Pseudo type III (PT-III) dyslipoproteinemia is characterized by a plasma accumulation of triglyceride-rich lipoproteins (TRL) and their remnants. It mimics type III, but its etiology can not be ascribed to a genetic apo E defect. In order to determine whether PT-III is associated with a genetic lipoprotein receptor abnormality, we have measured (in cultured fibroblasts from affected and nonaffected individuals) the in vitro activity of three lipoprotein receptors which are implicated in the catabolism of TRL, namely the low-density lipoprotein receptor (LDL-R), the lipoprotein receptor-related protein (LRP) and the lipolysis-stimulated receptor (LSR). Specific cell association and degradation of 125I-LDL by LDL-R-upregulated PT-III fibroblasts was not significantly different from that of control cells (103 +/- 10% and 98 +/- 17% of controls; 20 microg/ml 125I-LDL). Specific cell association and degradation of rabbit 125I-beta-VLDL was also not significantly different. LRP activity was assessed by measuring the ability of PT-III and control cells to bind three different LRP ligands: activated alpha2-macroglobulin (alpha2M-MA), lactoferrin and apo E-enriched rabbit beta-VLDL. No significant differences were observed (24.0 +/- 2.1 vs. 23.4 +/- 5.7 fmol/mg for 5 nM of 125I-alpha2M-MA; 4.8 +/- 0.3 vs. 5.2 +/- 1.3 microg/mg for 20 microg/ml of 125I-lactoferrin; 319.4 +/- 51.2 vs. 309.5 +/- 23.2 ng/mg for 5 microg/ml of 125I-beta-VLDL, PT-III vs. control, respectively). LSR activity, as assessed by the cell association or degradation of 125I-LDL by fibroblasts in the presence of 0.5 mM oleate and human leptin, was also not different. No evidence was obtained for deficient cellular recognition of PT-III TRL (d < 1.006 g/ml) by normal human fibroblasts or mouse macrophages. These results suggest that PT-III dyslipoproteinemia is not due to an accumulation in plasma of poorly recognized TRL, nor due to a genetic defect in LDL-R, LRP or LSR.

A unique non-laying strain of chickens with heritable hyperlipidemia and aortic atherosclerosis was first described in 1974. Subsequent work established that the phenotype results from a naturally occurring point mutation in the gene specifying the very low density lipoprotein (VLDL) receptor, a 95-kDa membrane protein which normally mediates the massive uptake of the main circulating hepatically-synthesized yolk precursors, VLDL and vitellogenin. As a result, hens of the mutant strain termed "restricted ovulator" (R/O) have approximately 5-fold elevations in circulating cholesterol and triglyceride concentrations compared with normal layers, and hepatic lipogenesis and cholesterogenesis are markedly attenuated due to feedback inhibition. R/O hens also exhibit hyperestrogenemia, hypoprogesteronemia, elevated circulating gonadotropins, and up-regulated pituitary progesterone receptor mRNA and isoforms. The ovaries of R/O hens are abnormal in that they lack a follicular hierarchy and contain many small preovulatory follicles of various colors, shapes, and sizes. However, since R/O hens occasionally lay eggs, it is possible that endocytic receptors other than the VLDL receptor may be able to facilitate oocyte growth and/or that yolk precursor uptake can occur via a nonspecific bulk process. A mammalian model of impaired fecundity with abnormal lipoprotein metabolism also has been described, but different mechanisms are likely responsible for its reproductive dysfunction. Nevertheless, as our understanding of the molecular physiology and biochemistry of avian oocyte growth continues to expand, in part due to studies of the R/O model, new analogies may emerge between avian and mammalian systems, which ultimately could help to answer important questions in reproductive biology.

It has been previously reported that VLDL unbound to monoclonal antibody against apoB-100 was rich in apoE, thus resembling remnant particles (J Lipid Res, 1993:33;369-380). In the current study, we have further analyzed the unbound VLDL fraction in plasma from hypertriglyceridemic patients using a mixture of monoclonal antibodies against apoB-100 and apoA-1. The unbound VLDL isolated from the plasma of hypertriglyceridemic patients was found to be rich in apoE, apoB-48, and triglyceride compared with the bound VLDL. Furthermore, these unbound VLDL, but not bound VLDL, significantly suppressed HMG CoA reductase activity of cultured human skin fibroblasts (-20 to -25%, P = 0.0022). The degree of suppression is significantly correlated with the apoE content of unbound VLDL (r = -0.769, P < 0.05). Unbound VLDL failed to suppress the activity of HMG CoA reductase of LDL receptor negative fibroblasts. These observations indicate a potential atherogenicity of remnant-like unbound VLDL by delivering more cholesterol through the LDL receptor dependent pathway with apoE as a ligand. In conclusion, this new immunoaffinity chromatography system is a useful method for directly quantifying atherogenic remnants in plasma.

Plasma newly synthesised cholesteryl ester transfer (NCET) rates from high density lipoproteins (HDL) to very low density lipoproteins (VLDL) and low density lipoproteins lipoproteins (LDL) were measured in 26 patients with non-insulin dependent diabetes mellitus (NIDDM), 26 healthy subjects with closely matching plasma triglyceride (TG) levels and 10 normolipidaemic healthy individuals. In addition, insulin mediated glucose uptake was measured in the NIDDM patients and the normolipidaemic subjects. Rates of NCET were significantly (P < 0.05) elevated in NIDDM patients compared with healthy normolipidaemic individuals but were similar to rates in healthy subjects with closely matching TG levels. In all groups of subjects plasma NCET was significantly (P < 0.001) correlated with plasma TG concentration. In NIDDM patients correlations between NCET and plasma glucose (r = 0.489, P = 0.011) independently of plasma TG levels, and glycated haemoglobin levels (r = 0.430, P = 0.028) were also recorded. Insulin mediated glucose uptake was unrelated to plasma NCET rates in the study. These data suggest that in NIDDM patients under good diabetic control elevated plasma NCET rates are mainly due to hypertriglyceridaemia and a specific and possibly stimulatory effect of diabetes on these rates may be seen only in patients with poorly controlled diabetes.

Patients with nephrotic syndrome have multiple abnormalities of lipoprotein metabolism, but the cause and exact nature of these abnormalities have not been established. In the present study we have determined the kinetics of plasma low-density lipoprotein (LDL) apoB in seven nephrotic patients demonstrating an elevated LDL apoB production rate (25.7 +/- 6.4 vs. 13.1 +/- 0.3 mgkg-1 day-1; P < 0.001) but a normal LDL apoB fractional catabolic rate (FCR) (0.31 +/- 0.04 vs. 0.33 +/- 0.008 pools day-1; NS) compared with 41 healthy control subjects. However, two out of the seven patients had a markedly low LDL apoB-FCR. Serum albumin was inversely correlated with the LDL apoB production rate (R = -0.82; P < 0.05). Plasma lipoprotein (a) [Lp(a)] levels were significantly (P < 0.001) increased in the nephrotic patients compared with control subjects. Significant correlations were observed between log Lp(a) and LDL apoB production rate (R = 0.90; P < 0.01), VLDL-cholesterol (R = 0.95; P < 0.001) and VLDL-triglycerides (R = 0.80; P < 0.05) respectively. In summary, the present study suggests that nephrotic hyperlipidaemia may be caused by at least two independent mechanisms. The elevated LDL apoB production rate is highly correlated with the prevailing levels of serum albumin, whereas some nephrotic patients seem to have a decreased LDL apoB clearance, suggesting impaired LDL receptor-mediated clearance. The present results also suggest that the elevated plasma Lp(a) levels in nephrosis are related to an increased hepatic synthesis rather than a decreased catabolism of lipoproteins.

Cholesterol efflux capacity (CEC) in atherosclerotic lesions is the main anti-atherosclerotic function of high-density lipoprotein (HDL). In recent studies, apolipoprotein (apo) B-depleted serum (BDS) obtained with the polyethylene glycol (PEG) precipitation method is used as a cholesterol acceptor (CA) substitution for HDL isolated by ultracentrifugation. However, the suitability of BDS as a CA is controversial. In the present study, CEC obtained from BDS (BDS-CEC) was evaluated based on a parameter, defined as whole-CEC, which was calculated by multiplying CEC obtained using fixed amounts of HDL by cholesterol concentration to HDL-cholesterol (HDL-C) levels in the serum. Significant correlation (r = 0.633) was observed between both CECs. To eliminate systematic errors from possible contamination with serum proteins and low-density lipoprotein (LDL) or very-LDL (VLDL) in BDS-CEC, the deviation of each CEC-BDS from the regression equation was compared with serum protein, LDL, and triglyceride (TG) levels. No correlation was observed between the deviation and the levels of each of these serum components, indicating that the deviations do not derive from systematic error. Further, to evaluate the effects of serum protein on the results, we measured BDS-CEC of reconstituted serum samples prepared using combinations of five levels of serum proteins with five levels of HDL-C. No significant change in BDS-CEC was observed in any combination. These results indicate that BDS-CEC reflects not only the function of HDL but also its concentration in serum.

In order to evaluate whether Hageman factor (XII) is increased in survivors of myocardial infarction and whether this in turn influences factor VII coagulant activity (VIIc), we examined the coagulation and lipoprotein profiles in 82 subjects, 51 of whom had a definite history of myocardial infarction and 31 healthy volunteers invited from a local general practice register for a cardiovascular screen. Both serum cholesterol (P = 0.03) and plasma fibrinogen levels (P = 0.02) were significantly elevated in cases compared with controls. There were no significant differences in coagulant activities, and in particular factor XII concentration was not significantly different between groups. Furthermore, in 47 of the subjects, 28 of whom had a history of myocardial infarction, a more detailed analysis, including measurement of VIIc after overnight incubation of plasma at 4 degrees C, was undertaken. Approximately half the subjects in either group showed some evidence of activation, though history of myocardial infarction was not in itself a significant predictor of this. All measures of XII concentration related positively to VIIc after cold activation, the strongest being the measure of amidolytic activity following activation of factor XII (XIIAm) (r = 0.5, P < 0.01). In addition, XIIa, a measure of activity due to enzymes derived from factor XII, related strongly to many of the measured lipoprotein variables, particularly VLDL cholesterol and triglycerides, supporting the hypothesis that negatively charged molecules such as free fatty acids on larger lipoprotein particles provide the contact surface necessary to activate factor XII. The findings confirm the importance of this alternative pathway in leading to activation of factor VII.

BACKGROUND

The Indian Diabetes Risk Score is a tool which was devised by the Madras Diabetes Research Foundation to screen people for the risk of developing Diabetes mellitus; it comprises of the family history, the abdominal circumference, age and the physical activity.

OBJECTIVE

This study was aimed at finding out whether the Indian Diabetes Risk Score (MDRF) correlated with the blood sugar levels, the lipid profile and the blood pressure readings of medical students.

METHODS

Seventy five female and 75 male students who signed the informed consent were selected for the study. Their IDRS was calculated by using a validated questionnaire which involved the family history, the abdominal circumference, age and the details of the physical activity. All of them had their blood pressure, fasting plasma glucose and lipid profiles measured.

RESULTS

There were 101 students with an IDRS of <30, 42 students with a moderate IDRS (30-50) and 7 who had a high IDRS of ≥60. The fasting plasma glucose was significantly correlated with the IDRS (P=0.001, r = 0.472), with a mean FPG of 84 ± 3.63mg/dl in the low risk groups, of 88 ± 4.93mg/dl in the moderate risk groups and of 94 ± 6.50mg/dl in the high risk groups. The total cholesterol value was r = 0.420 (P= 0.001), the total triglycerides value was r = 0.373 (P=0.001), the LDL cholesterol value was r = 0.578 (P=0.001) and the VLDL value was r = 0.566 (P=0.001), which positively correlated with the risk score and the HDL value r = -0.480 (P=0.001) correlated negatively with the risk score. There was no correlation between the IDRS and the blood pressure.

CONCLUSIONS

Our study showed that nearly 40% of the medical students had a moderate to a high IDRS. The IDRS significantly correlated with the fasting plasma glucose and with all the components of the lipid profile. The IDRS did not correlate with the blood pressure readings.

BACKGROUND

The aim of this study was to verify if an increase in Hnf1α gene expression could be a possible link between circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) and TAGs concentrations in chronic renal failure (CRF).

METHODS

Rats underwent 5/6 nephrectomy or a sham surgery. Liver expressions of Pcsk9, Mttp, ApoB-100, Hnf1α, Hnf4α, lipogenic enzymes and β-actin genes were quantified by qPCR. Liver levels of proteins coding by these genes were analyzed by Western blotting. Serum apoB-100 and PCSK9 concentration were estimated with an immunoassay.

RESULTS

CRF rats showed an increase in circulating concentrations of TAGs, VLDL, apoB-100 and PCSK9, along with an enhanced liver VLDL-TAG secretion rate and a coordinated liver up-regulation of genes coding: a) lipogenic enzymes; b) Mttp and ApoB-100; c) Pcsk9; d) Hnf1α and Hnf4α. Positive correlations were found between serum creatinine concentrations and: a) the liver levels of HNF1α mRNA (r = 0.79, p < 0.01) and HNF4α (r = 0.76, p < 0.01); b) the liver levels of PCSK9 mRNA (r = 0.88, p < 0.01) and serum PCSK9 concentrations (r = 0.73, p < 0.01); c) the liver levels of apoB-100 mRNA (r = 0.83, p < 0.01) and serum apoB-100 concentrations (r = 0.87, p < 0.01). Clofibrate treatment was shown to concomitantly decrease the liver levels of HNF1α, HNF4α and PCSK9 mRNA, as well as serum PCSK9, TAGs and total cholesterol concentrations in CRF rats.

CONCLUSIONS

The results presented are consistent with a cause-effect relationship between the enhanced liver expression of Hnf1α gene and its target genes the products of which are involved in synthesis, assembly and secretion of VLDL, as well as Pcsk9 gene in CRF rats. This may at least in part explain an association between circulating PCSK9 and TAGs in CRF rats and possibly also in humans with chronic kidney disease (CKD).

Patients with end-stage renal disease (ESRD) exhibit high morbidity as well as mortality for atherosclerotic cardiovascular diseases (CVD). Therefore, we investigated differences in individual lipoprotein classes and subclasses in ESRD patients under chronic high volume hemodiafiltration (HV-HDF) in comparison with a control group. We also assessed the prognosis of these patients and analyzed these parameters after 5 years follow-up.

57 patients and 50 controls were enrolled. We analysed high density (HDL) and low density (LDL) lipoprotein subfractions using the Quantimetrix Lipoprint(R) system. Subfractions were correlated with selected clinical-biochemical parameters including risk factors for atherosclerotic CVD at the beginning of and after 5 years follow-up.

Fourteen patients survived the 5-year follow-up. Follow-up results revealed a shift toward smaller HDL subfractions. In lipoproteins carrying apolipoprotein B, there was a shift of cholesterol from very low density (VLDL) to intermediate density (IDL) lipoproteins and LDLs. Hypolipidaemic therapy did not influence lipoprotein profiles in HV-HDF patients.

1. HV-HDF patients exhibit specific lipid profiles with elevated triacylglycerol, low HDL and LDL and higher content of cholesterol in remnant particles (VLDL and IDL) at the expense of large LDL. HDL subfractions were linked to the number of risk factors for CVD in the control group only. 2. Baseline lipoprotein profiles did not differ between survivors and non-survivors. Non-survivors had higher CRP and lower HDL-C. 3. During the 5 year follow-up period, cholesterol in HDL particles and lipoproteins carrying apolipoprotein B redistributed in survivors towards smaller particles, thus resembling the profile of control patients.

The metabolism of high density lipoprotein cholesteryl esters (HDL CE) was studied in the pony, an animal species without plasma cholesteryl ester transfer protein (CETP) activity. Studies were done in ponies fed a low- (1.5% fat, w/w) and a high-fat diet (11.5%, w/w fat). The ponies fed the high-fat diet had higher plasma HDL CE concentrations (1.08+/-0.15 vs. 0.84+/-0.11 mmol/l, mean+/-S.D., n=6, P<0.01) and plasma lipoprotein lipase (LPL) activities (14.3+/-4.0 vs. 5.7+/-3.4 micromol free fatty acids (FFA)/ml per h, P<0.05) than those on the low-fat diet. Plasma triacylglycerol (TAG) concentrations were lower on the high-fat diets (0.129+/-0.043 vs. 0.180+/-0.050 mmol/l), but these differences were not statistically significant. There was a negative correlation between the levels of plasma TAG (r=0.598, P<0.05) and VLDL CE (r=0.658, P<0.05) on the one hand and the HDL CE concentrations on the other hand. The transport rates of HDL CE were not significantly different between ponies fed high-fat (0.029+/-0.008 mmol HDL CE/h per l plasma) and those fed low-fat diets (0.024+/-0.004). HDL CE were transferred to low density lipoproteins (LDL) and we calculated that the percentage of LDL CE derived from HDL was 0.69+/-0.13 in the ponies fed the low-fat diet and 0.53+/-0.05 in the ponies fed the high-fat diet (P<0.05). The results of these in vivo studies suggest that in ponies, similarly as reported in rats and pigs, HDL CE can be transferred to LDL despite the absence of plasma CETP activity, and that the magnitude of this transfer is related to the levels of HDL CE as induced by the amount of fat in the diet.

The aim of this study was to evaluate whether soluble factors in plasma of familial combined hyperlipidemia (FCHL) patients affect hepatic protein secretion. Cultured human hepatocytes, i.e., HepG2 cells, were incubated with fasting plasma (20%, v/v, in DMEM) from untreated FCHL patients or normolipidemic controls. Overall protein secretion was 10-15% higher after incubation with FCHL plasma. This was specifically caused by an increase in four secreted proteins, with estimated sizes of 240, 180, 120, and <40 kD (P < 0.001, P < 0.006, P < 0.002, P < 0.02, respectively). The 240 kD protein in the secretion proteome was identified as fibronectin by mass spectrometry. Plasma fibronectin concentrations were elevated in FCHL patients, confirming biological relevance of these data. Overall protein secretion by HepG2 cells correlated with concentrations of triglycerides (r = 0.61, P < 0.001) in the applied plasma samples. VLDL+IDL isolated from FCHL patients, induced a higher protein secretion than lipoproteins isolated from controls (P < 0.001). Remarkably, secretion of apoB, the structural protein of VLDL, was stimulated to a similar extent by FCHL and control plasma. FCHL plasma did not induce excess secretion of apoB by HepG2 cells compared with control plasma. FCHL plasma did stimulate secretion of several distinct hepatic proteins, among which fibronectin was identified.

OBJECTIVE

To assess the cholesterol synthesis rate in primary hypertriglyceridaemia using the serum unesterified lathosterol concentration as an indicator.

METHODS

A cross-sectional, case-control study.

METHODS

The Karolinska Hospital, Stockholm.

METHODS

Randomly selected hyper- (n = 53) and normotriglyceridaemic (n = 57) males, 40-50 years, with a fasting serum triglyceride concentration (mean +/- SD) of 3.81 +/- 1.65 and 1.28 +/- 0.53 mmol L-1, respectively. The exclusion criterion was diabetes mellitus, defined according to the World Health Organization (WHO) guidelines.

METHODS

To compare the fasting serum concentration distributions of lathosterol, a cholesterol precursor, in hyper- and normotriglyceridaemic groups.

RESULTS

Thirty-six per cent of the hypertriglycerdaemic group had raised serum lathosterol concentrations, based on the 90th percentile of the lathosterol distribution of the normotriglyceridaemic group. In the hyper- but not in the normotriglyceridaemic group, lathosterol concentration was directly correlated with serum insulin responses to oral (r = 0.38; P = 0.007) and intravenous (r = 0.41; P = 0.005) glucose challenges.

CONCLUSIONS

One-third of a randomly selected non-diabetic hypertriglyceridaemic population had an increased serum lathosterol concentration and this might indicate an increased cholesterol synthesis rate compatible with increased production of VLDL particles, possibly as the result of chronic hyperinsulinaemia.

It has recently been shown that human red blood cells possess a voltage-independent calcium channel which can be influenced by in vitro modification of the membraneous cholesterol content. To determine whether there is also a link between plasma lipids and the calcium influx through this channel under in vivo conditions, the calcium influx was measured in red blood cells from 51 male donors (aged 41 +/- 5 years). The influx through the channel was defined as the nitrendipine (15 mumol/l)-inhibitable part of 45Ca2+ influx. The Ca(2+)-ejecting ATPase was inhibited by vanadate. The results demonstrate a strong inverse relationship (r = -0.81; P < 0.001) between the plasma concentration of high density lipoproteins (HDL) and 45Ca2+ influx. No significant correlation was found between 45Ca2+ influx and triglycerides, low density lipoproteins (LDL), very low density lipoproteins (VLDL), total plasma cholesterol or extracellular electrolytes (K+, Na+, Ca2+, Mg2+). The results indicate that HDL are involved in the modulation of the calcium channel and provide a link between the cellular cholesterol turnover and the calcium influx in the pathogenesis of atherosclerosis and hypertension.

The early detection of hyperlipoproteinemia in newborn infants has so far been based upon estimation of cord blood total lipids (cholesterol and triglyceride) and lipoprotein-lipids (VLDL-, LDL- and HDL-cholesterol). To be able to make a direct estimation of cord serum beta-lipoproteins (VLDL + LDL) two quite different methods were modified, one immunological and the other turbidimetric. Good correlations were found to VLDL- + LDL-cholesterol isolated in the ultracentrifuge (r = 0.848 and 0.831, respectively). If neonatal screening for hyperlipoproteinemia is considered, we recommend the very easy and inexpensive turbidimetric method. Furthermore, using cord serum, two conventional precipitation methods with heparin-CaCl2 and heparin-MnCl2 were compared by ultracentrifugation and high correlations were found (r = 0.923 and 0.899, respectively). A clamping study showed that following early clamping of the cord, the concentration of cord serum lipids and lipoproteins did not change markedly within the first five minutes. Storing experiments showed that serum should be separated within the first 12 h to avoid unpredictable changes in the concentration of cord serum lipids and lipoproteins.

OBJECTIVE

To investigate associations between plasma adiponectin concentration and very-low density lipoprotein-triglyceride (VLDL-TG) secretion and catabolism in postmenopausal women.

RESULTS

This cross-sectional study included 30 postmenopausal women. Plasma adiponectin concentration was measured by ELISA. Insulin sensitivity was assessed by a 2-h euglycemic-hyperinsulinemic clamp. Fasting plasma glucose (FPG) and 2-hour plasma glucose (2hPG) were measured during an oral glucose tolerance test. The calculation of VLDL-TG fractional catabolic rate (FCR) and VLDL-TG total secretion rate (TSR) were based on the monoexponential decrease of TG-[²H₅] glycerol values obtained following the administration of a ²H₅-glycerol bolus. Plasma adiponectin concentration was negatively associated with VLDL-TG TSR (r=-0.50; p=0.005) and positively associated with VLDL-TG FCR (r=0.54; p<0.002). This latter association remained significant after further adjustments for insulin sensitivity, visceral adipose tissue, HDL-C, FPG and 2hPG concentrations. In a multivariate model including adiponectin, insulin sensitivity and 2hPG, plasma adiponectin level was the strongest correlate of VLDL-TG FCR.

CONCLUSIONS

Elevated plasma adiponectin concentration is associated with a favourable VLDL-TG metabolism.

Previously, we have shown, in vivo, that the acyl coenzyme A: cholesterol acyltransferase (ACAT) inhibitor avasimibe decreases hepatic apolipoprotein (apo) B secretion into plasma. To test the hypothesis that avasimibe modulates postprandial triglyceride-rich lipoprotein (TRL) metabolism in vivo, an oral fat load (2 g fat/kg) containing retinol was given to 9 control miniature pigs and to 9 animals after 28 days treatment with avasimibe (10 mg/kg/day, n=5; 25 mg/kg/day, n=4). The kinetic parameters for plasma retinyl palmitate (RP) metabolism were determined by multi-compartmental modeling using SAAM II. Avasimibe decreased the 2-h TRL (d<1.006 g/mL; S(f)>20) triglyceride concentrations by 34%. The TRL triglyceride 0-12 h area under the curve (AUC) was decreased by 21%. In contrast, avasimibe had no effect on peak TRL RP concentrations, time to peak, or its rate of appearance into plasma, however, the TRL RP 0-12 h AUC was decreased by 17%. Analysis of the RP kinetic parameters revealed that the TRL fractional clearance rate (FCR) was increased 1.4-fold with avasimibe. The TRL RP FCR was negatively correlated with very low density lipoprotein (VLDL) apoB production rate measured in the fasting state (r=-0.504). No significant changes in total intestinal lipid concentrations were observed. Thus, although avasimibe had no effect on intestinal TRL secretion, plasma TRL clearance was significantly increased; an effect that may relate to a decreased competition with hepatic VLDL for removal processes.

Apoproteins of chylomicrons, very low density lipoprotein (VLDL), and a low density + high density fraction secreted by proximal and distal rat small intestine into mesenteric lymph were examined during triglyceride (TG) absorption. Apoprotein output and composition were determined and the turnover rates of labeled non-apoB (soluble) apoproteins in lipoprotein fractions were measured after an intraluminal [(3)H]leucine pulse during stable TG transport into lymph. The output of VLDL apoproteins exceeded that of chylomicrons during the absorption of 45 micro mol of TG per hour. More [(3)H]leucine was incorporated into VLDL than into chylomicrons and the decay of newly synthesized VLDL apoproteins was more rapid than that of chylomicrons, in part due to higher concentrations of apoA-I and apoA-IV with a rapid turnover rate. Chylomicrons from proximal intestine contained more apoA-I and less C peptides than chylomicrons from distal intestine. Ninety percent of [(3)H]leucine incorporated into soluble apoproteins was in apoA-I and apoA-IV, but little apoARP was labeled. The turnover rate of apoA-I and apoA-IV differed significantly in the lymph lipoproteins examined. Although total C peptide labeling was small, evidence for intestinal apoC-II formation and differing patterns of apoC-III subunit labeling was obtained. [(3)H]Leucine incorporation and apoprotein turnover rates in lipoprotein secreted by proximal and distal intestine were similar. The different turnover rates of apoA-I and apoA-IV in individual lipoproteins suggest that these A apoproteins are synthesized independently in the intestine.-Holt, P. R., A-L. Wu, and S. Bennett Clark. Apoprotein composition and turnover in rat intestinal lymph during steady-state triglyceride absorption.

OBJECTIVE

To study the fractional esterification rate of cholesterol on HDL particles (FERHDL) in adults with type 2 diabetes and assess its correlation with serum lipids and other coronary heart disease (CHD) risk factors.

METHODS

FERHDL was measured in 90 adult (57 men, 33 women) patients by an isotopic assay method involving several steps, including preparation of VLDL- and LDL-depleted plasma, labeling of the sample with a trace amount of tritiated cholesterol, separation of free and esterified cholesterol fractions by chromatography post incubation, and subsequent counting of radioactivity in the individual fractions.

RESULTS

Male patients have higher FERHDL values than their female counterparts. When HDL cholesterol was controlled for in a multivariate regression analysis, the sex factor was not significant. There was a significant positive correlation between FERHDL and plasma total cholesterol (r = 0.32), triglycerides (r = 0.82), apolipoprotein B (apo B; r = 0.48), insulin (r = 0.46), BMI (r = 0.31), and waist-to-hip ratio (WHR; r = 0.50). There was a negative correlation between FERHDL and HDL cholesterol (r = -0.76) and apolipoprotein AI (r = -0.60). When both HDL cholesterol and triglycerides were controlled for, the only significant correlation was between FERHDL and BMI.

CONCLUSIONS

Non-insulin-requiring type 2 diabetic patients have FERHDL, which correlated positively with triglycerides and negatively with HDL cholesterol. The positive correlation of FERHDL with serum insulin, WHR, total cholesterol, and apo B, but not that with BMI, loses its significance when HDL cholesterol and triglycerides are controlled. The sex difference between men and women in FERHDL also loses its significance when HDL cholesterol is controlled.

OBJECTIVE

The investigation of the association between retinol-binding protein 4 (RBP4) and lipoproteins in subjects with hypertriglyceridemia.

METHODS

Forty-six obese or overweight hypertriglyceridemic patients were studied at baseline and 20 of them underwent a hypocaloric low-fat diet for 3 months.

RESULTS

Plasma RBP4 levels were positively correlated with serum triglycerides (TG) in the subgroup of patients with TG <200 mg/dL (r=0.453, p=0.039) and negatively correlated with TG in patients with TG ≥200 mg/dL (r=-0.487, p=0.019). In the subgroup with TG <200 mg/ dL, subjects with circulating RBP4 above the median 46 mg/L had higher levels of intermediate density lipoprotein-cholesterol (IDL-C), low-density lipoprotein-cholesterol (LDL-C) and apolipoprotein B (ApoB), while these differences were absent in patients with TG ≥200 mg/dL. The associations of percentage changes of circulating RBP4 with the percentage changes of LDL-C, very low-density lipoprotein-cholesterol (VLDL-C) and ApoB were positive after the first month and 3 months of diet for patients with baseline TG <200 mg/dL, while no correlations existed for patients with TG ≥200 mg/dL.

CONCLUSIONS

The positive association between circulating RBP4 and ApoB-containing lipoproteins in a steady metabolic state, as well as during a hypocaloric diet, appears to be attenuated in patients with very high TG.

Eleven hyperlipidaemic patients received two formulations of fenofibrate (differing in in vitro dissolution) in randomized sequence, each for 6 weeks. Formulation N, giving a 2-3-fold higher plasma fenofibrate level compared to R, lowered both the cholesterol and triglyceride levels far more than R. Changes in the total and high density lipoprotein cholesterol levels were not significantly correlated with the fenofibrate level. A highly significant correlation was detected for triglycerides in Type IV patients, and for changes both in very low density lipoprotein (VLDL) cholesterol and triglycerides in the entire group of patients. In conditions of widely distributed steady state levels of an absorbable hypolipidaemic drug, a significant correlation may thus be detected between the plasma level and the reduction of VLDL - associated lipids.

Obese donkeys are susceptible to a hyperlipaemic crisis characterised by high plasma triglyceride concentrations. In this study, the relationships between the body condition of 24 donkeys and their basal lipid metabolism were investigated. Plasma cholesterol, triglyceride and lipoprotein cholesterol concentrations were measured in healthy donkeys classified according to their body condition as thin, ideal or obese. There were significant differences between the groups in the concentrations of triglyceride and very low density lipoprotein (VLDL), which increased in concentration with body condition (P less than 0.05). Cholesterol, low density lipoprotein (LDL) and high density lipoprotein (HDL) concentrations were similar in all the groups. Triglyceride and VLDL concentrations were positively correlated with body weight (r = 0.82) and plasma free fatty acid concentration (r = 0.48). There were no significant differences in basal plasma concentrations of insulin or cortisol. These results suggest that obesity in donkeys is associated with changes in lipid and lipoprotein metabolism that might predispose the animals to hyperlipaemia.

Oxidative modification of low-density lipoproteins has been implicated in impaired lipid metabolism and its deposition in the arterial wall, and atherosclerosis. This study was carried out to determine the relationship between the in vitro oxidizability of low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) and the cholesterol, phospholipid and triglyceride (TG) levels in the blood of Type-I diabetic patients. LDL+VLDL was isolated using a micro-affinity column from serum of diabetic patients (n = 34) and age-matched normal individuals (n = 22). The oxidative susceptibility of LDL+VLDL was determined by treatment with 25 microM CuCl(2) for 1.5 h. The levels of total-, LDL-, and HDL-cholesterol, phospholipids and triglycerides, as well as glycated hemoglobin (HbA(t)), were measured in the blood using standard methods. The diabetics had significantly higher levels of triglycerides and phospholipids, but cholesterol levels were similar between Type-I diabetics and age-matched normals. However, among diabetics, there was a significant correlation between the in vitro oxidation of LDL+VLDL at 1.5 h and total cholesterol (r = 0.49, P<0.002), and LDL cholesterol (r = 0.54, P<0.001) and TG (r = 0.34, P<0.05) levels. The level of in vitro oxidizability of LDL+VLDL did not have any correlation with HDL-cholesterol or phospholipid levels. The level of glycemic control (HbA(1)) did not have any correlation with levels of LDL- or HDL-cholesterol or triglycerides, but was significantly correlated with phospholipid levels (r = 0.48, P<0.005). This study suggests that the levels of LDL-cholesterol and triglycerides in the blood are directly related to the degree of in vitro oxidative susceptibility of low-density lipoproteins in Type-1 diabetic patients.

BACKGROUND

Existing studies have demonstrated the clinical significance of triglyceride content in VLDL (VLDL-TG) and intermediate-density lipoprotein (IDL-TG). We developed a homogeneous assay protocol to directly measure VLDL-TG.

METHODS

Possible reagents and conditions for measuring VLDL-TG were comprehensively tested, and the "best" combination was determined. Healthy persons were instructed to consume a fatty meal after 15-h overnight fasting. Serum VLDL-TG + IDL-TG concentrations were measured using the proposed method. Patients with serum LDL-cholesterol concentrations>> or = 3.62 mmol/L (140 mg/dL) were administered simvastatin at a daily dose of 5 mg, and serum VLDL-TG concentrations were then measured.

RESULTS

The combination of 2 nonionic surfactants played an important role in differentiating VLDL and IDL from other lipoproteins, probably via specific interactions with phospholipids and apolipoproteins. The regression line of the proposed method (y) and the ultracentrifugal assay (x) was: y = 0.98x + 0.31 mmol/L (r = 0.98; n = 73; P < 0.05). The difference between postprandial total TG and VLDL-TG concentrations was statistically significant (P < 0.05). After 8 weeks of therapy with simvastatin, total TG and LDL-cholesterol concentrations were 13.6% and 26.3% lower, respectively (P < 0.05), whereas VLDL-TG did not show any significant decrease.

CONCLUSIONS

Our homogeneous method can measure TG content in VLDL and IDL.