Appearance of multidisperse low density lipoprotein and altered lipoprotein composition in non-insulin-dependent diabetes with type IIa hyperlipoproteinemia

The purpose of the present study is to elucidate the characteristics of lipoprotein disorders in diabetes mellitus. By analytical ultracentrifugation, non-insulin-dependent diabetic patients (NIDDM) with type IIa hyperlipoproteinemia (HLP) showed significantly higher incidence of multidisperse low density lipoprotein (LDL) than non-diabetics with type IIa HLP. Furthermore, LDL multidispersity in diabetic subjects seemed to be directly related to neither triglyceride (TG) levels in very low density lipoprotein (VLDL) nor the degree of glycemic control. Diabetics with multidisperse LDL had a lipoprotein profile that was different from the subjects with paucidisperse LDL as follows: (1) enrichment in the cholesterol content of VLDL, (2) TG-rich LDL with small flotation coefficient, (3) low cholesterol levels in high density lipoprotein2 along with enrichment in TG, and (4) high plasma concentrations of apoprotein B. Although the underlying mechanism behind the prevalence of multidisperse LDL in NIDDM with type IIa HLP remains unknown, it seems important that lipoprotein disorders in diabetics with multidisperse LDL were potentially atherogenic.     

The effect of beta-pyridylcarbinol on lipoprotein lipids in primary type IIa hyperlipoproteinemia.

The effect of long-term treatment over 6 months with beta-pyridylcarbinol on the lipoprotein lipids was investigated in 12 patients with primary type IIa hyperlipoproteinemia. VLDL, LDL and HDL were separated by preparative ultracentrifugation. There was a significant decrease of serum cholesterol and phospholipids. The normal serum triglycerides were unaffected. While VLDL and HDL lipids showed no signicant alterations, the LDL lipids decreased. The atypical lipid composition of the LDL was changed towards normal. Though there was a significant decrease of the "atherogenic" LDL/HDL-lipid ratios after 6 months treatment, beta-pyridylcarbinol did not result in a normalization of this ratio.     

Effects of probucol on the composition and in vitro catabolism of LDL in type IIa hypercholesterolemia

A possible mechanism of action of probucol on low density lipoprotein uptake was examined in 7 type IIa hypercholesterolemic subjects. Probucol administration effectively lowered plasma cholesterol. Both apo B-associated cholesterol and HDL cholesterol were decreased but a great inter-patient variability was noted. Plasma triglycerides were unchanged and phospholipids decreased. The composition of the isolated LDL was unaffected. The LDL displaceable activity of reference [125I]LDL measured by competition assays in control fibroblasts, was increased in 3 subjects, decreased in 1 subject and unchanged in the other 3. No correlation was found between the change in apo B-associated cholesterol and the change in the in vitro catabolism of LDL of treated patients. The results did not allow a simple mechanism of action to be ascribed to the drug, but questioned the origin of the hypercholesterolemia.     

Altered platelet deformability in patients with type IIa and type IV hyperlipoproteinemia

Platelets from subjects with hyperlipoproteinemia (HLP) differ from normal platelets in lipid composition and function depending upon the phenotypic classification of the HLP. The present study has evaluated the deformability of platelets from human subjects with type IIa and type IV HLP. Platelets suspended in autologous plasma diluted 30-fold with buffer were aspirated into micropipettes 0.7-0.8 microns in diameter by step-wise increment in tension, and the resulting extension lengths were recorded. Platelets from type IIa subjects could not be aspirated as far into the micropipettes as normal platelets. However, less tension was required to reach maximum cell extension than with normal platelets, and the initial extension lengths and slopes of the stress responses were the same as the control. In contrast, platelets from subjects with type IV HLP showed a generalized increase in deformability. The initial cell extensions aspirated from type IV platelets were longer than normal, and larger maximum cell extensions were achieved at lower tensions than control platelets. The type IV platelets were also mechanically fragile and fragmented at lower tensions than control or type IIa platelets. The variance in platelet deformability between subjects of the same phenotype was not directly correlated to plasma lipid or lipoprotein concentrations. This study confirms alterations in the structural organization of platelets from subjects with type IIa and type IV HLP.     

Low density lipoprotein metabolism in type IV and type V hyperlipoproteinemia.

Low density lipoproteins (LDL) are thought to arise largely from degradation of triglyceride-rich very-low-density lipoproteins (VLDL). LDL kinetics in patients with Type IV and Type V hyperlipoproteinmia were studied and compared with normal subjects. LDL labeled in the protein moiety with 125I was used as a tracer. There was no significant difference in LDL turnover between the three groups, suggesting that a catabolic defect in VLDL degradation to LDL may exist in both Type IV and Type V hyperlipoproteinemia.     

Adipose tissue lipoprotein lipase activity in type III hyperlipoproteinemia.

An impairment in the catabolism of chylomicron and very low density lipoprotein remnants appears to cause the lipid abnormalities in type III hyperlipoproteinemia. A reduction in the activity of lipoprotein lipase (LPL) has been suggested as the catabolic defect. Results in this study indicate that the activity of adipose tissue LPL measured in the fasted and fed states are in the normal range in type III hyperlipoproteinemia (fasted: type III = 2.7 +/- 1.8 mU/10(6) cells, N = 8; normals = 3.4 +/- 2.5, N = 23, p, not significant; fed: type III = 3.6 +/- 2.1, N = 7; normals = 4.8 +/- 1.8, N = 12, p, not significant). This suggests that perhaps another mechanism, such as the interaction between LPL and its lipid substrate, is abnormal, or that the activity of LPL derived from another tissue source is deficient.     

The hypolipidemic effects of lovastatin and clofibrate alone and in combination in patients with type III hyperlipoproteinemia

The hypolipidemic effects of lovastatin and clofibrate have been evaluated in 12 patients with type III hyperlipoproteinemia. In these patients plasma concentrations of total cholesterol decreased from 500 +/- 56 mg/dL (mean +/- SEM) at baseline to 278 +/- 23 mg/dL on lovastatin (20 mg twice daily), and were 299 +/- 15 mg/dL during treatment with clofibrate (1 g twice daily). Nine patients were treated sequentially with lovastatin at doses of 20 and 40 mg twice daily and clofibrate; in these patients total plasma cholesterol concentrations decreased from 549 +/- 67 mg/dL at baseline to 291 +/- 24 mg/dL on lovastatin (20 mg twice daily), 247 +/- 20 mg/dL (40 mg twice daily) and were 297 +/- 18 mg/dL on monotherapy with clofibrate. Concentrations of very-low-density lipoprotein (VLDL) cholesterol were similar on clofibrate and the higher dose of lovastatin, whereas concentrations of low-density lipoprotein (LDL) cholesterol were significantly lower on lovastatin. In six patients who remained hyperlipidemic on monotherapy with either drug, combination drug therapy with lovastatin (20 mg twice daily) plus clofibrate reduced plasma concentrations of total cholesterol from 635 +/- 79 mg/dL to 205 +/- 11 mg/dL. No patients were discontinued from single or combined drug therapy and no significant biochemical abnormalities were observed. The results of this study demonstrate the potential usefulness of lovastatin in the therapy of type III hyperlipoproteinemia and indicate that, in selected patients who remain hypercholesterolemic on monotherapy with either clofibrate or lovastatin, combination drug therapy with both of these drugs is effective in further reducing plasma concentrations of total, VLDL, and LDL cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of cholestyramine on lipoprotein lipids in patients with primary type IIA hyperlipoproteinemia.

The effect of 3 months' treatment with cholestyramine on lipoprotein lipids was investigated in 12 patients. VLDL, LDL and HDL were separated by preparative ultracentrifugation. There was a significant decrease of serum cholesterol and phospholipids and an increase of serum triglycerides. All the VLDL-lipids increased by nearly 30%. The LDL-lipids decreased with a tendency for normalisation of their atypical lipid composition. The small but significant alterations of HDL triglycerides and cholesterol are correlated with the corresponding alterations of the other lipoproteins; the HDL-phospholipids were unchanged. The LDL/HDL-lipid ratios were decreased but not normalised. The 30% decrease of LDL-cholesterol is negatively correlated with an increase in all the VLDL-lipids.     

Effectiveness of mevinolin on plasma lipoprotein concentrations in type II hyperlipoproteinemia

Patients with low-density lipoprotein (LDL) concentrations in the top 10th percentile of the population (type II hyperlipoproteinemia [HLP]) are at increased risk for premature cardiovascular disease; however, the incidence of myocardial infarction and death can be decreased by LDL cholesterol reduction. Mevinolin, an inhibitor of endogenous cholesterol synthesis, has been shown to reduce LDL cholesterol concentrations in a subset of type II patients with heterozygous familial hypercholesterolemia (FH). Using a double-blind, randomized, crossover, placebo-controlled trial, the safety and efficacy of mevinolin were compared in 24 patients with type II HLP with heterozygous FH (n = 6) or without FH type II HLP (n = 18). Compared with placebo treatment, both apolipoprotein B and LDL cholesterol levels were reduced (p less than 0.01) in both FH and non-FH patients by 28 to 34% with mevinolin treatment. In addition, high-density lipoprotein cholesterol levels were significantly increased (p less than 0.001) in both patients with FH (16%) and those with non-FH type II HLP (14%). Patients had no serious or clinically significant adverse effects. Thus, mevinolin is a useful drug for treatment of most patients with elevated plasma LDL cholesterol concentrations.     

Lipid composition of serum lipoproteins in patients with primary type IIb and type IV hyperlipoproteinemia.

Cholesterol, triglyceride and phospholipid concentrations of VLDL, LDL and HDL were studied in 20 patients with primary type IIb, 25 patients with primary type IV and in 18 controls. Both types are not only characterized by different concentrations of lipoprotein lipids, but also by their different lipid composition. Type IIb had more triglycerides in the LDL, type IV in the LDL and HDL. The HDL cholesterol content of type IV was decreased. The percent phospholipid concentration of HDL was identical in the 3 groups, demonstrating the constant role of this lipid fraction. The lipid relationships between the lipoproteins showed that the LDL/HDL lipid ratio of type IIb exceeded type IV ratio in spite of normal HDL lipid concentration in type IIb.     

Diet and probucol in lowering cholesterol concentrations. Additive effects on plasma cholesterol concentrations in patients with familial type ii hyperlipoproteinemia.

Probucol [4,4-(isopropylidendithio bis)(2,6-di-t-butylphenol)], as as an adjunct to diet, was evaluated for its effect on lowering the plasma cholesterol level in patients with familial hypercholesterolemia (type II). The trial had a double-blind, placebo-controlled, crossover design. About half of the 30 patients responded to a low-cholesterol modified-fat diet with a decrease in the plasma cholesterol level of approximately 13%. When probucol was added to the diet of the responders, their plasma cholesterol level was lowered a further 13%. Patients who did not respond to the diet did show reduced plasma cholesterol concentrations when receiving probucol plus the diet. Analysis of the cholesterol content of the various lipoprotein fractions showed that the low-density lipoproteins accounted for most of the total plasma cholesterol level decrease. There was, as expected, no effect on plasma triglyceride concentrations. Neither the 7-dehydrocholesterol nor the desmosterol level was increased in the plasma of patients treated with probucol for three months. Probucol is useful as an adjunct to diet in lowering plasma cholesterol levels in patients with familial hypercholesterolemia. The drug was well tolerated by all patients.     

Decreased number of PGD2 binding sites on platelets from patients with type IIa hyperlipoproteinemia

Platelets from patients with familial hypercholesterolemia (type IIa hyperlipoproteinemia), a condition associated with a high prevalence of atherosclerosis and its ischemic complications, are claimed to be hyperresponsive to aggregating stimuli. We investigated the platelet responsiveness to and the binding of PGD2, a potent endogenous inhibitor of platelet aggregation via stimulation of adenylate cyclase, in a group of 7 patients affected by IIa hyperlipoproteinemia (IIa HLP) and in a control group of 10 healthy subjects. Inhibition by PGD2 of ADP-induced platelet aggregation was significantly lower in IIa HLP patients than in controls. The number of binding sites for PGD2 of platelets from IIa HLP patients was significantly reduced in comparison with that from controls (93 +/- 19 and 232 +/- 23 receptors/platelet, respectively), whereas the affinity for PGD2 was comparable to that of controls (Kd = 68.8 +/- 19.8 nM in patients and 66.1 +/- 15.9 nM in controls). The reduced number of platelet PGD2 binding sites in IIa HLP patients may account for the impaired sensitivity to PGD2 shown in vitro by platelets and may contribute to the increased tendency to thrombotic manifestations observed in IIa HLP.     

Effects of combination cholestyramine-neomycin treatment on plasma lipoprotein concentrations in type II hyperlipoproteinemia

Recent prospective clinical trials have established that cholesterol reduction in patients with elevated (upper 90th percentile) concentrations of low-density lipoproteins (LDL) reduces the incidence of myocardial infarction and sudden death. Because the level of protection from these cardiovascular sequelae is directly related to the degree of LDL reduction, combination therapy using different hypolipidemic agents has been used in patients with type II hyperlipoproteinemia (HLP). Neomycin is as effective as cholestyramine in reducing LDL levels and combination neomycin-niacin treatment normalizes the plasma lipoproteins in 92% of patients with type II HLP. Because neomycin could theoretically ameliorate some of the gastrointestinal side effects of cholestyramine in addition to further affecting cholesterol levels, the effects of combination cholestyramine-neomycin treatment on the plasma lipoprotein were assessed in 18 patients with type II HLP in a 9-month clinical trial. Compared with diet-only treatment, cholestyramine reduced total and LDL cholesterol levels by 77 mg/dl (22%) and 78 mg/dl (31%), respectively. In addition to relieving cholestyramine-induced constipation, neomycin further reduced the total cholesterol level by 20 mg/dl (6%). However, this further reduction in total cholesterol concentration was the result of a decrease in the concentration of high-density lipoprotein cholesterol. These findings indicate that combination therapy does not have an additive LDL cholesterol-lowering effect and that neomycin and cholestyramine is not a useful drug combination. In addition, these results illustrate the importance of determining the high-density lipoprotein cholesterol concentration to fully interpret the effects of hypolipidemic treatment.     

The effect of tibolone on the lipoprotein profile of postmenopausal women with type III hyperlipoproteinemia

OBJECTIVE: To investigate the short-term effect of treatment with tibolone on plasma lipid and lipoprotein levels in postmenopausal women with type III hyperlipoproteinemia (HLP). DESIGN AND INTERVENTION: Patients were randomized to receive, in a double-blind cross-over fashion, a fixed dose of tibolone, 2.5 mg once daily or placebo for 8 weeks. The two treatment periods were separated by a wash-out period of 6 weeks. At each visit body weight and blood pressure were determined. Before and after each treatment period, fasting venous blood samples were obtained from the patients for biochemical measurements. SETTING: The Leiden University Medical Center. SUBJECTS: Postmenopausal women with type III HLP (aged < or = 65 years) were recruited from the Lipid Clinics of the Leiden University Medical Center, the Amsterdam Medical Center, the Utrecht Medical Center and the University Hospital Rotterdam. Five out of 25 women with type III HLP were eligible to be included in the study. Four of the five included patients completed the study according to the protocol. One patient was excluded from blinded therapy because total cholesterol levels increased above 20 mmol L(-1). MAIN OUTCOME MEASURES: A significant reduction of plasma triglyceride, total cholesterol, VLDL cholesterol and VLDL triglyceride levels. RESULTS: Plasma triglyceride and total cholesterol levels decreased from 6.82 +/- 3.58 to 2.45 +/- 1.36 mmol L(-1) and from 13.53 +/- 3.64 to 6.61 +/- 2.03 mmol L(-1), respectively (both P < 0.05). The body mass index remained unchanged. The glycated haemoglobin percentage decreased significantly from 5.8 to 5.3%. Treatment with tibolone resulted in a profound reduction in plasma apolipoprotein E, VLDL cholesterol and VLDL triglyceride levels (mean reductions of 66, 77 and 70%, respectively, P < 0.05). CONCLUSIONS: Tibolone is a valuable adjuvant to current therapy in postmenopausal women with type III HLP.     

Familial and acquired type V hyperlipoproteinemia.

The nature of Type V hyperlipoproteinemia including mode of presentation, prominent clinical and biochemical features, and genetics, was examined in 29 adults presenting with the Type V lipoprotein phenotype. Initially 23 of the 29 patients had various metabolic stimuli (diabetes out of control, estrogenic agents, pancreatitis, ethanolism) superposed on their acute hypertriglyceridemia. After metabolic stabilization, 17 of the 29 subjects were shown to have familial hypertriglyceridemia. In the 17 kindreds with familial hypertriglyceridemia, the lack of a specific, distinctive genetic marker for the Type V genotype and for the Type IV genotype restricts the conclusion that the pattern of inheritance was consistent with an autosomal dominant trait.     

Molecular basis of lipoprotein lipase deficiency in two Austrian families with type I hyperlipoproteinemia

To determine the molecular basis for type I hyperlipoproteinemia in two Austrian families, the lipoprotein lipase (LPL) gene of two patients exhibiting LPL deficiency was analyzed by Southern blotting and by direct genomic sequencing of DNA amplified by polymerase chain reaction (PCR). All exons of the LPL gene except part of the noncoding region of exon 10, all splice donor and acceptor sites, as well as 430 basepairs of the 5'-region including the promotor were sequenced. A homozygous substitution of adenine for guanine in the fifth exon at cDNA position 818 of the LPL gene was found in both patients. Our sequencing strategy largely ruled out a linkage disequilibrium of the identified nucleotide change with another defect potentially causing the clinical phenotype. The base change described abolishes a normally present AvaII restriction site allowing the identification of carriers of the mutant allele by AvaII digestion of PCR fragments of exon 5; three members of the two families were homozygous for this mutation and ten members were heterozygous. The activity of LPL in postheparin plasma was almost completely absent in homozygotes and about half normal in heterozygotes. The loss of activity was related to LPL protein structure. This mutation alters the amino acid sequence at residue 188 from Gly to Glu. The conformational preferences of the protein chain around position 188 were calculated with the use of a knowledge-based computerized method. The most probable conformation is a beta-turn formed by residues 189-192. The mutation seems to destabilize the beta-turn and/or a yet larger domain critical for substrate alignment.     

Effects of probucol on low-density lipoprotein catabolism in guinea pigs.

We studied the effects of administering probucol on the catabolism of low density lipoprotein (LDL) in guinea pigs. Probucol administration significantly lowered the levels of total and LDL-cholesterol in animals given either normal chow or the high cholesterol (1% W/W) diet. High-density lipoprotein cholesterol was decreased significantly in the animals fed cholesterol, but not normal chow diet. Triglyceride levels were unaffected in both groups. No significant changes were observed in the LDL receptor-dependent and LDL receptor-independent catabolism of native LDL and LDL obtained from a probucol-treated patient. However, when the LDL isolated from a probucol-treated patient was injected, the fractional catabolic rate was significantly lower than that of injected native LDL. This study indicates that probucol lowered the plasma LDL cholesterol level neither by an increased catabolism of LDL via an LDL receptor nor an LDL receptor-independent pathway.