Body fat distribution, insulin sensitivity, ovarian dysfunction and serum lipoproteins in patients with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is characterized by various endocrine and metabolic abnormalities, whose mutual associations and symptoms are still not clear. In the present study, fifteen PCOS patients and fifteen controls, matched for age and body weight, were investigated. Endocrine profiles were evaluated by the nafarelin and the adrenocorticotropin (ACTH) test. Insulin sensitivity was determined by an intravenous insulin tolerance test. Patients showed a significant predominance of abdominal adiposity [waist-to-hip ratio (WHR), 0.86 +/- 0.05 vs. 0.79 +/- 0.04] with markedly higher fasting insulin levels (+75%) and reduced insulin sensitivity (-37%). Fasting insulin, testosterone and free androgen index were positively correlated with the body mass index (BMI). In contrast, insulin sensitivity and BMI were inversely correlated in patients only. In the nafarelin test increases of 17-OH-progesterone and androstenedione were higher in patients and positively correlated with fasting insulin levels. Lipoprotein profiles showed trends towards higher triglycerides, lower HDL-cholesterol and a preponderance of small, dense LDL in patients. In PCOS higher triglycerides and lower HDL cholesterol were correlated with insulin sensitivity. It is concluded that PCOS patients show metabolic abnormalities combined with a more adroid type of adiposity when compared to cyclic controls of similar BMI.

The metabolism of lipoprotein(a) and other apolipoprotein B-containing lipoproteins: a kinetic study in humans.

Lipoprotein(a) is a risk factor for cardiovascular disease composed of an apolipoprotein B-containing lipoprotein to which a second protein, apolipoprotein(a), is attached. We investigated in seven subjects with Lp(a) levels of 39--85 mg/dl the metabolism of four apo B-containing lipoproteins (VLDL(1), VLDL(2), IDL and LDL) together with that of apo B and apo(a) isolated from Lp(a). Rates of secretion, catabolism and where appropriate, transfer were determined by intravenous administration of d(3)-leucine, mass spectrometry for measurements of leucine tracer/tracee ratios and kinetic data analysis using multicompartmental metabolic modeling. Apo B in Lp(a) was secreted at a rate of 0.28 (0.17--0.40) mg/kg per day. It was found to originate from two sources -- 53% (43--67) were derived from preformed lipoproteins, i.e. IDL and LDL, the remainder was accounted for by apo B, directly secreted by the liver. The fractional catabolic rates (FCRs) of apo B and of apo(a) prepared from Lp(a) were determined as 0.27 (0.16--0.38) and 0.24 (0.12--0.40) pools per day, respectively, which is less than half of the FCR observed for LDL. Our in vivo data from humans support the view that Lp(a) assembly is an extracellular process and that its two protein components, apo(a) and apo B, are cleared from the circulation at identical rates.

Alterations of apolipoprotein B metabolism in HIV-infected patients with antiretroviral combination therapy.

BACKGROUND: Dyslipidemia (predominantly hypertriglyceridemia) is frequently seen in patients receiving antiretroviral combination therapy (ART). However, the underlying mechanisms and long-term risks (e.g., cardiovascular events) are still unclear. OBJECTIVES/METHODS: In 5 patients with ART-associated dyslipidemia, stable isotope labeled amino acid tracer (d3-Leu) kinetic analysis over 12 days was used to investigate the metabolism of apolipoprotein B-containing lipoproteins (very low density lipoproteins [VLDL]1, VLDL2, intermediate density lipoproteins [IDL] and low density lipoproteins [LDL]). Data were compared with those in 6 healthy normolipidemic controls. RESULTS: The patients under ART showed significantly increased fasting triglycerides (359 vs. 77 mg/dl) and VLDL (54 vs. 15 mg/dl), compared with controls. They had significantly higher total cholesterol (213 vs. 157 mg/dl) and there was a nonsignificant trend toward higher LDL (136 vs. 93 mg/dl), and toward lower HDL (26 vs. 46 mg/dl). The ratio of large, buoyant LDL1 over small, dense LDL2 was markedly reduced in patients under ART (0.80 vs. 2.00). Total apo B synthesis was significantly increased (25.5 vs. 14.5 mg/kg/d) and shifted toward triglyceride rich VLDL1 (18.5 vs. 8.7 mg/kg/d) in patients receiving ART. There was also a significantly reduced rate of apo B lipoprotein transfer from VLDL1 to VLDL2 (3.7 vs. 20.7 pools/d). In addition, all patients revealed insulin resistance. CONCLUSIONS: These data indicate that increased triglycerides in HIV-infected patients with ART are primary due to reduced rates of VLDL transfer into denser lipoproteins implying a lower rate of lipoprotein lipase-mediated delipidation. In addition, total apo B synthesis was increased and shifted toward triglyceride-rich VLDL1. Overall, this lipoprotein profile in patients with ART-associated dyslipidemia implies an increased risk for cardiovascular events.

[Diabetic dyslipoproteinemia: physiopathological bases and treatment prospects]. / Diabetische Dyslipoproteinämie. Pathophysiologische Grundlagen und therapeutische Perspektiven.

Dyslipoproteinemia associated with type 2 diabetes comprises hypertriglyceridemia caused by reduced insulin sensitivity, and consequently, low HDL levels and an increase in the proportion of small dense LDL particles. In addition, in both type 1 and 2 diabetes glycated LDL is formed in the presence of high plasma glucose levels. These lipoprotein disorders are all atherogenic and are responsible for the distinctly increased risk for cardiovascular disease in diabetics. Intensive glucose-lowering measures result in lower rates of micro- and macro-angiopathies in both types of diabetes. The benefit of additional lipid-lowering measures has not yet been confirmed by appropriate investigations. However, subgroup analyses from two large intervention trials do demonstrate that mortality from coronary heart disease may be substantially reduced. LDL cholesterol levels in diabetics should not exceed 115 mg/dl (3 mmol/l), and fasting triglycerides should be lower than 180 mg/dL (2 mmol/l).

Acute effects of low density lipoprotein apheresis on metabolic parameters of apolipoprotein B.

Apheresis is a treatment option for patients with severe hypercholesterolemia and coronary artery disease. It is unknown whether such therapy changes kinetic parameters of lipoprotein metabolism, such as apolipoprotein B (apoB) secretion rates, conversion rates, and fractional catabolic rates (FCR). We studied the acute effect of apheresis on metabolic parameters of apoB in five patients with drug-resistant hyperlipoproteinemia, using endogenous labeling with D(3)-leucine, mass spectrometry, and multicompartmental modeling. Patients were studied prior to and immediately after apheresis therapy. The two tracer studies were modeled simultaneously, taking into account the non-steady-state concentrations of apoB. The low density lipoprotein (LDL)-apoB concentration was 120+/-32 mg dl(-1) prior to and 52+/-18 mg dl(-1) immediately after apheresis therapy. The metabolic studies indicate that no change in apoB secretion (13.9+/- 4.9 mg kg(-1) day(-1)) is required to fit the tracer and apoB mass data obtained before and after apheresis and that in four of the five patients the LDL-apoB FCR (0.21+/-0.02 day(-1)) was not altered after apheresis. In one subject the LDL-apoB FCR temporarily increased from 0.22 day(-1) to 0.35 day(-1) after apheresis. The conversion rate of very low density lipoprotein (VLDL)-apoB to LDL-apoB is temporarily decreased from 76 to 51% after apheresis and thus less LDL-apoB is produced after apheresis. We conclude that an acute reduction of LDL-apoB concentration does not affect apoB secretion or LDL-apoB FCR, but that apoB conversion to LDL is temporarily decreased. Thus, in most patients the decreased rate of delivery of neutral lipids or apoB to the liver does not result in an upregulation of LDL receptors or in decreased apoB secretion.

Evaluation of the LIAISON thyroid chemiluminescence immunoassays.

The LIAISON thyroid hormone assays TSH, FT4, FT3, T4 and T3 were evaluated by determining the imprecision, the reference ranges, the functional sensitivity (TSH), the dilution characteristics (accuracy) (FT4, FT3), and the recovery after spiking (TSH, T4, T3). Furthermore, inter-method comparisons were performed with following methods: Elecsys (Roche Diagnostics; TSH), AxSYM (Abbott Diagnostics; TSH, FT4, FT3, T4), ACS:180 (Bayer Diagnostics; all analytes), Amerlex-M (Johnson & Johnson; T4) and LISO-Phase (Techno Genetics; FT4). The fully automated LIAISON random access analyser is based on microparticle immunoassays and chemiluminescence. The coefficients of variation (CV) of intra-assay imprecision were between 0.2-6.0%, except for the control sample with extremely low TSH concentrations and low T3 concentrations. Inter-assay imprecision was performed by measuring controls covering the measuring range over a period of 9 to 20 days, with CVs ranging from 2.3-16.0%. The suitability of the sample material was determined by analysing serum and samples treated with EDTA, citrate or heparin in parallel. The results showed good correlations of the thyroid hormone concentrations between serum and plasma samples except for LIAISON FT3, for which lower results were observed with EDTA-plasma. The regression analysis of correlation studies gave slopes from 0.849 to 0.957 for TSH, from 1.023 to 1.375 for FT4, from 0.670 to 0.911 for FT3, from 0.917 to 1.166 for T4 and 1.00 for T3 depending on the concentration range and the method of comparison. The LIAISON FT4 assay showed a trend towards higher values in the high concentration range when compared with the ACS:180. The ranges of thyroid hormone concentrations determined in serum taken from apparently healthy subjects were found to be in accordance with published data. The clinical sample study confirmed that the LIAISON thyroid hormone assays are sensitive methods for the differentiation of euthyroid subjects and patients with hyper- and hypothyroidism. In conclusion, the automated thyroid hormone immunoassays on the random-access LIAISON immunoassay analyser proved to be very satisfactory, both from the analytical and the clinical point of view.

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 VLDL(1) (S(f) 60-400), VLDL(2) (S(f) 20-60), IDL (S(f) 12-20), and LDL (S(f) 0;-12) apoB were analyzed using a trideuterated leucine tracer and a multicompartmental model which allowed input into each fraction. VLDL(1) apoB production varied widely (from 5.4 to 26.6 mg/kg/d) as did VLDL(2) 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 VLDL(1) and VLDL(2) 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 VLDL(2) apoB production (r = 0.48, P = 0.018) and the LDL FCR (r = -0.77, P < 0. 001) but not with VLDL(1), IDL, or LDL apoB production. Subjects with predominantly small, dense LDL (pattern B) had lower VLDL(1) and VLDL(2) apoB FTRs, higher VLDL(2) 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.

Effects of creatine supplementation on exercise performance.

While creatine has been known to man since 1835, when a French scientist reported finding this constitutent of meat, its presence in athletics as a performance enhancer is relatively new. Amid claims of increased power and strength, decreased performance time and increased muscle mass, creatine is being hailed as a true ergogenic aid. Creatinine is synthesised from the amino acids glycine, arginine and methionine in the kidneys, liver and pancreas, and is predominantly found in skeletal muscle, where it exists in 2 forms. Approximately 40% is in the free creatine form (Crfree), while the remaining 60% is in the phosphorylated form, creatine phosphate (CP). The daily turnover rate of approximately 2 g per day is equally met via exogenous intake and endogenous synthesis. Although creatine concentration (Cr) is greater in fast twitch muscle fibres, slow twitch fibres have a greater resynthesis capability due to their increased aerobic capacity. There appears to be no significant difference between males and females in Cr, and training does not appear to effect Cr. The 4 roles in which creatine is involved during performance are temporal energy buffering, spatial energy buffering, proton buffering and glycolysis regulation. Creatine supplementation of 20 g per day for at least 3 days has resulted in significant increases in total Cr for some individuals but not others, suggesting that there are 'responders' and 'nonresponders'. These increases in total concentration among responders is greatest in individuals who have the lowest initial total Cr, such as vegetarians. Increased concentrations of both Crfree and CP are believed to aid performance by providing more short term energy, as well as increase the rate of resynthesis during rest intervals. Creatine supplementation does not appear to aid endurance and incremental type exercises, and may even be detrimental. Studies investigating the effects of creatine supplementation on short term, high intensity exercises have reported equivocal results, with approximately equal numbers reporting significant and nonsignificant results. The only side effect associated with creatine supplementation appears to be a small increase in body mass, which is due to either water retention or increased protein synthesis.

Lipoprotein (a) metabolism estimated by nonsteady-state kinetics.

Lipoprotein (a) [Lp(a)] is a low-density lipoprotein (LDL) particle with an additional apolipoprotein named apo(a). The concentration of Lp(a) in plasma is determined to a large extent by the size of the apo(a) isoform. Because elevated Lp(a) concentrations in plasma are associated with risk for premature coronary heart disease it is important to determine whether variations in production or catabolism mediate differences in Lp(a) concentration. We determined metabolic parameters of Lp(a) in 17 patients with heterozygous familial hypercholesterolemia or severe mixed hyperlipidemia by fitting a monoexponential function to the rebound of Lp(a) plasma concentration following LDL-apheresis. In 8 of those 17 patients this was done twice following two different aphereses. Although this approach allows one to estimate metabolic parameters without the use of a tracer, it requires several major assumptions such as that apheresis itself does not change production or catabolism of Lp(a) and that Lp(a) metabolism can be described by a single compartment. One apheresis decreased Lp(a) concentration by 59.1+/-8.3%. The fractional catabolic rate (FCR) was 0.16+/-0.12 d(-1) and production rate 6.27+/-5.26 mg x kg(-1) x d(-1). However, observed (concentration before first apheresis) and predicted steady-state concentrations differed considerably (more than 20%) in 9 of 17 patients, indicating that not all assumptions were fulfilled in all patients. Production rate but not FCR was correlated with Lp(a) plasma concentration (r2 = 0.43, P = 0.004) and molecular weight of apo(a) (r2 = 0.48, P = 0.011), which confirms radiotracer experiments showing that variations in Lp(a) plasma concentrations are due to differences in production not catabolism. When parameters were estimated twice in a subgroup of eight patients, satisfactory reproducibility was observed in six patients. Although parameters determined on two occasions correlated well, only FCR was concordant (intraclass correlation coefficient). Thus, despite the limitations arising from the assumptions implicit to this method, metabolic parameters of Lp(a) can be estimated from the rebound of plasma concentration following apheresis.

A simultaneous study of the metabolism of apolipoprotein B and albumin in nephrotic patients.

BACKGROUND: The nephrotic syndrome is characterized by proteinuria, hypoalbuminemia and hyperlipidemia. Despite intensive research it is not clear at present what the causal links are between these pathological findings. METHODS: Stable isotope labeled amino acid tracer kinetic analysis was used to simultaneously investigate the metabolism of four apolipoprotein B-containing lipoproteins (VLDL1, VLDL2, IDL and LDL) and albumin in seven patients with nephrotic syndrome and marked hypercholesterolemia, in two additional nephrotic patients with concomitant renal failure and mixed hyperlipidemia, and in a matched group of normolipidemic controls. RESULTS: Increased concentrations of VLDL2, IDL and LDL were due to (a) impaired VLDL2 and IDL delipidation, (b) reduced LDL catabolism, and (c) a trend towards an increased rate of total apolipoprotein B production. The rate of fractional albumin elimination was three times higher in patients than in controls and the rate of albumin synthesis was increased by 45%. No correlations were detectable between rates of apolipoprotein B production and the rate of albumin synthesis. CONCLUSIONS: The results of this study suggest that hyperlipidemia in nephrotic syndrome is predominantly the result of delayed lipoprotein delipidation and catabolism. There is no evidence that it is driven by a general increase of the rate of hepatic protein synthesis.

Treatment with protease inhibitors associated with peripheral insulin resistance and impaired oral glucose tolerance in HIV-1-infected patients.

BACKGROUND: The use of protease inhibitors in the treatment of HIV-1 infection is associated with the new onset of diabetes mellitus, hyperlipidaemia and lipodystrophy. It is unclear whether these findings are coincidental or whether they reflect a causative effect of protease inhibitors. OBJECTIVE: To evaluate the effect of treatment with protease inhibitors on insulin sensitivity, oral glucose tolerance and serum lipids in HIV-infected patients in order to determine whether treatment with protease inhibitors can cause peripheral insulin resistance. DESIGN: Cross-sectional controlled study in HIV-infected patients treated with protease inhibitors to assess insulin sensitivity, oral glucose tolerance and changes in serum lipids. METHODS: Sixty-seven patients treated with protease inhibitors, 13 therapy-naive patients and 18 HIV-negative control subjects were tested for insulin sensitivity (intravenous insulin tolerance test). In a subgroup of 24 treated patients, oral glucose tolerance was determined. Serum lipids prior to and under treatment with protease inhibitors were compared. RESULTS: Patients on protease inhibitors had a significantly decreased insulin sensitivity when compared with therapy-naive patients (median, 75 and 156 micromol/l/min, respectively; P < 0.001). All treated patients with impaired (n=4) or diabetic (n=9) oral glucose tolerance, and four out of 11 patients with normal glucose tolerance showed peripheral insulin resistance; all therapy-naive patients had normal insulin sensitivity. Treatment with protease inhibitors led to a significant increase in total triglycerides and cholesterol in the 67 treated patients (median increase, 113 and 37 mg/ml, respectively). CONCLUSION: Treatment with protease inhibitors is associated with peripheral insulin resistance, leading to impaired or diabetic oral glucose tolerance in some of the patients, and with hyperlipidaemia. Overall, there is a large variation in the severity and clinical presentation of protease inhibitor-associated metabolic side-effects.

In vivo studies of VLDL metabolism and LDL heterogeneity.

The association between plasma triglyceride levels and coronary heart disease may be explained by the metabolism of triglyceride-apolipoprotein (apo) B100-containing lipoproteins to an atherogenic low density lipoprotein (LDL) fraction. Apo B100 is secreted into the plasma compartment mainly as large triglyceride-rich very low density lipoprotein1 (VLDL1) particles and smaller, comparatively cholesterol ester-rich VLDL2. Both forms of VLDL undergo stepwise delipidation to LDL. A dual tracer VLDL technique has investigated the metabolism of apo B-containing lipoproteins and established that about one-third of the VLDL2 pool is transferred to LDL compared with less than 20% of VLDL1. In addition, LDL derived from VLDL1 has a longer plasma residence time than LDL from VLDL2. A series of experiments using a stable isotope tracer technique showed that the LDL fractional catabolic rate was inversely correlated with plasma triglyceride concentration, which itself is largely determined by VLDL1 concentration. In subjects with triglyceride concentrations between 150-200 mg. dl-1 (1.36 - 2.26 mmol .1(-1)), the prevailing small dense LDL is derived to a larger extent from VLDL precursors, rather than entering the plasma as LDL or IDL, and catabolized more slowly than the large buoyant LDL prevailing in subjects with lower triglyceride levels. These two independent methods show that triglyceride-rich VLDL is the precursor of slowly catabolized LDL particles which constitute an atherogenic lipoprotein subfraction.

Studies of apolipoprotein B-100 metabolism using radiotracers and stable isotopes.

Apolipoprotein B metabolism can be investigated in-vivo either by exogenous radiolabeling of preformed lipoproteins or by endogenous labelling of denovo synthesized apo B using a stable isotope substituted amino acid tracer. The potential of both methods and results obtained by in-vivo studies in genetically determined dys- or hyperlipidaemic subjects will be discussed.

Effects of weekly LDL-apheresis on metabolic parameters of apolipoprotein B in heterozygous familial hypercholesterolemia.

Apheresis is a treatment option for patients with severe hypercholesterolemia and coronary artery disease. It is, however, unknown whether such therapy changes kinetic parameters of lipoprotein metabolism, such as apolipoprotein B (apoB) secretion rates, conversion rates, and fractional catabolic rates (FCR). We studied the long-term effect of regular apheresis therapy on metabolic parameters of apoB in five patients with heterozygous familial hypercholesterolemia (FH) using endogenous labeling with D3-leucine, mass spectrometry, and multicompartmental modeling. Patients were studied prior to (study 1) and after 3-6 months of weekly apheresis therapy (study 2). LDL-apoB concentration was 183 +/- 16 mg d-1 prior to apheresis therapy (study 1), 135 %/- 7 mg. dl-1 at the beginning of study 2, and 163 +/- 10 mg . dl-1 at the end of study 2. VLDL-apoB and IDL-apoB were not different between the two studies and did not change during study 2. Separate modeling of the two studies revealed very similar parameters in each patient. In a second step simultaneous modeling of both studies was performed taking the changing pool size as a non-steady-state condition into account. ApoB tracer data of both kinetic studies and the change in pool size could be described with one set of kinetic parameters (VLDL-apoB FCR 4.32 +/- 1.06 d-1, LDL-apoB FCR 0.17 +/- 0.05 d-1, apoB secretion rate 11.9 +/- 3.7 mg . kg-1 . d-1). These parameters are well within the range of those previously published for FH heterozygotes in steady state. We conclude that regular apheresis therapy did not alter kinetic parameters of apoB metabolism in these patients with heterozygous FH in the long term and that the decreased rate of delivery of neutral lipids or apoB to the liver does not regulate plasma apoB metabolism.

Apolipoprotein B metabolism in primary and secondary hyperlipidaemias.

Important advances in our understanding of apolipoprotein B100 metabolism have been made in the last year. Here we review a diverse group of studies designed to examine the underlying metabolic defects in primary hyperlipidaemia or to define the impact of diseases such as diabetes nephrotic syndrome and thyroid dysfunction on the metabolism of apoB-containing lipoproteins.

Sensitive methods to study human apolipoprotein B metabolism using stable isotope-labeled amino acids.

The objective of the study was to develop a sensitive method using stable isotope-labeled tracers that would permit the determination of apolipoprotein B (apoB) metabolism in very low-density lipoprotein subfractions (VLDL1, Sf 60-400; VLDL2, Sf 20-60), intermediate-density lipoprotein (IDL, Sf 12-20), and low-density lipoprotein (LDL, Sf 0-12). Six normolipidemic subjects were given trideuterated leucine, and its clearance from plasma and appearance in the four apoB-containing lipoprotein fractions were followed by use of a highly sensitive gas chromatography-mass spectrometry technique in which the m + 3-to-m + 2 ion ratio was selectively monitored. This analytic approach permitted the precise measurement of low enrichments in IDL and LDL and extension of the turnover out to 250-300 h. A compartmental model was developed to derive rate constants from the plasma and apoB enrichment curves. The model was uniquely identifiable once parameter dependencies had been introduced to reduce the number of unknowns. Values were obtained for apoB input into all lipoprotein density intervals, together with rates of interconversion and catabolism; these agreed well with results from radioiodinated tracer experiments. An alternative model structure was also explored in which input occurred only into VLDL1. Altering the protocol of tracer administration (bolus vs. primed constant infusion) and dose (over a 10-fold range) had no influence on the results obtained. The analytic and modeling approach described will permit stable isotopes to be used to elucidate key features of apoB metabolism in normal and pathological states.

Development and application of a multicompartmental model to study very low density lipoprotein subfraction metabolism.

A multicompartmental model has been devised to explain apolipoprotein B (apoB) kinetics in very low density lipoprotein subfractions (VLDL1 Sf 60-400 and VLDL2 Sf 20-60), intermediate density (IDL Sf 12-20) and low density lipoproteins (LDL Sf 0-12). Normal and hyperlipemic subjects were given tracer doses of 131I-labeled VLDL1 and 125I-labeled VLDL2 and the metabolism of apoB in VLDL1, VLDL2, IDL, and LDL was followed over a period of 13 days. VLDL1 apoB and VLDL2 apoB clearance curves had an initial shoulder, a rapid decay, and a 'tail' of slowly metabolized lipoprotein. ApoB derived from VLDL1 appeared in IDL over 10-50 h and exhibited bi-exponential decay that was attributed to the presence of two metabolically distinct species. A further compartment was required to explain the observation that a substantial proportion of apoB from VLDL2 appeared and disappeared from the IDL density range faster than apoB derived from VLDL1 delipidation. Both of the more rapidly removed IDL species gave rise to LDL apoB that was also modeled as a heterogeneous entity with two plasma compartments. The final model, which has much in common with previous versions (M. Berman et al. 1978. J. Lipid Res. 19: 38-56), a multi-step delipidation pathway and slowly metabolized remnant compartments in VLDL, incorporates parallel delipidation routes in VLDL2, IDL, and LDL. These parallel pathways linked kinetic heterogeneity in VLDL with that in IDL and LDL.

Metabolism of apoB-100-containing lipoproteins in familial hyperchylomicronemia.

The metabolism of apolipoprotein B-100 was studied in three patients with familial hyperchylomicronemia (type I hyperlipoproteinemia) using a very low density lipoprotein (VLDL) dual-tracer technique. Radioiodinated VLDL1 (Sf 60-400) and VLDL2 (Sf 20-60) were injected and their catabolism and rate of the transfer of apoB into VLDL2, intermediate density lipoprotein (IDL) (Sf 12-20), and low density lipoprotein (LDL) (Sf 0-12) were compared in patients and in five normolipidemic controls. The rates of delipidation of large triglyceride-rich VLDL1 to VLDL2 (0.26-0.54 pools/day vs. 2.5-5.2 pools/day in controls) and VLDL1 direct catabolism (0.33-0.92 pools/day vs. 4.2-14.7 pools/day in controls) were found to be significantly reduced in type I patients resulting in a tenfold increase of VLDL1 pool size. ApoB synthesis into this density interval was, however, normal as was that into smaller VLDL2. the circulating apoB mass in VLDL2 was not increased. In fact, apart from a modest decrease in the rate of VLDL2 delipidation to IDL and LDL, the behavior of apoB in this density interval was similar in hyperchylomicronemic and normal subjects. Likewise, the transfer of apoB through the IDL and LDL density ranges was not significantly different from normal. Pool sizes of these fractions, however, were reduced, the latter significantly (354-491 mg vs. 1,160-2,505 mg in controls) due to increased direct catabolism in hyperchylomicronemic patients. The results of this study indicate that lipoprotein lipase deficiency primarily affects VLDL1 metabolism, both its delipidation and direct removal from plasma. Lipolysis further down the delipidation cascade is not dependent on this enzyme. Hypercatabolism rather than a failure of synthesis of IDL and LDL was responsible for the decreased pools for both lipoproteins.