Atypical type III hyperlipoproteinemia in a patient with Ig A myelomatosis

Summary We studied a 58-year-old woman with severe therapy-refractory hyperlipidemia, xanthomatosis, and multiple myeloma (immunoglobulin A, lambda light chain). The lipid disorder became evident about half a year prior to the expression of myelomatosis. Clinical symptoms were similar to those found in classical type III hyperlipoproteinemia but the underlying metabolic defect was different from the one described in this primary dyslipoproteinemia. The patient has the heterozygous apolipoprotein E3/2 phenotype and her VLDL-cholesterol/serum-triglyceride ratio is unusually low at 0.05. Evidence is given that the hyperlipoproteinemia is due to an impaired catabolism of intermediate density lipoproteins probably because of a reduced hepatic triglyceride lipase activity.Abbreviations AIH autoimmune hyperlipidemia - Chol cholesterol - HDL high density lipoproteins - HLP hyperlipoproteinemia - HTGL hepatic triglyceride lipase - IDL intermediate density lipoproteins - IEF isoelectric focusing - Ig immunoglobulin - LDL low density lipoproteins - LPL lipoprotein lipase - PL phospholipids - TG triglycerides - VLDL very low density lipoproteins     

Effect of pravastatin on metabolic parameters of apolipoprotein B in patients with mixed hyperlipoproteinemia

Summary 3-Hydroxy-3-methylgluratyl coenzyme A reductase inhibitors reduce plasma cholesterol in different forms of hyperlipoproteinemia. Although an increase in low-density lipoprotein (LDL) receptor activity is the proven mechanism of this therapy in familial hypercholesterolemia, the mechanism remains controversial in mixed hyperlipoproteinemia. A decreased production of apolipoprotein B (apoB) and/or an increased removal of lipoproteins could mediate the hypocholesterolemic effect of these drugs. The effect of pravastatin on the metabolism of apoB was evaluated in a randomized, double blind, placebo controlled, cross-over study in five men with mixed hyperlipoproteinemia. Metabolic parameters for apoB were determined using endogenous labeling with [1^t3C]leucine and [¹⁵N]glycine and multicompartmental modeling. During pravastatin therapy cholesterol, LDL cholesterol, apoB, and LDL apoB levels were significantly reduced (P < 0.01) by 18%, 20%, 27%, and 29%, respectively, while triglyceride and high-density lipoprotein cholesterol levels remained unchanged. Pravastatin therapy increased the fractional catabolic rate of very low density lipoprotein apoB from 3.9±0.6 to 5.1±1.7 per day (P = 0.08) and that of LDL apoB from 0.37±0.09 to 0.46±0.10 per day (P<0.01). The apoB production (placebo 35.2±11.9 mg/kg per day; pravastatin 25.8±8.7 mg/kg per day) and conversion of very low density lipoprotein apoB to LDL apoB (placebo 65%, pravastatin 57%) remained stable. Thus, also in mixed hyperlipoproteinemia 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase the catabolism of apoB-containing lipoproteins without significantly affecting the production of apoB.Abbreviations apoB apolipoprotein B - FCR fractional catabolic rate - HMG hydroxy-methylglutaryl - CoA coenzyme A - FH familial hypercholesterolemia - HDL high-density lipoprotein - IDL intermediate-density lipoprotein - LDL low-density lipoprotein - VLDL very low density lipoprotein Dedicated to Prof. Dr. G. Paumgartner on the occasion of his 60th birthday     

Homogenous low-density lipoprotein assay in type III hyperlipoproteinemia

To investigate whether homogenous analysis of serum low-density lipoprotein cholesterol(LDL-C) was applicable in type III hyperlipoproteinemic subjects, 3 reagents were used to estimate LDL-C in 2 cases with apoE 2/2 phenotype. Each measurements were compared to LDL-C levels by ultracentrifugation(density: 1.019-1.063). LDL-C levels by homogenous analysis with any of the reagents were higher than those by ultracentrifugation, and the difference was varied between the reagents: +14-24% by LDL-EX, +29-55% by Cholestest LDL, and +89-115% by Determiner LDL-C. The cross-reaction by the reagents to intermediate density lipoprotein(IDL) and very low density lipoprotein(VLDL) cholesterol was studied in a case; 22% of cholesterol in these fractions was measured by LDL-EX, 32% by Cholestest LDL, and 110% by Determiner LDL-C. A part of the sample serum was stored at -60 degrees C for several days and melted for re-analysis of homogenous LDL-C levels. After the freezing process, IDL fraction pattern on electrophoresis had been changed and homogenous LDL-C levels by all reagents were different from the measurements of native serum. These results indicated that using reagents with low cross-reaction to IDL and VLDL fractions and careful sample handling are important in homogenous LDL-C analysis in type III hyperlipoproteinemia.     

Disturbance of apolipoprotein B100 containing lipoprotein metabolism in severe hyperlipidemic and lipodystrophic HIV patients on combined antiretroviral therapy: evidences of insulin resistance effect

The aim was to study the mechanisms involved in the dyslipidemia associated with lipodystrophy in HIV infected patients on antiretroviral therapy (ART). We investigated the in vivo kinetics of apolipoprotein B100 (apoB) containing lipoproteins using a 14 h primed constant infusion of [5,5,5, (2)H(3)] leucine and compartmental modelling in normolipidemic without lipodystrophy (7 patients, NLD) or dyslipidemic with lipodystrophy (7 patients, LD) treated with ART. Subjects in group LD showed higher plasma triglycerides (5.73+/-3.58 vs 1.29+/-0.54 g/L, p<0.005), total cholesterol (2.98+/-0.95 vs 1.74+/-0.26 g/L, p<0.05), apoB (1.49+/-1.11 vs 0.51+/-0.11 g/L, p<0.005) and apolipoprotein CIII in apoB containing lipoproteins (117.7+/-42.2 vs 22.6+/-23.9 g/L, p<0.005). LD subjects exhibited an insulin resistant as observed by higher HOMA (3.44+/-1.62 vs 1.60+/-0.61, p<0.05). They exhibited an increase in VLDL (1.24+/-0.33 vs 0.80+/-0.21 mg/kg/h, p<0.05), decrease in IDL (0.20+/-0.10 vs 0.48+/-0.24 mg/kg/h, p<0.05) and no difference in LDL (0.38+/-0.19 vs 0.45+/-0.25 mg/kg/h) production rate. LD subject also showed a dramatic decrease in transformation of VLDL to IDL (0.013+/-0.010 vs 0.258+/-0.206 h(-1), p<0.005) and IDL to LDL (0.088+/-0.093 vs 0.366+/-0.189 h(-1), p<0.05) and a decrease in fractional catabolic rate (FCR) of VLDL (0.199+/-0.132 vs 0.555+/-0.398 h(-1), p<0.05), IDL (0.110+/-0.08 vs 0.523+/-0.275 h(-1), p<0.05) and LDL (0.010+/-0.005 vs 0.025+/-0.014 h(-1), p<0.05). These disturbances, overproduction and an overall delayed catabolism of apoB, are similar to those observed using the same protocol in insulin resistant subjects. Our study suggests that metabolic disturbance of apoB100 observed in lipodystrophic HIV in combined antiretroviral therapy are consecutive to insulin resistance induced by the treatment.     

Elevated circulating levels of tumor necrosis factor in severe chronic heart failure

BACKGROUND AND METHODS. Although cachexia often accompanies advanced heart failure, little is known about the causes of the cachectic state. To assess the potential role of tumor necrosis factor in the pathogenesis of cardiac cachexia, we measured serum levels of the factor in 33 patients with chronic heart failure, 33 age-matched healthy controls, and 9 patients with chronic renal failure. RESULTS. Mean (+/- SEM) serum levels of tumor necrosis factor were higher in the patients with heart failure (115 +/- 25 U per milliliter) than in the healthy controls (9 +/- 3 U per milliliter; P less than 0.001). Nineteen of the patients with chronic heart failure had serum levels of tumor necrosis factor greater than or equal to 39 U per milliliter (greater than 2 SD above the mean value for the control group), whereas the remaining 14 patients had serum levels of tumor necrosis factor below this level. The patients with high levels of tumor necrosis factor were more cachectic than those with low levels (82 +/- 3 vs. 95 +/- 6 percent of ideal body weight, respectively; P less than 0.05) and had more advanced heart failure, as evidenced by their higher values for plasma renin activity (2.92 +/- 0.53 vs. 1.06 +/- 0.53 ng per liter per second [10.5 +/- 1.9 vs. 3.8 +/- 1.9 ng per milliliter per hour]; P less than 0.01) and lower serum sodium concentration (135 +/- 1 vs. 138 +/- 1 mmol per liter; P less than 0.05). The group with high levels of tumor necrosis factor also had lower hemoglobin levels (7.82 +/- 0.2 vs. 8.69 +/- 0.4 mmol per liter [12.6 +/- 0.4 vs. 14.0 +/- 0.6 g per deciliter]) and higher values for blood urea nitrogen (19.5 +/- 2.2 vs. 12.5 +/- 1.8 mmol per liter) than the group with low levels of tumor necrosis factor (P less than 0.05 for both). The high levels of tumor necrosis factor were not due solely to decreased renal clearance, however, since the levels in the patients with heart failure were considerably higher than those in the nine patients with chronic renal failure (115 +/- 25 vs. 45 +/- 25 U per milliliter; P less than 0.05). CONCLUSIONS. These findings indicate that circulating levels of tumor necrosis factor are increased in cachectic patients with chronic heart failure and that this elevation is associated with the marked activation of the renin-angiotensin system seen in patients with end-stage cardiac disease.     

The pathophysiology of cholesterol metabolism in man

Summary The concentration of low density lipoprotein in human plasma depends on the balance between its rates of synthesis and catabolism. Although both processes appear to be independently regulated they occur side by side in the liver and may be linked via the activity of the high affinity low density lipoprotein receptor on hepatocyte membranes. Dietary changes such as cholesterol feeding or variation in fat content can promote synthesis of the lipoprotein without changing catabolism while other interventions (e.g. sequestrant resin therapy) have the opposite effect. These different responses may be explained on the basis of compartmentalisation of regulatory sterol pools in the liver cell.Abbreviations apo apolipoprotein - FH familial hypercholesterolaemia - HDL high density lipoproteins (d=1.063–1.21 kg/l) - HMG CoA reductase 3-hydroxy-3-methylglutaryl Coenzyme A reductase - IDL intermediate density lipoproteins (d=1.006–1.019 kg/l) - LDL low density lipoproteins (d=1.019–1.063 kg/l) - VLDL very low density lipoproteins (d<1.006 kg/l)     

Evaluation of the classical methods for the diagnosis of type III hyperlipoproteinemia

Summary Familial type III hyperlipoproteinemia is characterized by the presence of elevated plasma levels of very low density lipoproteins (VLDL) which contain an increased amount of cholesterol and by the presence of a significant amount of lipoproteins with an intermediate density between that of VLDL and low density lipoproteins (LDL); the intermediate density lipoproteins, designated IDL or Lp III, have a slower electrophoretic migration rate than VLDL, and are found in the ultracentrifugal top fraction as a contaminant. Classically, the diagnosis of type III is based on the demonstration of beta-migrating lipoproteins in the ultracentrifugal top fraction (density <1.006), thus floating beta-lipoprotein. More recently, it has been proposed that an elevated VLDL-cholesterol to triglyceride ratio is diagnostic of the disorder. In the present report, we have compared the two methods for their diagnostic value and have concluded that the chemical index definition is the more reliable method for the diagnosis of type III hyperlipoproteinemia.     

Improvement in lipid profile by nocturnal hemodialysis in patients with end-stage renal disease

Dyslipidemia is associated with uremia and an increased risk of cardiovascular disease. The uremic dyslipidemia syndrome is characterized by an abnormal lipoprotein profile that results in (1) an elevation of triglyceride (TG) rich lipoproteins, very low density lipoprotein (VLDL), and intermediate density lipoprotein (IDL); (2) a reduction in high density lipoprotein (HDL) levels; and (3) a higher fraction of atherogenic, small dense low density lipoprotein (LDL). Nocturnal hemodialysis (NHD) is a home based renal replacement therapy that provides better control of uremia than conventional hemodialysis (CHD) and that may improve dyslipidemia. To test this hypothesis, we conducted a prospective cohort study of 11 patients with end-stage renal disease (ESRD) (age 38+/-3 years [mean+/-SEMI) before and after conversion from CHD to NHD. Weight, blood pressure (BP), serum hemoglobin (Hb), phosphate (PO4), and albumin (Alb) were assessed at baseline and at 3 months after conversion to NHD. Dialysis dose on CHD and NHD was assessed using equilibrated Kt/V (eKt/V). A 12 hour fasting lipid profile (total cholesterol [TC], TG, HDL, LDL, HDL/TC) was obtained once while on CHD and at 3 months after conversion to NHD. After conversion from CHD to NHD, eKt/V per session increased significantly (from 1.13+/-0.05 to 2.10+/-0.07; p < 0.05). TG level decreased significantly (from 2.05+/-0.30 to 1.01+/-0.14 mmol/L; p < 0.001), and HDL level increased significantly (from 1.17+/-0.13 to 1.65+/-0.14 mmol/L; p < 0.001). HDL/TC also increased significantly (from 0.26+/-0.03 to 0.35+/-0.02; p < 0.001). TC and LDL levels were unchanged. HDL levels increased and TG levels decreased in all patients. There was no difference in weight, Hb, and Alb. Systolic BP and PO4 were significantly lower, and there was a trend toward a reduction in cardiovascular medications. The mechanism for the improvement in lipid profile requires further study.     

Higher values of hepatic lipase activity in postmenopause: relationship with atherogenic intermediate density and low density lipoproteins

OBJECTIVE: To investigate the enzymatic activity of hepatic lipase (HL) in postmenopausal women (PMW) and reproductive age women (RAW); and to evaluate the relationship between this enzyme and the atherogenic intermediate density lipoproteins (IDL) and low density lipoproteins (LDL), and antiatherogenic high density lipoproteins (HDL) and its subfractions (HDL2 and HDL3). DESIGN: We studied 55 PMW receiving no hormonal treatment in a cross-sectional study in comparison with a control group of 55 RAW, matched by body mass index. Follicle-stimulating hormone was > 40 mUI/ml in PMW and 3-12 mUI/ml in RAW. PMW presented at least 1 year of natural menopause and no more than 10 years of amenorrhea with E2 serum concentration < 15 pg/ml. RESULTS: HL activity was significantly higher in PMW versus RAW (14.0 +/- 1.4 vs. 10.9 +/- 0.4 micromol of fatty acids/ml of postheparin plasma, respectively, mean +/- SEM, p < 0.001). In PMW, IDL cholesterol showed a positive correlation with LDL cholesterol (r = 0.28, p < 0.05), and HDL2 cholesterol was inversely correlated with HL activity (r = 0.31, p < 0.05). HL was positively correlated with plasma concentration of LDL cholesterol in both groups (r = 0.27, p < 0.05). The higher values of HL activity and IDL cholesterol were independent of age. CONCLUSIONS: Higher HL activity is associated with a more atherogenic profile in PMW.     

The influence of simvastatin alone or in combination with gemfibrozil on plasma lipids and lipoproteins in patients with type III hyperlipoproteinemia

Summary Nineteen adult patients with type III hyperlipoproteinemia (HLP) and homozygosity for apolipoprotein (apo) E2 were treated with the 3-hydroxy-3-methyl glutaryl coenzyme A (HMG CoA) reductase inhibitor simvastatin (20 or 40 mg per day) alone or in combination with the fibrate derivative gemfibrozil (450 mg per day) during a 30-week outpatient study. With the 20-mg dose (n = 19) the mean plasma cholesterol level decreased from 13.24±8.04 8.04 at baseline to 8.04±4.19 mmol/l (mean reduction 39.3%; P<0.05), and the mean plasma triglyceride level decreased from 13.47±19.22 to 7.84±7.71 mmol/l (–41.8%; NS); this was due to a decrease in very low density lipoprotein (VLDL) cholesterol from 8.95±8.64 to 4.94±4.24mmo1/l (–44.8%; NS), a decrease in low density lipoprotein (LDL) cholesterol from 3.54±0.93to 2.25 ± 0.59 mmol/l (–36.5%; P<0.01), and an increase in high density lipoprotein (HDL) cholesterol from 0.72±0.28 to 0.85±0.34 (+18.1%; NS). Thirteen patients were treated with 40 mg simvastatin per day. Under this regimen there was a further significant decrease in LDL cholesterol from 2.33±0.62 to 1.81±0.49 mmol/l (–22.3%; P<0.01). In six patients who remained hyperlipidemic on monotherapy combination drug therapy with simvastatin (40 mg per day) and gemfibrozil (450 mg per day) was given. Compared to simvastatin alone the addition of gemfibrozil further lowered plasma concentrations of total cholesterol by 14.9%, VLDL cholesterol by 23.5%, and triglycerides by 17.1%, although this was not statistically significant. No patient was discontinued from single or combination drug therapy, and no severe clinical or biochemical side effects were observed. The results of this study demonstrate the usefulness of simvastatin in the therapy of type III HLP and indicate that in individual patients who remain hyperlipidemic on monotherapy combination drug therapy with both of these drugs is effective in further reducing plasma concentrations of total cholesterol, VLDL cholesterol, and triglycerides. Although no patient in this investigation developed myopathy or rhabdomyolysis, combined fibrate-HMG CoA reductase inhibitor treatment should be considered only for severe forms of hyperlipidemia and for patients who do not respond sufficiently to mon-therapy of any of these drugs.Abbreviations Apo Apolipoprotein - CPK creatine phosphokinase - GGT gamma-glutamyl transpeptidase - HDL high density lipoproteins - HLP hyperlipoproteinemia - HMG CoA 3-hydroxy-3-methyl glutaryl coenzyme A - IDL intermediate density lipoproteins - LDL low density lipoproteins - TG triglycerides - VLDL very low density lipoproteins     

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.     

Lipoprotein (a), low-density,intermediate-density lipoprotein,and blood pressure in a young male population

Summary Both hypercholesterolemia and hypertension are risk factors for atherosclerotic vascular disease, and elevated cholesterol levels occur more frequently than expected in patients with hypertension. Elevated levels of intermediate-density lipoproteins (IDL) and low-density lipoproteins (LDL) were shown to be atherogenic, and LDL, comprising the major cholesterol-carrying fraction in human plasma, are structurally related to lipoprotein (a) [Lp(a)], a further risk factor for atherosclerosis. In the present study we investigated 200 male employees (mean age 26±7 years) to determine whether the relationship of IDL and Lp(a) to systemic blood pressure is similar to the reported correlations between total and LDL cholesterol and systemic blood pressure. To this end blood pressure was measured several times in each individual, and lipids, lipoprotein-cholesterol, apolipoprotein B (apo B), and Lp(a) were determined in fasting serum. IDL cholesterol and apo B, the main protein component of IDL and LDL correlated with blood pressure. However, levels of Lp(a) correlated neither with systolic or diastolic blood pressure nor with lipoprotein cholesterol, body weight, or age. Although IDL and Lp(a) are considered lipoprotein risk factors for atherosclerosis, levels of Lp(a), unlike IDL, are not related to blood pressure, body weight, or age. Our data suggest different metabolic and pathophysiological mechanisms of the risk factors, IDL, LDL, and Lp(a).Abbreviations VLDL very low density lipoprotein - IDL intermediate-density lipoprotein - LDL low-density lipoprotein - ApoB Apolipoprotein B - Lp(a) lipoprotein (a) - BMI body mass index Dedicated to Prof. Dr. N. Zöllner on the occasion of his 70th birthday     

Very low density lipoprotein apolipoprotein B metabolism in humans

Summary The human plasma lipoproteins encompass a broad spectrum of particles of widely varying physical and chemical properties whose metabolism is directed by their protein components. Apolipoprotein B₁₀₀ (apo B₁₀₀) is the major structural protein resident in particles within the Svedberg flotation range 0–400. The largest of these, the very low density lipoprotein (VLDL), rich in triglyceride, are metabolised by sequential delipidation through a transient intermediate density lipoprotein (IDL) to cholesterol-rich low density lipoproteins (LDL). Several components contribute to the regulation of this process, including (a) the lipolytic enzymes lipoprotein lipase and hepatic lipase (b), apolipoproteins B, CII, CIII and E, and (c) the apolipoprotein B/E or LDL receptor. Lipoprotein lipase acts primarily on large VLDL of Sf 60–400. Hepatic lipase on the other hand seems to be critical for the conversion of smaller particles (Sf 12–60) to LDL (Sf 0–12). Although most apo B₁₀₀ flux is directed to the production of the delipidation end product LDL, along the length of the cascade there is potential for direct removal of particles from the system, probably via the actions of cell membrane receptors. This alternative pathway is particularly evident in hypertriglyceridaemic subjects, in whom the delipidation process is retarded.VLDL metabolism shows inter subject variability even in normal individuals. In this regard, apolipoprotein E plays an important role. Normolipidaemic individuals homozygous for the apo E₂ variant exhibit gross disturbances in the transit of B protein through the VLDL-IDL-LDL chain.Abbreviations apo B, C, E Apolipoprotein B, C, E - CETP Cholesteryl ester transfer protein - FCH Familial combined hyperlipidaemia - FH Familial hypercholesterolaemia - FHTG Familial hypertriglyceridaemia - HDL High density lipoprotein - HL Hepatic lipase - IDL Intermediate density lipoprotein - LDL Low density lipoprotein - LpL Lipoprotein lipase - RFLP Restriction fragment length polymorphism - Sf Svedberg flotation coefficient - VLDL Very low density lipoprotein - WHHL Watanabe heritable hyperlipidemic     

Protein of Escherichia coli interacting specifically with human low density lipoproteins

Escherichia coli 48 kDa protein interacting specifically with human low-density lipoproteins is described. The dissociation constant of this highly specific interaction was found to be equal to 4 mkg LDL per 1 ml or 7.3 x 10 M, which is comparable with the dissociation constant of the complex formed by LDL and human LDL receptor. A protocol for purifying the E. Coli binding protein was developed and antibodies against this purified protein were raised. The absence of sequences with homology to the ligand-binding repeats of the human LDL receptor in E. Coli proteome was shown by computer analysis of E. Coli genome. A conclusion was made that binding of the human LDL with specific E. Coli protein is thus mediated by other sequences and by another mechanism different from that, which occurs in human cells during the interaction of lipoproteins with their specific receptor. The establishment of specific interaction between E. Coli protein and human LDL can turn out to be useful in the future for purifying lipoproteins of a specific class and for administering plasmapheresis in patients with severe hyperlipoproteinemia.     

Erythrocyte-bound low-density lipoprotein immune complexes lead to cholesteryl ester accumulation in human monocyte-derived macrophages

We have recently shown that incubation of macrophages with insoluble immune complexes (IC) containing low-density lipoproteins (LDL) leads to intracellular accumulation of esterified cholesterol (CE). This accumulation is associated with morphological transformation of the macrophages into "foam cells." In order to better characterize the conditions that lead to the uptake of LDL-IC and CE accumulation on macrophages, we studied the effects of soluble, insoluble, and red blood cell (RBC)-bound LDL-IC on macrophage lipid and lipoprotein metabolism. Using both apoB or IgG [anti-LDL] as the labeled moieties, we observed that the uptake of LDL-IC by human monocyte-derived macrophages (HMM) was markedly enhanced when the IC were adsorbed to RBC. Competition studies with unlabeled heat-aggregated IgG, native LDL, and acetylated LDL demonstrated that LDL-IC were ingested via the Fc receptor of HMM. The uptake of RBC-bound LDL-IC led to a marked intracellular accumulation of cholesteryl esters in HMM (78.4 +/- 1.7 vs 5.5 +/- 0.6 micrograms/mg cell protein; P less than 0.01) which apparently resulted from delayed degradation of the ingested LDL. Thus, it appears that the metabolism of LDL is altered when it is ingested as part of an antigen-antibody complex. These findings suggest that the formation of LDL-IC and their adsorption to red cells may play a significant role in the onset or in the evolution of human atherosclerosis.     

Insulin resistance in essential hypertension

High blood pressure is prevalent in obesity and in diabetes, both conditions with insulin resistance. To test whether hypertension is associated with insulin resistance independently of obesity and glucose intolerance, we measured insulin sensitivity (using the euglycemic insulin-clamp technique), glucose turnover (using [3H]glucose isotope dilution), and whole-body glucose oxidation (using indirect calorimetry) in 13 young subjects (38 +/- 2 years [+/- SEM]) with untreated essential hypertension (165 +/- 6/112 +/- 3 mm Hg), normal body weight, and normal glucose tolerance. In the postabsorptive state, all measures of glucose metabolism were normal. During steady-state euglycemic hyperinsulinemia (about 60 microU per milliliter), hepatic glucose production and lipolysis were effectively suppressed, and glucose oxidation and potassium disposal were normally stimulated. However, total insulin-induced glucose uptake was markedly impaired (3.80 +/- 0.32 vs. 6.31 +/- 0.42 mg per minute per kilogram of body weight in 11 age- and weight-matched controls, P less than 0.001). Thus, reduced nonoxidative glucose disposal (glycogen synthesis and glycolysis) accounted for virtually all the defect in overall glucose uptake (1.19 +/- 0.24 vs. 3.34 +/- 0.44 mg per minute per kilogram, P less than 0.001). Total glucose uptake was inversely related to systolic or mean blood pressure (r = 0.76 for both, P less than 0.001). These results provide preliminary evidence that essential hypertension is an insulin-resistant state. We conclude that this insulin resistance involves glucose but not lipid or potassium metabolism, is located in peripheral tissues but not the liver, is limited to nonoxidative pathways of intracellular glucose disposal, and is directly correlated with the severity of hypertension.     

Stimulating effect of intermediate-density lipoproteins (IDL) from hyperlipemic plasma on hepatic lipase

Summary The main lipoprotein density classes, namely very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), high-density lipoproteins₂ (HDL₂) and HDL₃ were investigated with respect to their influence on hepatic lipase (HTGL) activity in vitro.Lipoproteins from pooled normal plasma (NP) and from pooled hyperlipemic plasma (HP) were prepared by means of sequential ultracentrifugation. Hepatic lipase was determined radioenzymatically after preincubation with protamine sulfate. It could be demonstrated that IDL from HP were able to stimulate HTGL activity by approximately 100% above the baseline value. HDL₃ from both NP and HP revealed an inhibiting effect on HTGL activity. VLDL, LDL, and HDL₂ exhibited no significant effect on HTGL activity.It is speculated that HTGL could possibly represent a second pathophysiological pathway for the catabolism of IDL in hyperlipemia but this presumption is supported by only a few investigations in vivo.

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Abbreviations HDL₂ High-density lipoproteins₂ - HDL₃ High-density lipoproteins₃ - HP Hyperlipemic plasma pool - HTGL Hepatic lipase - IDL Intermediate-density lipoproteins - LDL Low-density lipoproteins - NP Normal plasma pool - VLDL Very low-density lipoproteins     

The hyperlipidemia of the nephrotic syndrome. Relation to plasma albumin concentration, oncotic pressure, and viscosity

Although hyperlipidemia is a common feature of the nephrotic syndrome, the distribution of cholesterol among the plasma lipoproteins and the mechanism of the enhanced hepatic synthesis of lipoprotein lipids are not well understood. We studied the distribution of cholesterol among the plasma lipoproteins, as well as the relation between total cholesterol and plasma albumin concentration, oncotic pressure, and viscosity in 20 consecutive adult patients with uncomplicated nephrotic syndrome. The total plasma cholesterol (mean +/- S.D., 302 +/- 100 mg per deciliter [7.8 +/- 2.6 mmol per liter]) and low-density-lipoprotein cholesterol concentrations (215 +/- 89 mg per deciliter [5.6 +/- 2.3 mmol per liter]) were elevated in most patients, but the high-density-lipoprotein cholesterol level was normal or low (46 +/- 18 mg per deciliter [1.2 +/- 0.5 mmol per liter]) in 95 per cent of the patients. Thus, many hypercholesterolemic patients with unremitting nephrotic syndrome may be at increased risk for atherosclerotic heart disease. A significant inverse correlation was found between the total plasma cholesterol concentration and both the plasma albumin concentration (r = -0.528) and the plasma oncotic pressure (r = -0.674), but not the plasma viscosity (r = +0.319). Enhanced hepatic synthesis of lipoprotein lipids may be stimulated by a decreased plasma albumin concentration or oncotic pressure but does not appear to be due to changes in plasma viscosity.     

Pulsatile secretion of human chorionic gonadotropin in normal adults

We used very sensitive and specific monoclonal-antibody sandwich assays for human chorionic gonadotropin (hCG) and human luteinizing hormone (hLH) to measure both hormones in serum samples from normal men and women. When single serum samples from 92 men were studied, 73 percent had detectable hCG. In normal men, the amount of detectable hCG averaged 8.9 pg per milliliter, with a range of less than 3.0 to 160 pg per milliliter (biologic potency = 13,450 IU per milligram). In postmenopausal women the hCG level averaged 111 pg per milliliter and ranged from 32 to 510. In women of reproductive age the hCG level varied with the menstrual cycle. Gonadotropin-releasing hormone administered to 10 normal men increased both hCG and hLH. When daily serum samples were studied throughout a normal menstrual cycle, hCG concentrations paralleled those of hLH; follicular-phase concentrations were higher than those of the luteal phase, and there was a midcycle ovulatory peak of hCG coincident with the hLH peak. When hCG was measured every 10 minutes for six hours in eight postmenopausal women, distinct pulses were detected in parallel with those of hLH: hLH pulsed at a mean (+/- SEM) frequency of 0.56 +/- 0.08 pulses per hour; hCG pulsed at 0.54 +/- 0.07 pulses per hour. The mean pulse durations were 89 +/- 22 and 56 +/- 20 minutes for hLH and hCG, respectively. We conclude that hCG is produced in a pulsatile fashion, probably by the pituitary, in all normal adults.