Acquired (secondary) forms of hypertriglyceridemia.
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Diabetes Complications↗
Biomedical subjects
D Pometta
Publications and source records attributed to D Pometta.
Distribution of apolipoprotein E between free and A-II complexed forms in very-low- and high-density lipoproteins: functional implications.
The stability of apolipoprotein E/lipoprotein associations has been examined as a function of apolipoprotein E phenotype. Visualisation by immunoblotting showed plasma apolipoprotein E to be present in two forms; the free form and, as previously described, an E-A-II complex. In very low density lipoproteins isolated by gel filtration from subjects with E3/3 and E4/3 phenotypes, apolipoprotein E was present essentially in the free form (ratio free: complex of 12.2 and 37.5, respectively). Exploiting ultracentrifugation as the disruptive agent, very-low-density lipoproteins thus isolated were shown to have substantially lower ratios (5.6 and 5.4, respectively) reflecting preferential loss of free apolipoprotein E. In high-density lipoproteins isolated by gel filtration from E3/3 phenotypes, apolipoprotein E was largely present as an E-A-II complex (80.3%). In contrast, the majority of apolipoprotein E in high-density lipoproteins from E4/3 phenotypes was present in the free form (58.7%). In both phenotypes, the content of free apolipoprotein E was markedly reduced by ultracentrifugation. The results confirm the notion that the formation of the E-A-II complex is a major determinant of the stability of apolipoprotein E-high-density lipoprotein associations. Moreover, that the predominant, ancestral isoform, apolipoprotein E3, exists largely as an E-A-II complex in higher density lipoproteins has important functional implications for this plasma source of apolipoprotein E.
Antibodies, Monoclonal↗
Distribution of cholesterol within high density lipoproteins fractionated by immunoaffinity chromatography.
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Chemical Fractionation↗
The distribution profiles of very low density and low density lipoproteins in poorly-controlled male, type 2 (non-insulin-dependent) diabetic patients.
The distribution and composition of lipoproteins spanning the very low density and low density lipoprotein spectra have been analysed in ten poorly-controlled, male, Type 2 (non-insulin-dependent), diabetic patients pre-disposed to mild, secondary hypertriglyceridaemia. As compared to age-matched control subjects, the diabetic patients displayed grossly modified, distinctly atherogenic lipoprotein profiles. Modifications were not limited to the very low density lipoprotein profile, as would be expected from the pre-treatment hypertriglyceridaemia. There was also an aberrant low density lipoprotein profile, which was not evident from plasma cholesterol measurements, especially as the diabetic patients at entry were well matched to control subjects with respect to plasma levels of this lipid. Compositional abnormalities were also observed in the poorly-controlled diabetic group, although these were less marked than the distributional changes. There were substantial improvements of the abnormalities detailed above, even over a short treatment period (two weeks), with therapy designed primarily to ameliorate metabolic control. The data suggest that, in the presence of poor metabolic control and hypertriglyceridaemia, occult, atherogenic modifications of low density lipoproteins can occur. The results argue in favour of strict control of triglyceride levels even in diabetic patients with apparently acceptable cholesterol levels.
Blood Glucose↗
Immunological confirmation of the presence of NA1/NA2 (cytolysis inhibitor) in cerebrospinal fluid.
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Blood Proteins↗
Preparative isoelectrofocusing and high resolution 2-dimensional gel electrophoresis for concentration and purification of proteins.
We have analysed the potential of liquid phase isoelectrofocusing allied to high resolution 2-dimensional gel electrophoresis for concentrating and purifying in particular plasma proteins present in low concentrations. The primary fractionation step, liquid phase isoelectrofocusing, offers several advantages. Firstly, it allows protein profiles to be examined within defined pH ranges. Additionally, it confines the bulk plasma proteins to their respective pI ranges, allowing larger quantities of protein to be employed for the second fractionation phase. Concurrently, it concentrates proteins present at low concentrations, also by restricting them to their pI ranges. Yields are such that detailed characterisation studies of the proteins can be undertaken, providing the means of generating comprehensive data banks to complement plasma protein maps. The procedure should be applicable to a wide range of biological fluids and tissues.
Blood Proteins↗
[Dyslipidemia in diabetes mellitus: significance, diagnosis and treatment].
Dyslipidemias are frequent in diabetic subjects: they increase the risk for atherosclerosis, in addition to the risk of diabetes mellitus per se. The pathogenesis of dyslipidemias differs between type I and type II diabetes: untreated type I diabetic subjects demonstrate frequently increased triglyceride concentrations due to diminished removal of triglyceride-containing particles, as a result of diminished activity of lipoprotein lipase. In addition, more triglycerides are produced due to increased lipolysis and increased free fatty acid supply to the liver. Type II diabetic subjects demonstrate very low density lipoprotein (VLDL) over-production due to obesity, insulin resistance and caloric overconsumption. In addition, triglyceride removal may be diminished due to diminished lipoprotein lipase activity when diabetes mellitus is poorly controlled. In addition, high density lipoprotein (HDL) is frequently lowered. During decompensation low density lipoprotein (LDL) concentrations may also increase. LDL particle composition is frequently abnormal. A severe dyslipidemia in diabetes mellitus is frequently a combined effect of diabetes mellitus and a congenital lipoprotein abnormality. The evaluation and treatment of dyslipidemias in diabetic subjects should be performed similarly to non-diabetics according to the guidelines published recently by the Working Group 'Lipids' of the Swiss Foundation of Cardiology. Additional accents in diabetic subjects are necessary. It is recommended that serum cholesterol, triglycerides and HDL are determined in every patient when diabetes mellitus is diagnosed. If serum cholesterol is greater than 6.5 mmol/l and the cholesterol/HDL-ratio is greater 6.5, dietary treatment should be reinforced; if its effect is insufficient, drug therapy should be considered.(ABSTRACT TRUNCATED AT 250 WORDS)
Arteriosclerosis↗
A novel high-density lipoprotein particle and associated protein in rat plasma.
This report describes the characterization of a novel rat apolipoprotein, which, as partial sequencing suggests, does not correspond to any described protein. The protein (termed PX) has an estimated molecular mass of 19.5 kDa and pI in the range 5.5-5.8. Monoclonal antibodies were obtained against protein PX and results on distribution among rat lipoproteins show it to be associated mainly with high-density lipoproteins (HDL), but also with VLDL. Immunoaffinity chromatography of total HDL shows protein PX to be included in a distinct lipoprotein particle, particularly enriched in free cholesterol, with which only traces of other apolipoproteins are associated. Immunologically crossreacting entities are found in the plasma of several species, including man. Retention of the epitope carried by the protein PX would suggest that it is of particular structural or functional importance. It remains to be established whether its function is associated with lipid metabolism.
Animals↗
Immunofractionation of high density lipoprotein subclasses 2 and 3. Similarities and differences of fractions isolated from male and female populations.
High density lipoprotein (HDL) subclasses 2 and 3 isolated from male and female populations were further subfractionated by immunoaffinity techniques. Each subclass gave rise to 2 fractions: one contained apolipoprotein (apo) A-I but no apo A-II (LpAI); the other contained apo A-I and apo A-II (LpAI,AII). The bulk fraction (HDL-3(LpAI,AII)) comprised over 70% of total HDL and was present in similar concentrations in both populations. There were, however, significant male-female differences in plasma levels of the minor HDL-3 fraction i.e. HDL-3(LpAI). Females had significantly higher plasma concentrations of both fractions within HDL-2. These fractions also exhibited strong, positive correlations with total HDL cholesterol concentrations, both in males as well as females. It suggests that metabolic activities giving rise to both HDL-2(LpAI) and HDL-2(LpAI,AII) determine plasma HDL cholesterol concentrations. Several similarities were noted between the male and female populations. Triglyceridaemia was negatively correlated with HDL-2 derived fractions and positively correlated with the bulk fraction HDL-3(LpAI,AII). Compositional data showed that the fraction (LpAI) had a lower esterified cholesterol to total cholesterol ratio than the fraction (LpAI,AII), the differences being more apparent at the HDL-3 level. Additionally, analysis of the surface components of HDL-3 fractions suggested that (LpAI,AII) had a greater potential than (LpAI) for absorbing lipoprotein surface material. Finally, the relative concentrations of the individual components of fractions within the same population and defined by the same apolipoprotein criterion showed highly significantly, positive correlations. Such correlations were not apparent for apolipoprotein dissimilar fractions. These observations could reflect a metabolic link between apolipoprotein similar fractions.
Adult↗
Differences in lipoprotein subfraction composition and distribution between type I diabetic men and control subjects.
Subfractions of very-low-density and low-density lipoproteins were examined in 10 male normolipidemic type I (insulin-dependent) diabetic patients before and after improvement of metabolic control and were compared with subfractions from male control subjects matched to the diabetic patients at entry for age, body mass index, plasma cholesterol, and plasma triglycerides. Two consistent differences in subfraction composition were noted between the diabetic patients at entry and the control subjects. First, subfractions from diabetic patients tended to be cholesterol-ester poor and triglyceride rich; this was particularly marked for the low-density lipoprotein subfractions. Second, the subfractions from pretreatment diabetic patients contained higher proportions of non-apolipoprotein B apolipoproteins. This compositional anomaly, but not the lipid modifications, responded to but was not completely normalized by improved glycemic control, which was also accompanied by reductions in the plasma concentrations of all subfractions. Treatment modified subfraction distribution so that the lipoprotein profile of posttreatment diabetic patients more closely resembled the profile observed in the control subjects. These changes were achieved without significant modification of daily insulin dose. In the context of blood lipid risk factors, the results argue for the need to maintain optimal insulinization even in apparently normolipidemic diabetic patients to avoid modifications of the lipoprotein pattern toward a potentially more atherogenic profile.
Adult↗
[Remnant disease associated with apoprotein E1; clinical importance of apoprotein E (apo E) phenotypes].
The diagnosis of type III hyperlipoproteinemia, or remnant disease, is greatly facilitated by the determination of the apoprotein E (apo E) phenotype. The disease is associated, in over 90% of the documented cases, with homozygosity for the E2 isoform of apo E. Phenotyping apo E directly from plasma offers certain advantages as compared to phenotyping from very low density lipoprotein samples. Elaboration of such a procedure in our laboratory allowed us to detect a rare isoform of apo E, apo E1, which was associated with remnant disease in 3 patients.
Adult↗
Immunoaffinity fractionation of high-density lipoprotein subclasses 2 and 3 using anti-apolipoprotein A-I and A-II immunosorbent gels.
High-density lipoprotein (HDL) subclasses 2 and 3 prepared by density gradient ultracentrifugation have been further fractionated by immunoaffinity chromatography using antibody affinity gels targetting the major HDL apolipoproteins, A-I and A-II. Fractions containing A-I without A-II (AI w/o AII) and A-I with A-II (AI w AII) were isolated from both density ranges. Whereas there were similar concentrations of the major subfraction (HDL3(AI w AII] in both males and females, the remaining subfractions were present in higher concentrations in females as compared to males, in the order HDL3 (AI w/o AII) less than HDL2(AI w AII) less than HDL2(AI w/o AII). The difference was most marked for HDL2 (AI w/o AII), where plasma concentrations in females were almost 3-fold greater than in males. Compositional analyses indicated that the plasma concentrations of the fractions, rather than their compositions, were the major determinants of male-female differences in HDL levels. In contrast, fractions defined by similar apolipoprotein criteria and isolated from different density subclasses (i.e., HDL2(AI w/o AII) vs. HDL3(AI w/o AII) and HDL2(AI w AII) vs. HDL3(AI w AII] showed major compositional differences. This is suggestive of distinct lipoprotein particles.
Adult↗
Actin stress fiber content of regenerated endothelial cells correlates with intramural retention of intermediate plus low density lipoproteins in rat aorta after balloon injury.
The rat aortic model of endothelial injury (balloon catheter induced) has been used to establish whether changes in protein intramural penetration in specific areas of the injured aorta were accompanied by phenotypic modifications of the regenerated endothelial cells covering these particular regions. Iodinated lipoproteins (IDL/LDL fraction) and albumin were used as tracers to localize protein permeability and retention in the aorta. Lipoproteins, but not albumin, were retained in the thickened areas covered with regenerated endothelium (i.e., 60 days after balloon induced injury). Neither lipoproteins nor albumin were retained in the other aortic areas studied, including the intimal thickening of de-endothelialized areas (15 days after injury). The relative volume of cytoplasmic stress fibers was significantly increased in regenerated endothelium covering thickened areas as compared with the other regions of the injured or normal aorta. The accumulation of lipids usually observed in atherosclerotic lesions, compatible with the trapping of lipoproteins by the matrix component of the intimal thickening, may be related to modulated features of endothelial cells regenerated over thickened areas of the aorta.
Actin Cytoskeleton↗
[Dyslipidemias and diabetes mellitus].
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Diabetes Complications↗
Apolipoprotein B metabolism in homozygous familial hypercholesterolemia.
This report describes the metabolism of apolipoprotein B-containing lipoproteins in seven familial hypercholesterolemic (FH) homozygotes and compares the results to the values obtained from five healthy control subjects. The concentration, composition, and metabolism of large, triglyceride-rich very low density lipoproteins (VLDL1, Sf 60-400) were the same in the control and FH groups, indicating that this component of the VLDL delipidation cascade ws unaffected by the absence of receptors. In contrast, familial hypercholesterolemic small VLDL2 (Sf 20-60) was enriched with cholesterol and depleted in triglyceride. Moreover, its plasma concentration was elevated as a result of an increase in its synthesis and a defect in the removal of a remnant population within this density interval. The latter accounted for up to 50% of the total mass of the fraction. Onward transfer of apolipoprotein B (apoB) from small VLDL through intermediate density lipoprotein (IDL) to low density lipoprotein (LDL) was retarded, suggesting that receptors were involved in this supposedly lipase-mediated event. IDL and LDL concentrations increased up to fourfold above normal in the plasma of the FH patients due partly to the delay in maturation and partly to defective direct catabolism. We conclude that the LDL receptor plays multiple and important roles in the metabolism and transformation of apoB-containing particles in the Sf 0-400 flotation interval.
Adult↗
[Lipoprotein metabolism and atherosclerosis].
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Arteriosclerosis↗
High density lipoprotein (HDL) subfractions in cardiovascular patients with low levels of HDL-cholesterol. Influence of hypertriglyceridaemia on subfraction concentration and composition.
The major high density lipoprotein (HDL) subfractions were examined in angiographically defined cardiovascular patients with low HDL-cholesterol (HDL-C) levels. The aims were to study subfraction concentration and composition, and the extent to which hypertriglyceridaemia (HTG) modified these variables. Normotriglyceridaemic (NTG)-low HDL-C patients showed similar subfraction composition to age-matched healthy controls. However, these groups showed notable differences in subfraction composition compared to HTG-low HDL-C patients, particularly with regard to the HDL2 subfraction. HDL subfraction mass was significantly reduced in both cardiovascular groups; the HTG group showed a greater reduction in HDL2, whilst the NTG group showed a greater reduction in HDL3. The major HDL apoprotein (apo A-I) was lower in both subfractions of the cardiovascular patients. Apo A-II showed significant reductions only in the HTG patients.
Apolipoprotein A-I↗
The influence of metabolic control on very low density lipoprotein composition in hypertriglyceridemic type II diabetics. A study using heparin-sepharose chromatography.
The composition and heparin-binding capacity of very low density lipoproteins (VLDL) from type II diabetics prone to develop secondary hypertriglyceridemia have been examined. Twelve diabetic patients whose triglyceride levels normalized during short-term treatment for hyperglycemia were studied. Normalization of triglyceride values reduced plasma levels of VLDL without modifying its relative lipid composition. There was, however, an increase in its relative apoprotein (apo) content, to which apo B made a greater percentage contribution. The calculated average particle diameter of posttreatment VLDL was reduced. The fraction of VLDL binding to heparin increased after treatment. Binding was strongly correlated to the apo B content and, to a lesser extent, to the apo E content. The data suggest that treatment of hyperglycemia favorably modified VLDL such that they more closely resemble VLDL from normolipidemic subjects, with potentially beneficial physiological consequences.
Apolipoproteins B↗