weight loss -10.2 ± 2.9% body weight, P&lt;0.01). This was followed by consumption of the MedDiet (5 weeks) under isoenergetic conditions (MedDiet+WL). Features of LDL and apo B kinetics were assessed at the end of the three controlled feeding periods. MedDiet-WL reduced VLDL-apoCIII (-41.5%), cholesteryl ester transfer protein (-7.0%) and hepatic lipase concentrations (-7.1%), reduced the proportion of small LDL (LDL&lt;255 å, -11.7%) and increased LDL peak particle diameter (LDL-PPD, +0.7%) as well as the proportion of medium size LDL (LDL255-260 å, +11.1%) vs. control diet (all P&lt;0.05). MedDiet-WL also decreased LDL-apoB pool size (PS, -14.2%) and increased the fractional catabolic rate (FCR) of LDL-apoB (+30.4%) vs. the control diet (both P&lt;0.05), with no change in LDL-apoB production rate (PR). MedDiet+WL was associated with further increase in LDL-PPD (0.2%) and further reduction in VLDL-apoCIII concentrations (-28.7%) compared with MedDiet-WL (both P&lt;0.05) but had no further impact on LDL-apoB PS and on LDL-apoB FCR. Conclusion Data from this controlled feeding study suggest that consumption of MedDiet, even in the absence of weight loss, decreases LDL-C concentrations and LDL-apoB pool size primarily by enhancing the clearance of LDL particles in men with MetS. This is accompanied by a reduction in the proportion of small dense LDL and an increase in LDL particle size. Combining weight loss to MedDiet has no additional impact on LDL-apoB pool size and catabolism but may have further beneficial effects on the LDL particle size phenotype in men with MetS.

Lack of association between plasma PCSK9 and LDL-apoB100 catabolism in patients with uncontrolled type 2 diabetes

ObjectivePro-protein convertase subtilisin/kexin type 9 (PCSK9) is a post-transcriptional inhibitor of LDL-receptor. In non-diabetic men, plasma PCSK9 levels were found to be inversely correlated with low-density lipoprotein (LDL) apolipoprotein B100 (apoB) fractional catabolic rate (FCR). Here, we aimed to determine the effect of type 2 diabetes on the association between plasma PCSK9 and FCR of LDL. MethodsA kinetic study of LDL-apoB100, using stable isotopes, was performed in 38 individuals (20 men, 18 women) including 23 non-diabetic normolipidemic subjects and 15 patients with type 2 diabetes. ResultsIn the non-diabetic group, plasma PCSK9 was positively correlated with LDL-C (r=0.64, p=0.001), apoB (r=0.67, p<0.001), and inversely correlated with LDL-apoB FCR (r=−0.61, p=0.002). In contrast, in type 2 diabetic patients, plasma PCSK9 was not associated with LDL-C, apoB and LDL-apoB FCR. However, the lack of association between PCSK9 and LDL-apoB FCR seemed to be limited to the patients with “uncontrolled” diabetes (HbA1c>7%) since a borderline significant negative correlation between PCSK9 and LDL FCR (r=−0.70, p=0.08) was retrieved in patients with HbA1c≤7%. In multivariate analysis, LDL-apoB FCR was independently associated with PCSK9 (p=0.001) and fasting glycaemia (log) (p=0.030) in the non-diabetic population and with PCSK9 (p=0.040) and HbA1c (p=0.029) in diabetic patients. ConclusionOur data indicate that both PCSK9 and glycaemia are independent factors influencing LDL catabolism. Plasma PCSK9 influences significantly the catabolism of LDL-apoB100 in individuals without diabetes, but not in patients with uncontrolled type 2 diabetes. Thus, the influence of diabetes on LDL-apoB FCR catabolism may overwhelm the influence of PCSK9.

Variation in Niemann–Pick C1‐like 1 gene as a determinant of apolipoprotein B‐100 kinetics and response to statin therapy in centrally obese men

Niemann-Pick C1-like 1 protein (NPC1L1) plays a key role in lipoprotein metabolism. We examined the association of common genetic polymorphisms in NPC1L1 on apolipoprotein (apo) B-100 metabolism and the response to statin treatment in 37 men with central obesity. Very-low density lipoprotein (VLDL) and low-density lipoprotein (LDL)-apoB kinetics were determined using stable isotope method. NPC1L1 genotypes (1735G > C, 25432A > C and 27677T > C) were determined by allele-specific methods. These three polymorphisms are defined as haplotype, namely 1735C-25432A-27677T, and was designated as 'haplotype 2'. Relative to non-2/2 haplotype (n = 23), subjects with the 2/2 haplotype (n = 14) had significantly increased plasma concentrations of total, LDL-cholesterol, and total apoB (P < 0.05). The fractional catabolic rate (FCR) of LDL-apoB was significantly lower in 2/2 subjects compared with non-2/2 subjects (P < 0.05), with an associated increase in LDL-apoB pool size in the former group. Sixteen subjects were then treated with 40 mg atorvastatin (6 weeks): 2/2 subjects (n = 8) had a significantly greater reduction in plasma concentrations of cholesterol and total apoB and in LDL-apoB pool size, as well as a greater increase in LDL-apoB FCR compared with non-2/2 subjects. There were no significant treatment-related between-haplotype differences in VLDL-apoB kinetics or in plasma concentrations of lathosterol and campesterol. Our data demonstrate that NPC1L1 2/2 haplotype was associated with variation in LDL-apoB metabolism and its response to statin therapy in centrally obese men, by a mechanism that did not involve changes in VLDL-apoB kinetics, nor cholesterol synthesis or absorption.

Delayed In Vivo Catabolism of Intermediate-Density Lipoprotein and Low-Density Lipoprotein in Hemodialysis Patients as Potential Cause of Premature Atherosclerosis

Premature cardiovascular disease is the leading cause of death in patients with end-stage renal disease treated by hemodialysis (HD). Low-density lipoprotein (LDL) levels are not generally increased in HD patients, but their LDL metabolism is still poorly understood. We therefore investigated the in vivo metabolism of apoB-containing lipoproteins in two different ethnic populations of HD patients and controls. We performed stable isotope kinetic studies using a primed constant infusion of deuterated leucine in 12 HD patients and 13 healthy controls. Tracer/tracee ratio of apoB was determined by means of gas chromatography/mass spectrometry, and the modeling program SAAMII was used to estimate the fractional catabolic rate (FCR) of apoB. Mean LDL-apoB plasma concentrations were almost identical in both groups (HD: 95+/-30 mg/dL, controls: 91+/-40 mg/dL), whereas LDL-apoB FCR was 50% lower in HD patients as compared with controls (0.22+/-0.12 days(-1) versus 0.46+/-0.20 days(-1), P=0.001) with concomitantly decreased production rates of LDL. Compared with controls, intermediate-density lipoprotein (IDL)-apoB FCR was 65% lower (2.87+/-1.02 days(-1) versus 8.89+/-4.94 days(-1), P=0.014), accompanied by 1.5-fold higher IDL-apoB levels in HD. Very low-density lipoprotein metabolism was similar in both study groups. In vivo catabolism of LDL and IDL is severely impaired in HD patients but misleadingly masked by normal plasma cholesterol levels. The resulting markedly prolonged residence times of both IDL and LDL particles might thus significantly contribute to the well-documented high risk for premature cardiovascular disease in HD patients.

Inhibition of the apical sodium-dependent bile acid transporter reduces LDL cholesterol and apoB by enhanced plasma clearance of LDL apoB.

Cloning of the ileal apical sodium-dependent bile acid transporter (ASBT) has identified a new pharmacological target for the modulation of plasma lipoproteins. The objective of this study was to determine whether a novel, specific, minimally absorbed ASBT inhibitor (SC-435) decreases LDL cholesterol through the alteration of plasma apoB kinetics. Miniature pigs were treated for 21 days with 10 mg/kg/day of SC-435 or placebo. SC-435 decreased plasma cholesterol by 9% and LDL cholesterol by 20% with no effect on other lipids. Autologous (131)I-VLDL, (125)I-LDL, and [(3)H]-leucine were injected simultaneously to determine apoB kinetics. LDL apoB concentrations decreased significantly by 10% resulting entirely from an increase in LDL-apoB fractional catabolic rate. SC-435 had no effect on either total LDL apoB production or VLDL apoB converted to LDL. SC-435 increased VLDL apoB production by 22%; however, the concentration was unchanged as a result of increased VLDL apoB direct removal. SC-435 increased hepatic mRNA and enzymatic activity for both cholesterol 7alpha-hydroxylase and HMG-CoA reductase. Hepatic LDL receptor mRNA increased significantly, whereas apoB expression was unaffected. A low dose of the ASBT inhibitor, SC-435, significantly reduces plasma LDL cholesterol through enhanced LDL receptor-mediated LDL apoB clearance, secondary to increased expression of cholesterol 7alpha-hydroxylase.

Apolipoprotein B metabolism and the distribution of VLDL and LDL subfractions

Apolipoprotein B (apoB) metabolism was investigated in 20 men with plasma triglyceride 0.66–2.40 mmol/l and plasma cholesterol 3.95–6.95 mmol/l. Kinetics of VLDL1 (Sf 60–400), VLDL2 (Sf 20–60), IDL (Sf 12–20), and LDL (Sf 0–12) apoB were analyzed using a trideuterated leucine tracer and a multicompartmental model which allowed input into each fraction. VLDL1 apoB production varied widely (from 5.4 to 26.6 mg/kg/d) as did VLDL2 apoB production (from 0.18 to 8.4 mg/kg/d) but the two were not correlated. IDL plus LDL apoB direct production accounted for up to half of total apoB production and was inversely related to plasma triglyceride (r = −0.54, P = 0.009). Percent of direct apoB production into the IDL/LDL density range (r = 0.50, P < 0.02) was positively related to the LDL apoB fractional catabolic rate (FCR). Plasma triglyceride in these subjects was determined principally by VLDL1 and VLDL2 apoB fractional transfer rates (FTR), i.e., lipolysis. IDL apoB concentration was regulated mainly by the IDL to LDL FTR (r = −0.71, P < 0.0001). LDL apoB concentration correlated with VLDL2 apoB production (r = 0.48, P = 0.018) and the LDL FCR (r = −0.77, P < 0.001) but not with VLDL1, IDL, or LDL apoB production. Subjects with predominantly small, dense LDL (pattern B) had lower VLDL1 and VLDL2 apoB FTRs, higher VLDL2 apoB production, and a lower LDL apoB FCR than those with large LDL (pattern A). Thus, the metabolic conditions that favored appearance of small, dense LDL were diminished lipolysis of VLDL, resulting in a raised plasma triglyceride above the putative threshold of 1.5 mmol/l, and a prolonged residence time for LDL. This latter condition presumably permitted sufficient time for the processes of lipid exchange and lipolysis to generate small LDL particles. —Packard, C. J., T. Demant, J. P. Stewart, D. Bedford, M. J. Caslake, G. Schwertfeger, A. Bedynek, J. Shepherd, and D. Seidel. Apolipoprotein B metabolism and the distribution of VLDL and LDL subfractions.

Inhibition of cholesterol esterification by DuP 128 decreases hepatic apolipoprotein B secretion in vivo: effect of dietary fat and cholesterol

To further test the hypothesis that newly synthesized cholesteryl esters regulate hepatic apolipoprotein B (apoB) secretion into plasma, apoB kinetic studies were carried out in seven control miniature pigs and in seven animals after 21 days intravenous administration of the acyl coenzyme A:cholesterol acyltransferase (ACAT) inhibitor DuP 128 (2.2 mg/kg/day). Pigs were fed a fat (34% of calories; polyunsaturated/monounsaturated/saturated ratio, 1:1:1) and cholesterol (400 mg/day; 0.1%; 0.2 mg/kcal) containing pig chow based diet. DuP 128 significantly reduced total plasma triglyceride and very low density lipoprotein (VLDL) triglyceride concentrations by 36 and 31%, respectively ( P<0.05). Autologous 131I-VLDL and 125I-LDL were injected simultaneously into each pig and apoB kinetic data was analyzed using multicompartmental analysis (SAAM II). The VLDL apoB pool size decreased by 26% (0.443 vs. 0.599 mg/kg; P<0.001) which was due entirely to a 28% reduction in VLDL apoB production or secretion rate (1.831 vs. 2.548 mg/kg/h; P=0.006). The fractional catabolic rate (FCR) for VLDL apoB was unchanged. The LDL apoB pool size and production rate were unaffected by DuP 128 treatment. Hepatic microsomal ACAT activity decreased by 51% (0.44 vs. 0.90 nmol/min/mg; P<0.001). Although an increase in hepatic free cholesterol and subsequent decrease in both LDL receptor expression and LDL apoB FCR might be expected, this did not occur. The concentration of hepatic free cholesterol decreased 12% ( P=0.008) and the LDL apoB FCR were unaffected by DuP 128 treatment. In addition, DuP 128 treatment did not alter the concentration of hepatic triglyceride or the activity of diacylglycerol acyltransferase, indicating a lack of effect of DuP 128 on hepatic triglyceride metabolism. In our previous studies, DuP 128 treatment of miniature pigs fed a low fat, cholesterol free diet, decreased VLDL apoB secretion by 65% resulting in a reduction in plasma apoB of 60%. We conclude that in miniature pigs fed a high fat, cholesterol containing diet, the inhibition of hepatic cholesteryl ester synthesis by DuP 128 decreases apoB secretion into plasma, but the effect is attenuated relative to a low fat, cholesterol free diet.

Low-density lipoprotein-apolipoprotein B metabolism following apheresis: simulation studies of mass changes and tracer kinetics.

Low-density lipoprotein (LDL) apheresis is an effective method to treat severe hyperlipoproteinemia such as heterozygous familial hypercholesterolemia (FH). It is unknown whether apheresis induces changes in metabolic parameters of LDL-apolipoprotein B (apoB) such as the fractional catabolic rate (FCR) or production rate. We performed simulation studies to determine the effect of potential changes in the LDL FCR on LDL-apoB mass and on exogenous and endogenous tracer studies. For these studies, we assumed a two-compartment LDL model and the following metabolic parameters: plasma LDL-apoB, 180 mg.dL(-1); LDL-apoB production rate, 36 mg.dL(-1).d(-1) (approximately 14.4 mg.kg(-1).d(-1)); and LDL-apo FCR, 0.2 d(-1). It was also assumed that apheresis instantaneously decreased the LDL-apoB concentration to 60 mg.dL(-1) and that LDL-apoB production was not perturbed. The simulations examined three possible outcomes: (1) no change in FCR, (2) a temporary doubling in FCR, and (3) a temporary tripling in FCR. Monoexponential models were fit to the rebound of LDL-apoB mass data generated using the different FCRs. In no instance did the FCR determined from the fit match the FCR used to generate the data; FCRs were either higher or lower than the original FCR used to generate the data. Simulations of the kinetics of exogenously labeled LDL showed that if apheresis was performed on day 7 of a turnover study, it would be possible to detect large changes in LDL-apoB FCR. In contrast, during an endogenous labeling study, potential increases in FCR induced by apheresis may not be detected. However, our simulations do show that endogenous labeling studies performed before and after apheresis should yield data that will permit detection of changes in the FCR. Thus, these studies indicate that large differences in the LDL-apoB FCR induced by apheresis can be detected by either an exogenous tracer experiment perturbed by apheresis or by endogenous labeling experiments performed before and after apheresis. Small changes in the FCR that may be induced by apheresis will probably be indistinguishable from experimental noise.

Replacing Dietary Palmitic Acid with Elaidic Acid (t-C18:1Δ9) Depresses HDL and Increases CETP Activity in Cebus Monkeys

The question whether dietary trans fatty acids affect lipoprotein metabolism similarly to specific saturated fatty acids was investigated in 11 normolipemic cebus monkeys by exchanging 5% dietary energy (%en) between elaidic (t-C18:1 delta9) and palmitic acid (16:0) in two test diets (30%en fat + 100 mg cholesterol/1000 kcal diet) conforming to the American Heart Association (AHA) Step 1 guidelines. These were compared with a normal control diet rich in saturated fat and cholesterol (38%en fat + 180 mg cholesterol/1000 kcal diet). The control diet was fed initially for 14 wk, followed by each of the the two test diets in a crossover design. Plasma lipid concentrations were determined four times between the 6th and 14th wk. Turnover studies (using 125I-HDL and 131I-LDL) were conducted after 9 wk in each dietary period. Relative to the control diet, both test diets significantly reduced plasma total cholesterol (TC), HDL cholesterol (HDL-C) and VLDL plus LDL cholesterol (LDL-C) concentrations; triglyceride (TG) concentrations tended to be lower. However, the trans diet resulted in a significantly greater reduction in HDL-C than the palmitate diet (124 +/- 17, 117 +/- 18 and 106 +/- 13 mg/dL for the control, palmitate and trans diets, respectively). The palmitate diet significantly decreased the TC/HDL-C ratio by 11% when compared with the control diet (1.68 +/- 0.17 vs. 1.89 +/- 0.30), whereas the trans diet had no effect (1.81 +/- 0.20 vs. 1.89 +/- 0.30). Kinetic studies revealed that, relative to the control diet, both test diets significantly lowered the LDL apolipoprotein B (apoB) pool size, principally reflecting an increase in the LDL apoB fractional catabolic rate (FCR) related to the reduced cholesterol intake. Between the two test diets, no significant differences in LDL kinetic parameters were observed. Both test diets significantly decreased HDL apoA1 concentrations in comparison with the control diet, which was partly explained by an increase in the fractional catabolic rate of HDL. Of the two test diets, the trans diet was associated with a 9.5% greater HDL FCR than the palmitate diet (P < 0.08) and a significant increase in plasma cholesteryl ester transfer protein (CETP) activity (% transfer 114 +/- 7 vs. 91 +/- 7; P < 0.03). Thus, palmitic acid- and elaidic acid-rich diets produced identical effects on LDL metabolism in normocholesterolemic cebus monkeys fed diets with low levels of cholesterol, whereas elaidic acid depressed HDL-C, attributable to both increased CETP activity and HDL clearance.

Effects of Colestipol Alone and in Combination With Simvastatin on Apolipoprotein B Metabolism

The effects of colestipol therapy alone (20 g/d) or combined with simvastatin (20 mg/d) were examined in a group of eight male patients with primary moderate hypercholesterolemia (total cholesterol > or = 6.5 mmol/L [> or = 250 mg/dL]) who had undergone coronary artery bypass grafting more than 3 months previously. Colestipol therapy decreased total cholesterol by 14% (P < .001) and LDL cholesterol (LDL-C) by 23% (P < .001), while dual therapy decreased total cholesterol by 38% and LDL-C by 52% (both P < .001 versus baseline). No significant changes were observed in plasma triglyceride, VLDL cholesterol, or HDL cholesterol levels. VLDL subfraction turnovers were conducted at baseline and again on each regimen. ApoB kinetic parameters derived from a multicompartmental model suggested that colestipol therapy resulted in an expansion of the total VLDL apoB pool (36%, P < .05) that was largely due to a fall in the clearance rate of VLDL1 apoB (49%), while the LDL apoB pool decreased 23% as a result of diminished direct LDL input. The model used also revealed that addition of simvastatin to the resin therapy caused increases in the fractional transfer rates of VLDL2 to IDL and IDL to LDL together with a 37% increment in the LDL apoB fractional catabolic rate. Compared with baseline, combined therapy generated falls in both IDL (35%, P = .01) and LDL (37%, P < .04) apoB pools due to enhanced clearance of IDL (214%, P < .03) and reduced total input of LDL (39%, P < .003).

Tracer kinetic studies of the low density lipoprotein metabolism in the fetal rat: an example for estimation of flux rates in the nonsteady state.

To get insight into the low density lipoprotein (LDL)-apoB flux in the rat fetus near term and in the early postnatal period, homologous apoE-free 125I-labeled LDL was injected into the umbilical vein of the rat fetus immediately after Caesarean section. Since the serum LDL-apoB spontaneously declined after birth, a time-dependent two-pool model was used to calculate the flux rates in the neonate from the specific activities of LDL-apoB up to 15 h post partum. An approximate value of LDL-apoB flux in the fetus at birth was obtained by extrapolation of the kinetic data to the time of injection of the tracer. The data revealed that the turnover of LDL-apoB in the fetus (18.6 micrograms LDL-apoB/h per g body weight) exceeded that in the adult rat (0.4 microgram/h per g body weight) by at least one order of magnitude. Even 15 h after delivery, the LDL-apoB influx amounted to 2.5 micrograms/h per g body weight. The fractional catabolic rate of LDL-apoB in the fetus at term (0.39, h-1) slightly exceeded that in the adult animal (0.15, h-1) and reached the adult level within the first 3 h after birth and remained constant thereafter. In the rat fetus, LDL-apoB flux greatly exceeds that of VLDL-apoB. The data support the view of a direct synthesis and secretion of LDL, most probably by the fetal membranes.

Low density lipoprotein metabolism in hypertriglyceridemic and normolipidemic patients with coronary heart disease.

The turnover rates of low density lipoprotein-apolipoprotein B (LDL-apoB) were determined in 32 men with coronary heart disease (CHD) and 11 control men with normal plasma lipids. Thirty patients with CHD had normal levels of LDL-cholesterol (LDL-C); of these patients, 9 had hypertriglyceridemia and 21 had normal plasma lipids. Mean concentrations of total cholesterol and LDL-C were similar among the control subjects and CHD patients, although the latter had significantly lower HDL-C. In control subjects, transport rates and fractional catabolic rates (FCR) of LDL-B were 10.6 +/- 0.5 (SEM) mg/kg-day and 0.31 +/- 0.01 pools/day, respectively. In 10 hypertriglyceridemic patients with CHD, transport rates were 21.7 +/- 1.7 mg/kg-day, and FCRs averaged 0.56 +/- 0.06 pools/day; both were significantly higher than normal (P less than 0.05). Six normolipidemic patients also had abnormally high transport rates of LDL-apoB (19.4 +/- 2.8 mg/kg-day) and FCRs (0.51 +/- 0.03 pools/day); again both were higher than normal. The remaining 16 normolipidemic patients with CHD had normal transport rates (9.9 +/- 0.6 mg/kg-day) and FCRs (0.28 +/- 0.01 pools/day). Thus, hypertriglyceridemic patients with CHD and a portion of normolipidemic patients with CHD were characterized by increases in both transport and fractional catabolic rate of LDL-apoB; these abnormalities in LDL metabolism may have contributed to their coronary heart disease. However, the majority of normolipidemic patients with CHD did not show a distinct defect in their LDL metabolism.