Postprandial plasma lipoprotein responses to a mixed meal in subjects with hyperapobetalipoproteinaemia.
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Apolipoproteins B↗
Biomedical subjects
P N Durrington
Publications and source records attributed to P N Durrington.
Effects of treatment of hypertriglyceridaemia with gemfibrozil on serum lipoproteins and the transfer of cholesteryl ester from high density lipoproteins to low density lipoproteins.
Lipoprotein composition and cholesterol esterification, before and after treatment with gemfibrozil, have been examined in the fasting and postprandial state in nine patients with primary hypertriglyceridaemia who participated in a double-blind, placebo controlled study. After 8 weeks of treatment fasting serum triglycerides were reduced significantly from 6.05 mmol/l (range 2.48-10.99 mmol/l) to 1.76 mmol/l (range 1.16-11.90 mmol/l) (P less than 0.001). This was mainly due to a decrease in the triglyceride content of the Sf 12-20, 60-400 and Sf greater than 400 lipoprotein fractions (P less than 0.05). The Sf 0-12 fraction showed an increase in cholesteryl ester, free cholesterol, phospholipids and protein. Consistent with these findings there was a net increase in the mass concentration of the Sf 0-12 fraction (P less than 0.05) and a decrease in that of small very low density lipoproteins (Sf 20-60) (P less than 0.05). In the 8 patients in whom it was measured there was a 40% reduction in the rate at which cholesteryl esters derived from radiolabelled-free cholesterol appeared in very low density lipoprotein (VLDL) and low density lipoprotein (LDL) measured in an in vitro system (P less than 0.02), but serum lecithin:cholesterol acyl transferase (LCAT) activity was unchanged. At the end of each treatment phase (placebo or gemfibrozil) patients were given a mixed meal containing 100 g of fat. Treatment with gemfibrozil resulted in a reduction in serum triglyceride concentrations at all time points for at least 5 h after the meal (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Lipolysis of triglyceride-rich lipoproteins activates coagulant factor XII: a study in familial lipoprotein-lipase deficiency.
A high factor VII coagulant activity (VIIc), a marker of increased risk of coronary heart disease, is frequently found in types IIb and IV hyperlipidaemia, but its cause is not fully understood. Factor VII can be activated by factor XIIa, generated from factor XII upon activation of the contact system of coagulation. Ten patients with familial lipoprotein-lipase (LPL) deficiency and 10 healthy control subjects were therefore compared to explore the hypothesis that high concentrations of unesterified fatty acids (UFA), released from triglyceride-rich lipoproteins by LPL, are a source of factor XII activation and hence the increased VIIc that is observed post-prandially and in non-LPL-deficient hypertriglyceridaemic states. Mean plasma cholesterol and triglyceride concentrations were, respectively, 1.5- and 19-fold higher in the patients than controls, due to increases in very-low-density lipoproteins and chylomicrons. The concentration and composition of plasma UFA were similar in both groups. In conformity with the hypothesis, VIIc was not increased in the LPL-deficient group, despite their massive hypertriglyceridaemia. Furthermore, when the patients' plasma was treated with LPL, factor XII was activated promptly and substantially, whereas no similar effect was observed in the controls. These results suggest that high concentrations of circulating triglyceride-rich lipoproteins will increase VIIc in the presence of LPL.
Adult↗
The effect of bezafibrate on very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and low density lipoprotein (LDL) composition in type 1 diabetes associated with hypercholesterolaemia or combined hyperlipidaemia.
Lipoprotein composition was examined in type 1 diabetic subjects with hypercholesterolaemia +/- hypertriglyceridaemia during a 3-month double-blind placebo controlled assessment of bezafibrate therapy. The predominant effect was on lipoprotein lipid content. In those with hypercholesterolaemia alone, bezafibrate significantly reduced the cholesterol (particularly esterified cholesterol) and triglyceride content of large very low density lipoprotein (VLDL) (Svedberg flotation units (Sf) 60-400) in comparison to the placebo group (P less than 0.05), and a trend towards a reduction in free and esterified cholesterol within the intermediate density lipoprotein fraction (IDL) (Sf 12-20) was noted. Low density lipoprotein (LDL) composition was unaltered and in general phospholipid and protein concentrations and cholesteryl ester/protein ratios within the lipoprotein fractions were unaffected. Large VLDL cholesterol and triglyceride concentrations in those with combined hyperlipidaemia were significantly decreased following bezafibrate therapy, both in comparison to placebo-treated subjects and to baseline concentrations (P less than 0.05). An additional significant reduction in small VLDL (Sf 20-60) free cholesterol was recorded (P less than 0.05). Average reductions of large and small VLDL protein of 50-56% were not significant because of wide variation in responses. Bezafibrate had no effect on the abnormal composition of IDL and LDL, characteristic of Type 1 diabetes, regardless of whether or not hypertriglyceridaemia was associated with hypercholesterolaemia. Its major action was to lower VLDL lipid concentrations, but it may also reduce the lipid content of intermediate density lipoprotein in Type 1 diabetes.
Adolescent↗
Non-enzymatic glycation of apolipoprotein B in the sera of diabetic and non-diabetic subjects.
Utilising a combination of m-aminophenyl-borate affinity chromatography and an immunoradiometric assay for apolipoprotein B (apo B), we have developed a specific and highly sensitive (6 ng/ml) procedure for the assay of glycated apo B. We studied 52 diabetic patients, 50 non-diabetic control subjects and 12 patients heterozygous for familial hypercholesterolaemia (FH). Both insulin-dependent and non-insulin dependent diabetics were included in our study. Total apo B in the diabetics (108 +/- 5 mg/dl; mean +/- S.E.M) was increased (controls: 95 +/- 4 mg/dl; P less than 0.05). In the FH group the serum apo B concentration (216 +/- 24 mg/dl) was significantly higher (P less than 0.001) than both the other groups studied. Both the serum glycated apo B concentration (9.3 +/- 0.8 mg/dl versus 4.8 +/- 0.7 mg/dl) and the percentage glycated apo B (7.9 +/- 0.4% compared to 3.9 +/- 0.2%) were significantly higher in the diabetics than in non-diabetic controls (P less than 0.001). A positive correlation was found between the percentage of glycated apo B and glycated haemoglobin (r = 0.65; P less than 0.001) and fasting glucose concentration (r = 0.52; P less than 0.001) in diabetics. The percentage of glycated apo B in FH patients was not significantly different from controls, but the serum concentration of glycated apo B, because of the greatly increased total level of apo B was raised (8.2 +/- 1.4 mg/dl) to a similar extent to that of the diabetics.
Adult↗
A cross-sectional evaluation of cardiovascular risk factors in coronary heart disease associated with type 1 (insulin-dependent) diabetes mellitus.
The contribution from lipoproteins, blood pressure, albuminuria and demographic variables to coronary heart disease in 90 adult subjects with and 172 without Type 1 diabetes mellitus was examined in order to investigate whether risk factors were of equivalent importance in diabetic and non-diabetic coronary heart disease. Coronary heart disease (CHD) was present in roughly 25% of subjects in each group. In Type 1 diabetes those with CHD had significantly higher levels of systolic blood pressure, albumin excretion, serum creatinine, triglycerides, VLDL cholesterol and C-peptide, and reductions in serum concentrations of HDL and HDL2 cholesterol, in comparison to those without. However, the prevalence of smokers, and concentrations of Lp(a), ApoB and fibrinogen were comparable. Blood pressure and HDL cholesterol were higher in the CHD group with Type 1 diabetes in comparison to the nondiabetic group with CHD, although LDL concentrations and the prevalence of Lp(a) concentrations > 200 mg/l were lower. Logistic regression analysis revealed the strongest independent predictors of CHD in Type 1 diabetes were serum triglycerides, systolic blood pressure, age, serum LDL cholesterol, and the daily insulin dosage, whereas in the non-diabetic control group HDL2 cholesterol, Lp(a), ApoA1 and ApoB, total serum cholesterol and body mass index were additional predictors. CHD in Type 1 diabetes appears to be most closely associated with increasing age and levels of blood pressure and total serum lipids. Apolipoproteins and albuminuria did not seem to be important independent predictors of CHD in Type 1 diabetes, whereas the former were more clearly associated with CHD in non-diabetic controls.
Adult↗
Laboratory facilities for investigating lipid disorders in the United Kingdom: results of the British Hyperlipidaemia Association survey.
AIMS: To determine the availability of facilities for the investigation of hyperlipidaemia in the United Kingdom. METHODS: A questionnaire was sent to all health districts in the United Kingdom. RESULTS: The response rate was 81%. All laboratories used enzymatic techniques to measure serum triglyceride and cholesterol concentrations, although there were differences in standardisation procedures. Reference ranges for serum lipids were quoted by 58% of laboratories while 50% quoted "desirable limits". Almost half specified that fasting blood samples were required. High density lipoprotein cholesterol concentrations were estimated by 75% and apolipoproteins AI and B by 14% of laboratories; there were differences in specimen type and considerable diversity in procedures used for measurement. CONCLUSIONS: Many laboratories were unaware of current recommendations for screening for hypercholesterolaemia in the community. The present survey indicated an urgent need for the introduction of better reference methods, standardisation, and quality assurance procedures before apolipoproteins become a routine part of coronary heart disease risk assessment.
Apolipoproteins↗
Abnormalities of VLDL, IDL, and LDL characterize insulin-dependent diabetes mellitus.
To identify abnormalities of serum lipoprotein composition and concentration that were specific to insulin-dependent diabetes mellitus (IDDM), the procedure of discontinuous gradient ultracentrifugation was employed to isolate lipoprotein fractions in 44 patients with IDDM, 24 nondiabetic subjects with similar lipid and lipoprotein concentrations, and 19 healthy normocholesterolemic (less than 5.2 mmol/l [less than 200 mg/dl]) subjects. The mass concentration of low density lipoprotein (LDL) was greater in IDDM than in both control groups. The free cholesterol to phospholipid ratio in large very low density lipoprotein (VLDL) was greatest in IDDM in comparison with both of the other groups. The contribution of triglyceride to total large VLDL mass was greater, whereas that of phospholipids was lower, in IDDM than in the dyslipidemic nondiabetic group. Protein concentration was reduced and phospholipid increased in small VLDL in IDDM in comparison with both control groups, and the contribution from protein to lipoprotein mass was least in IDDM. Similarly in intermediate density lipoprotein (IDL), the protein concentration and its contribution to overall mass was also lower in IDDM than in either control group, but by contrast, the phospholipid content was increased. The cholesteryl ester to protein ratio was highest in both small VLDL and IDL in IDDM in comparison with both control groups, whereas the free cholesterol to phospholipid ratio in IDL was least in IDDM. In LDL, total cholesterol and triglyceride concentrations were greatest and the contribution from protein to lipoprotein mass was least in IDDM in comparison with both control groups. The LDL free cholesterol to phospholipid ratio was greater in IDDM than in dyslipidemic control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Serum lipoprotein (a) in men with proteinuria due to idiopathic membranous nephropathy.
Patients with heavy proteinuria have an increased incidence of venous thrombosis and coronary heart disease (CHD). They also exhibit perturbations in lipoprotein metabolism. Lipoprotein (a) (Lp(a)) predisposes to CHD; it may also promote intravascular thrombosis since it contains apolipoprotein (a), which could act as a competitive inhibitor of plasminogen activation. We have measured the concentration of serum Lp(a) in 10 men with proteinuria due to idiopathic membranous nephropathy (IMN), in eight men with a similar diagnosis but who were in remission, and in 103 healthy men. Serum Lp(a) levels were significantly elevated in the men with active IMN, having a median value of 31.3 (range 3.2-75.0) mg/dl, whereas they were 8.4 (3.4-31.5) mg/dl in the patients in remission, which was similar to the value of 11.3 (< 0.8-87.4) mg/dl found in the healthy controls. Lp(a) is unique in containing an apolipoprotein which is a giant mutant of plasminogen and it is thus possible that the high circulating levels of Lp(a) contribute to the vascular morbidity associated with proteinuria by promoting thrombosis or atherogenesis or both.
Adult↗
Lipoprotein secretion by the human hepatoma cell line Hep G2: differential rates of accumulation of apolipoprotein B and lipoprotein lipids in tissue culture media in response to albumin, glucose and oleate.
Serum low-density lipoprotein (LDL) concentration is a major determinant of susceptibility to the development of atherosclerosis. A major component of the protein moiety of LDL and its precursor very-low-density lipoprotein is apolipoprotein B (apo B). The human hepatoma cell line, Hep G2, was used as a model for the investigation of mechanisms which control hepatic secretion of the apo B and lipid components of lipoproteins. Using a sensitive immunoradiometric assay for apo B developed in this laboratory, we showed that bovine serum albumin inhibited and glucose, and fatty acids enhanced the rate of accumulation of apo B in the culture medium of Hep G2 cells. However, these substances did not necessarily affect LDL lipids in the same way as apo B. This finding appeared to be due to Hep G2 cells expressing lipase activities which led to triacylglycerol and phospholipid hydrolysis and lipid reuptake. Reuptake of apo B also occurred, but its rate of accumulation in the culture medium suggested it was a closer reflection of its true secretory rate.
Apolipoproteins B↗
Paraoxonase prevents accumulation of lipoperoxides in low-density lipoprotein.
Oxidative modification of low-density lipoprotein (LDL) enhances its uptake by macrophages in tissue culture and in vivo may underly the formation of arterial fatty streaks, the progenitors of atheroma. We investigated the possible protection which high-density lipoprotein (HDL) affords against LDL oxidation. The formation of lipoperoxides and thiobarbituric acid reactive substances when LDL was incubated with copper ions was significantly decreased by HDL. The enzyme, paraoxonase (E.C. 3.1.8.1), purified from human HDL, had a similar effect and thus may be the component of HDL responsible for decreasing the accumulation of lipid peroxidation products.
Aryldialkylphosphatase↗
Influence of early diabetic nephropathy on very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and low density lipoprotein (LDL) composition.
The procedure of discontinuous gradient ultracentrifugation (DGU) was used to characterize the influence of early diabetic nephropathy on the composition of very low density lipoprotein (VLDL, flotation density 60-400 Svedberg (Sf) units), low density lipoprotein (LDL, flotation density 0-12 Sf) and subfractions of intermediate density lipoprotein (IDL1 and IDL2, 20-60 and 12-20 Sf, respectively). Forty-six subjects with type 1 (insulin-dependent) diabetes and serum creatinine, less than 140 mumol/l were studied, of whom 23 consistently had normal rates of albumin excretion (AER less than 15 micrograms/min), and 23 had persistent albuminuria (AER 20.0-960.6 micrograms/min). The two groups were similar with respect to total serum lipids, glycaemic control, age and body mass. The composition (lipid, protein and phospholipid) and mass of VLDL, LDL and IDL2 was not appreciably altered by early nephropathy, but free and total cholesterol concentration in IDL1 (Sf 20-60) was increased (total cholesterol 0.68 (0.09) (mean (SE)) vs. 0.47 (0.07) mmol/l, and free cholesterol 0.27 (0.04) vs. 0.17 (0.03) mmol/l, both P less than 0.05). The explanation of these findings was probably an accumulation in the circulation of the remnants of chylomicron metabolism and/or intermediates in the conversion from VLDL to IDL1. In addition, there was a decrease in serum high density lipoprotein (HDL) cholesterol in early nephropathy (1.27 (0.06) vs. 1.38 (0.10) mmol/l, P less than 0.05), due to a decrease in the HDL2 cholesterol subfraction (P less than 0.05). These findings may in part explain the increased risk of premature atherosclerosis associated with the development of albuminuria.
Adolescent↗
Oral carbocisteine does not lower serum lipoprotein(a) levels.
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Administration, Oral↗
Serum paraoxonase activity in familial hypercholesterolaemia and insulin-dependent diabetes mellitus.
The activity of serum paraoxonase, an enzyme located on high-density lipoprotein, has been investigated in familial hypercholesterolaemia (FH) and insulin dependent diabetes mellitus (IDDM). Increases in total serum cholesterol and apolipoprotein B were present in both FH and IDDM compared to healthy controls and in the patients with IDDM, serum triglycerides were also raised. The serum HDL-cholesterol concentrations in controls and patients with FH and IDDM did not differ significantly. Serum paraoxonase activity was significantly lower in both the FH and IDDM populations than in controls (P less than 0.001 and P less than 0.01, respectively). 72% of the FH population and 67% of the IDDM population were in the lower half of the frequency distribution for serum paraoxonase (activity of less than 112 U/l). It is likely that the common factor related to low paraoxonase activity is hyperlipidaemia. It is possible that paraoxonase has a physiological role in lipid metabolism and that decreases in its activity may accelerate atherogenesis.
Apolipoproteins B↗
Substrate specificity of human serum paraoxonase.
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Aryldialkylphosphatase↗
A randomized cross-over study of the effects of proinsulin on lipid metabolism in type 2 diabetes.
The effects of human proinsulin and insulin on lipid metabolism in Type 2 diabetes were examined in a randomized cross-over study in 15 patients. Blood glucose control was indistinguishable at the end of the two treatment periods, but fasting levels of triglycerides appeared somewhat lower after proinsulin (1.17(SE 0.16) vs 1.39(0.21) mmol I-1; p less than 0.07), and the maximal postprandial triglyceride response (2.19 (0.25) vs 2.87(0.28) mmol I-1, p less than 0.001) and triglyceride area under the curve (p less than 0.01) were significantly reduced. In five hyperlipidaemic patients postprandial triglyceridaemia was reduced with proinsulin (2.89(0.60) vs 3.68(0.56); p less than 0.001), but in addition fasting serum triglycerides (1.20(0.30) vs 1.96(0.30) mmol I-1, p less than 0.04) and possibly VLDL-cholesterol (0.49(0.15) vs 0.60(0.20) mmol I-1; p less than 0.10) were lower and fasting LDL-cholesterol levels higher (4.82(0.42) vs 3.92(0.57) mmol I-1, p less than 0.03) after proinsulin therapy. Proinsulin appears to preferentially suppress the production of triglyceride-rich lipoproteins in Type 2 diabetes, particularly postprandially, and may enhance their clearance and conversion to LDL, especially in hyperlipidaemic Type 2 diabetes.
Adult↗
Lipoprotein (a) and microvascular disease in type 1 (insulin-dependent) diabetes.
The influence of albuminuria and proliferative retinopathy on concentration of serum lipoprotein (a) was examined cross-sectionally in 90 Type 1 diabetic patients. Concentrations of lipoprotein (a) were less in those with normoalbuminuria (90 (8-882) (median (range] U l-1) than in those with micro- or macro-albuminuria (137 (19-1722) U l-1, p less than 0.05). The prevalence of patients whose lipoprotein (a) concentrations were greater than 200 U l-1 was also greater (45% vs 24%, p = 0.03) among patients with albuminuria, but no difference was found between the microalbuminuric and macroalbuminuric groups (53 and 41%, respectively), or between those with or without proliferative retinopathy. The present finding that lipoprotein (a) concentrations may be increased at an early stage of diabetic renal disease may in part account for the excess ischaemic heart disease associated with diabetic nephropathy.
Albuminuria↗