Plasma Lp Research Articles

Characterization of the basis of lipoprotein [a] lysine-binding heterogeneity

Although elevated plasma concentrations of lipoprotein [a] (Lp[a]) are considered to be a risk factor for atherosclerosis, the mechanisms by which Lp[a] mediates its pathogenic effects have not been conclusively determined. The apolipoprotein [a] (apo[a]) component of Lp[a] confers unique structural properties to this lipoprotein, including the ability to bind to lysine residues in biological substrates. It has been shown, however, that only a fraction of plasma Lp[a] (Lp[a]-Lys+) binds to lysine-Sepharose in vitro. The nature of the non-lysine-binding Lp[a] fraction in plasma (Lp[a]-Lys−) is currently unknown. In the present study, the Lp[a]-Lys+ fraction was determined in the plasma of six unrelated individuals; the Lp[a]-Lys+ fraction in these plasma samples ranged from ~37 to ~48%. Interestingly, purification of the Lp[a] by density gradient ultracentrifugation followed by gel filtration and ion-exchange chromatography resulted in progressive increases in the Lp[a]-Lys+ fraction. Addition of either purified low density lipoprotein (LDL) or fibronectin to the purified Lp[a] at a 1:1 molar ratio reduced the Lp[a]-Lys+ fraction (maximal decrease of 34 and 20%, respectively) whereas addition of both fibronectin and LDL to the purified Lp[a] resulted in a further decrease (45% maximally) in this fraction. Similar results were obtained by using a recombinant expression system for apo[a]: addition of a 4-fold molar excess of either LDL or fibronectin to conditioned medium containing metabolically labeled recombinant apo[a] reduced the Lys+ fraction by 49 and 23%, respectively. Taken together, our data suggest that the lysine-binding heterogeneity of plasma Lp[a] is not primarily an intrinsic property of the lipoprotein, but rather results in large part from its ability to noncovalently associate with abundant plasma components such as LDL and fibronectin. These interactions appear to mask the lysine-binding site in apo[a] kringle IV type 10, which mediates the interaction of Lp[a] with lysine-Sepharose. The contribution of these interactions to the function of Lp[a] in vivo remains to be investigated.—Xia, J., L. F. May, and M. L. Koschinsky. Characterization of the basis of lipoprotein [a] lysine-binding heterogeneity. J. Lipid Res. 2000. 41: 1578–1584.

Plasma lipoprotein (a) concentrations and apolipoprotein (a) phenotypes in an Aboriginal population from Western Australia

Factors contributing to the variation in plasma lipoprotein (a) (Lp(a)) concentration were surveyed in an Aboriginal population (175 men and 219 women), aged 24-86 years, from Western Australia. The plasma Lp(a) levels were highly skewed towards low levels in this population, with a median of 84 mg/L and a mean of 166 mg/L. Approximately 20% had plasma Lp(a) above the threshold value of 300 mg/L, while 52% had Lp(a) levels below 100 mg/L. The most commonly occurring phenotype was apolipoprotien(a) S4. In this phenotype, Lp(a) concentrations ranged from not detectable to 468 mg/L. There was a positive relationship between cigarette smoking and plasma Lp(a) concentration in men. Apolipoprotein A1 and bilirubin were positively associated with Lp(a) in the 40-60 age group and a positive relationship between weight and Lp(a) concentrations was observed in those aged 60 years or over. Thus, although Lp(a) is mainly genetically determined, there are clearly other factors which contribute to variations in Lp(a) concentrations.

The effect of apolipoprotein(a)-, apolipoprotein E-, and apolipoprotein A4- polymorphisms on quantitative lipoprotein(a) concentrations.

The effects of apolipoprotein (a), apolipoprotein-E, and apolipoprotein-A4 isoforms on quantitative lipoprotein(a) [Lp(a)] levels were assessed in a sample of 142 Dutch families consisting of two parents and their adolescent twin offspring. A total heritability of 95% was estimated for plasma Lp(a) concentrations. The largest part of this heritability was due to the apo(a) locus which explained 61% of the total variance in Lp(a) levels. The pattern of familial correlations for the residual part of the Lp(a) variance that could not be attributed to the apo(a) isoforms, suggested genetic influences on the residual variance. We addressed the question whether this residual genetic variance could be ascribed to the apoE or the apoA4 locus. A simultaneous analysis of all three loci showed that both the apoE and the apoA4 polymorphism did not contribute significantly to Lp(a) variation.

Oxidative stress in families of type 1 diabetic patients.

The link between hyperglycemia and the complications of diabetes is unknown. It is still discussed whether oxidative stress precedes or merely reflects diabetic complications. To search for a familial predisposition to oxidative stress, we investigated indexes of glucose and lipid metabolism, markers of plasma and cell lipid oxidation, a marker of oxidant-induced protein damage, and the effects of oxygen radicals on erythrocytes (or red blood cells [RBCs]) of patients with type 1 diabetes and their relatives. We recruited 30 type 1 diabetic subjects (10 without diabetic complications, 10 with retinopathy, and 10 with nephropathy), 36 nondiabetic siblings, 37 nondiabetic parents of type 1 diabetic subjects, and 3 control groups of healthy subjects without a family history of diabetes. Levels of blood creatinine, glucose, HbA(1c), cholesterol, triglycerides, lipoprotein(a) (Lp[a]), fibrinogen, malondialdehyde (MDA), and advanced oxidation protein products were determined. The RBC response to oxidative stress (3-h incubation at 37 degrees C with or without a radical generating system) was evaluated by measuring RBC glutathione (GSH), RBC-MDA, and hemolysis. Diabetic patients had higher levels of blood glucose (P < 0.001), HbA(1c) (P < 0.001), Lp(a) (P < 0.01), and fibrinogen (P < 0.05) than control subjects. Siblings of diabetic patients had higher Lp(a) levels (P < 0.001). Parents had higher levels of plasma glucose (P < 0.05) and Lp(a) (P < 0.01). Plasma and RBC-MDA were significantly elevated in diabetic subjects and relatives compared with control subjects. Basal RBC-GSH was lower in diabetic subjects (P < 0.01). In diabetic subjects, incubations of cells caused a decrease in RBC-GSH of a lesser degree than that in control subjects, but they caused a significant increase in hemolysis. Among relatives, hemolysis was increased both at baseline and after incubation. Plasma MDA levels were associated with blood glucose, creatinine, and fibrinogen levels (multiple r = 0.5, P < 0.001), and basal RBC-MDA levels were associated with plasma Lp(a), fibrinogen, and plasma MDA levels (r = 0.6, P < 0.001). Basal RBC-GSH content correlated with serum glucose and RBC-MDA production (r = 0.3, P < 0.01). Our study is the first to present evidence that markers of lipoprotein metabolism (Lp[a]), oxidative stress (plasma and RBC-MDA), and cellular fragility (hemolysis) are abnormal in nondiabetic relatives of type 1 diabetic subjects, thereby supporting the view that familial elements of diabetes even precede the onset of diabetes. It seems reasonable that the same biological markers considered major predictors of cardiovascular disease can also trace familial susceptibility to type 1 diabetes, just as they have been associated with the development of type 2 diabetes.

Ascorbic acid supplementation does not lower plasma lipoprotein(a) concentrations

Elevated plasma concentrations of lipoprotein(a) (Lp[a]) are associated with premature coronary heart disease (CHD). Lp(a) is a lipoprotein particle consisting of low-density lipoprotein (LDL) with apolipoprotein (apo) (a) attached to the apo B-100 component of LDL. It has been hypothesized that ascorbic acid supplementation may reduce plasma levels of Lp(a). The purpose of this study was to determine whether ascorbic acid supplementation at a dose of 1 g/day would lower plasma concentrations of Lp(a) when studied in a randomized, placebo-controlled, blinded fashion. One hundred and one healthy men and women ranging in age from 20 to 69 years were studied for 8 months. Lp(a) values at baseline for the placebo group ( n=52) and the ascorbic acid supplemented group ( n=49) were 0.026 and 0.033 g/l, respectively. The 8-month concentrations were 0.027 g/l (placebo) and 0.038 g/l (supplemented group). None of these values were significantly different from each other. In addition, no difference in plasma Lp(a) concentration was seen between the placebo and supplemented groups when only subjects with an initial Lp(a) value of ≥0.050 g/l were analyzed. Our data indicate that plasma Lp(a) concentrations are not significantly affected by ascorbic acid supplementation in healthy human subjects.

Absence of relationship between plasma Lp(a), Lp-AI, anti-oxidized LDL autoantibodies, LDL immune complexes concentrations and restenosis after percutaneous transluminal coronary angioplasty

To determine the relation between the concentration of Lp(a), LpAI, immunological markers of LDL oxidation (antioxidized-LDL autoantibodies (LDL-AB), LDL immune complexes (LDL-IC)) and restenosis after percutaneous transluminal coronary angioplasty (PTCA) in a Caucasian population (France), we studied 77 consecutive patients who successfully underwent PTCA. All were evaluated by follow-up angiography at an average of 6 months after PTCA and were divided into two groups: existence of restenosis (32 patients, group (G+)) and absence of restenosis (45 patients, negative group (G−)). The prevalence of diabetes mellitus was higher in the restenosis positive group than in the negative group (28% versus 2% respectively, P=0.001). Before and after adjustment in diabetes mellitus frequency there was no difference in the usual lipid parameters (total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, phospholipids, apolipoprotein AI, apolipoprotein B) between the two groups of patients nor in the other parameters (Before adjustment: Lp(a): 0.306±0.352 g/l (G+) vs. 0.263±0.270 g/l (G−); LpAI: 0.414±0.126 g/l (G+) vs. 0.390±0.092 g/l (G−); LDL-AB: arbitrary unit (AU) 3.75±1.91 (G+) vs. 3.67±1.24 (G−); LDL-IC: (AU) 0.93±0.82 (G+) vs. 0.86±0.44 (G−)). Spearman correlation coefficients did not report any correlation between late loss, loss index, gain and the above mentioned plasma parameters. In conclusion, usual tested plasma lipids, Lp(a), LpAI and in vivo markers of LDL oxidation (LDL-AB and LDL-IC) are not risk factors for restenosis after PTCA in this French population.

Time course and dose dependence of activity of the aminophosphonate SR-74829i/SB253149 on plasma Lp(a) in cynomolgus monkeys

Time course and dose dependence of activity of the aminophosphonate SR-74829i/SB253149 on plasma Lp(a) in cynomolgus monkeys

Role of calnexin, calreticulin, and endoplasmic reticulum mannosidase I in apolipoprotein(a) intracellular targeting.

Apolipoprotein(a) [apo(a)] is a component of atherogenic lipoprotein(a) [Lp(a)]. Differences in the extent of endoplasmic reticulum (ER) associated degradation (ERAD) of apo(a) allelic variants contribute to the >1000-fold variation in plasma Lp(a) levels. Using human apo(a) transgenic mouse hepatocytes, we analyzed the role of the ER chaperones calnexin (CNX) and calreticulin (CRT), and ER mannosidase I in apo(a) intracellular targeting. Co-immunoprecipitation and pulse-chase analyses revealed similar kinetics of apo(a) interaction with CNX and CRT, peaking 15-30 min after apo(a) synthesis. Trapping of apo(a) N-linked glycans in their monoglucosylated form, by posttranslational inhibition of ER glucosidase activity with castanospermine (CST), enhanced apo(a)-CNX/CRT interaction and prevented both apo(a) secretion and ERAD. Delay of CST addition until 20 or 30 min after apo(a) synthesis [when no apo(a) had yet undergone degradation or Golgi-specific carbohydrate modification] allowed a portion of apo(a) to be secreted or degraded. These results are consistent with a transient apo(a)-CNX/CRT association and suggest that events downstream of CNX/CRT interaction determine apo(a) intracellular targeting. Inhibition of ER mannosidase I with deoxymannojirimycin or kifunensine had no effect on apo(a) secretion, but inhibited proteasome-mediated apo(a) ERAD even under conditions where apo(a)-CNX/CRT interaction was prevented. These results suggest a role for an additional, mannose-specific, ER lectin in targeting secretory proteins to the proteasome for destruction.

Gender differences in plasma Lp A-I and Ip A-I:A-I levels in the heritage family study

Gender differences in plasma Lp A-I and Ip A-I:A-I levels in the heritage family study

Polygenic hypercholesterolemia is associated with elevated plasma Lp(a) and apolipoprotein (a) fragments levels in plasma and urine

Polygenic hypercholesterolemia is associated with elevated plasma Lp(a) and apolipoprotein (a) fragments levels in plasma and urine

Defects of the LDL receptor in WHHL transgenic rabbits lead to a marked accumulation of plasma lipoprotein[a

In this study, we created LDL receptor (LDLr) defective (WHHL) transgenic rabbits expressing human apo[a] to examine whether LDLr mediates the Lp[a] clearance from the plasma. By crossbreeding WHHL rabbits with human apo[a] transgenic rabbits, we obtained two groups of human apo[a] transgenic rabbits with defective LDLr functions: apo[a]+/0 WHHL heterozygous (LDLr+/−) and apo[a]+/0 WHHL homozygous (LDLr−/−) rabbits. The lipid and lipoprotein levels of human apo[a] WHHL rabbits were compared to those of human apo[a] transgenic rabbits with normal LDLr functions (LDLr+/+). The apo[a] production rate was evaluated by analyzing apo[a] mRNA expression in the liver, the major site for apo[a] synthesis in transgenic rabbits. We found that pre-β lipoproteins were markedly increased accompanied by a 2-fold increase in the plasma Lp[a] in apo[a]+/0/LDLr+/− rabbits and a 4.2-fold increase in apo[a]+/0/LDLr−/− rabbits compared with that in apo[a]+/0 rabbits with normal LDLr function. In apo[a]+/0/LDLr−/− rabbits, there was a marked increase in plasma total cholesterol and triglycerides, as was found in their counterpart non-transgenic WHHL rabbits. Northern blot analysis revealed that hepatic apo[a] expression in WHHL transgenic rabbits was similar to that in LDLr+/+ transgenic rabbits, suggesting the accumulation of plasma Lp[a] in WHHL transgenic rabbits was not due to increased apo[a] synthesis.In conclusion, absence of a functional LDLr leads to a marked accumulation of plasma Lp[a] in human apo[a] transgenic WHHL rabbits and LDLr may participate in the catabolism of Lp[a] in rabbits.

The effect of apolipoprotein(a)-, apolipoprotein E-, and apolipoprotein A4- polymorphisms on quantitative lipoprotein(a) concentrations

AbstractThe effects of apolipoprotein (a), apolipoprotein-E, and apolipoprotein-A4 isoforms on quantitative lipoprotein(a) [Lp(a)] levels were assessed in a sample of 142 Dutch families consisting of two parents and their adolescent twin offspring. A total heritability of 95% was estimated for plasma Lp(a) concentrations. The largest part of this heritability was due to the apo(a) locus which explained 61% of the total variance in Lp(a) levels. The pattern of familial correlations for the residual part of the Lp(a) variance that could not be attributed to the apo(a) isoforms, suggested genetic influences on the residual variance. We addressed the question whether this residual genetic variance could be ascribed to the apoE or the apoA4 locus. A simultaneous analysis of all three loci showed that both the apoE and the apoA4 polymorphism did not contribute significantly to Lp(a) variation. Twin Research (2000) 3, 152–158.

Major reduction in plasma Lp(a) levels during sepsis and burns.

Plasma levels of lipoprotein(a) [Lp(a)], an atherogenic particle, vary widely between individuals and are highly genetically determined. Whether Lp(a) is a positive acute-phase reactant is debated. The present study was designed to evaluate the impact of major inflammatory responses on plasma Lp(a) levels. Plasma levels of C-reactive protein (CRP), low density lipoprotein cholesterol, Lp(a), and apolipoprotein(a) [apo(a)] fragments, as well as urinary apo(a), were measured serially in 9 patients admitted to the intensive care unit for sepsis and 4 patients with extensive burns. Sepsis and burns elicited a major increase in plasma CRP levels. In both conditions, plasma concentrations of Lp(a) declined abruptly and transiently in parallel with plasma low density lipoprotein cholesterol levels and closely mirrored plasma CRP levels. In 5 survivors, the nadir of plasma Lp(a) levels was 5- to 15-fold lower than levels 16 to 18 months after the study period. No change in plasma levels of apo(a) fragments or urinary apo(a) was noticed during the study period. Turnover studies in mice indicated that clearance of Lp(a) was retarded in lipopolysaccharide-treated animals. Taken together, these data demonstrate that Lp(a) behaves as a negative acute-phase reactant during major inflammatory response. Nongenetic factors have a major, acute, and unexpected impact on Lp(a) metabolism in burns and sepsis. Identification of these factors may provide new tools to lower elevated plasma Lp(a) levels.

Are lipid-dependent indicators of cardiovascular risk affected by renal transplantation?

Hyperlipoproteinemia has been reported to frequently occur in kidney transplanted patients, thus possibly explaining, at least in part, the increased incidence of cardiovascular disease in this population. To evaluate the impact of renal transplantation (Tx), and related immunosuppressive therapy, on plasma lipoprotein and Lp(a) profile, we selected a cohort of kidney transplanted patients (36 M/14 F; age 33.8 + 12.0 yr, range 13-62) lacking significant causes of hyperlipidemia. All patients received a triple immunosuppressive regimen and showed a stable renal function after Tx (plasma creatinine: 1.36 +/- 0.35 mg/dL). One year after Tx, we found a significant increase of total cholesterol (TC), LDL, HDL, ApoB and ApoA-I (p < 0.005), while plasma triglyceride levels remained unmodified. Lp(a) plasma levels after Tx were within the normal range and displayed a significant inverse relationship with apo(a) size. Noteworthy, LDL/HDL ratio and ApoB/ ApoA-I ratio in kidney transplanted patients were almost superimposable with those of normal controls. Specifically, LDL/HDL ratio significantly decreased in 64% of patients after Tx, due to a prevalent increase of HDL, and was associated with a moderate amelioration of plasma TG. In a multiple linear regression model, post-Tx HDL level was significantly related to recipient's age, gender, BMI and cyclosporine (CyA) trough levels (Adj-R2 = 0.35, p = 0.0002), with gender and CyA trough levels being the better predictors of HDL. In conclusion, immunosuppressive regimens, in themselves, do not appear to significantly increase the atherogenic risk related to lipoproteins. Rather, other factors can affect the lipoprotein profile and its vascular effects in renal transplant recipients.

Lipoprotein(a) in the Nephrotic Syndrome

Abstract. Plasma levels of lipoprotein(a) (Lp(a)), an atherogenic particle, are elevated in kidney disease, which suggests a role of this organ in the metabolism of Lp(a). Additional evidence for a role of the kidney in the clearance of Lp(a) is provided by the fact that circulating N-terminal fragments of apolipoprotein(a) (apo(a)) are processed and eliminated by the renal route. To further understand the mechanism underlying such renal excretion, the levels of apo(a) fragments in plasma and urine relative to plasma Lp(a) levels were determined in patients with nephrotic syndrome (n = 15). In plasma, the absolute (24.7 ± 20.4 versus 2.16 ± 2.99 μg/ml, P &lt; 0.0001) as well as the relative amounts of apo(a) fragments (4.6 ± 3.4% versus 2.1 ± 3.3% of total Lp(a), P &lt; 0.0001) were significantly elevated in nephrotic patients compared with a control, normolipidemic population. In addition, urinary apo(a) excretion in patients with nephrotic syndrome was markedly elevated compared with that in control subjects (578 ± 622 versus 27.7 ± 44 ng/ml per mg creatinine, P &lt; 0.001). However, the fractional catabolic rates of apo(a) fragments were similar in both groups (0.68 ± 0.67% and 0.62 ± 0.47% in nephrotic and control subjects, respectively), suggesting that increased plasma concentrations of apo(a) fragments in nephrotic subjects are more dependent on the rate of synthesis rather than on the catabolic rate. Molecular analysis of apo(a) immunoreactive material in urine revealed that the patterns of apo(a) fragments in nephrotic patients were distinct from those of control subjects. Full-length apo(a), large N-terminal apo(a) fragments similar in size to those present in plasma, as well as C-terminal fragments of apo(a) were detected in urine from nephrotic patients but not in urine from controls. All of these apo(a) forms were in addition to smaller N-terminal apo(a) fragments present in normal urine. This study also demonstrated the presence of Lp(a) in urine from nephrotic patients by ultracentrifugal fractionation. These data suggest that in nephrotic syndrome, Lp(a) and large fragments of apo(a) are passively filtered by the kidney through the glomerulus, whereas smaller apo(a) fragments are secreted into the urine.

Lipoprotein (a) levels in normal pregnancy and in pregnancy complicated with pre-eclampsia

Lipoprotein (a) (Lp(a)) is recognised as a risk factor for arterial and venous thrombosis, a property which may relate to its structural similarity to plasminogen. Pregnancy is associated with a hypofibrinolytic state. Elevated Lp(a) may influence fibrinolysis and have an unfavourable role in pregnancy outcome. In this study alterations in plasma Lp(a) concentrations during normal pregnancy was examined, in a detailed longitudinal investigation, in ten women together with changes in other lipid parameters. In addition, Lp(a) concentrations were examined in subjects with pre-eclampsia ( n=10) relative to matched controls ( n=10), since it has recently been reported that a substantial increase in circulating Lp(a) occurs in this disorder. Lp(a) concentration increased steadily in normal pregnancy between 10 and 35 weeks with a doubling of the median value from 14.5 to 27.0 mg/dl ( P=0.01). A significant increase in Lp(a) values was observed in all subjects with increasing gestation (median rise 190%, range 117–340%). This increase was intermediate to those seen in plasma triglyceride and cholesterol. No significant difference in Lp(a) values was observed in subjects with pre-eclampsia, compared with matched normal pregnancy controls (median 14 mg/dl [IQR 4.7–69.0] in pre-eclampsia vs 20 mg/dl [9.0–56.3] in controls; P=0.57), at a median gestation of 32 weeks. In conclusion, there is a 2-fold increase in Lp(a) during normal pregnancy, which may influence fibrinolysis. Circulating Lp(a) is not significantly elevated in women with pre-eclampsia, and thus is unlikely to play a role in the pathophysiology of this disorder.

Endothelium-dependent vasorelaxation in the aorta of transgenic mice expressing human apolipoprotein(a) or lipoprotein(a).

Elevated plasma level of lipoprotein(a) (Lp(a)) is a well established risk factor for premature atherosclerosis and coronary artery disease. Recent studies showed impaired endothelium-dependent vasodilatation in humans with elevated plasma Lp(a). However, these human studies could not determine whether (1) elevated Lp(a) levels alone are the cause of endothelial dysfunction (these patients had multiple risk factors), and (2) native or oxidatively modified Lp(a) contributes to endothelial dysfunction (no measurements of native/oxidized Lp(a) ratio was reported in humans). In order to test whether apo(a) (an essential component of Lp(a) which is required for binding to endothelial cells) and native Lp(a) cause endothelial dysfunction, in the present study we tested endothelium-dependent vasorelaxation in aortic rings isolated from control and transgenic male mice either expressing the human apo(a) gene (TgA) or both the human apo(a) and human apo B100 genes (TgL). The TgA mice had plasma apo(a) levels of 8.8 +/- 1.2 mg/dl (n=6) and the double transgenic TgL mice had plasma Lp(a) levels of 15.3 +/- 1.4 mg/dl (n=8). Isolated aortic rings with and without endothelium were mounted in organ chambers and contracted with U46619 (10(-8) M) in the presence of ibuprofen (10(-5) M). Acetylcholine caused concentration-dependent (10(-9)-10(-5) M) relaxation, which could be prevented by endothelium removal and by NG-L-nitro-arginine (10(-4) M). Basal and acetylcholine-stimulated endothelium-dependent relaxation and endothelium-independent relaxation to nitroglycerin (10(-6) M) were not significantly different in aortic rings isolated from control and TgA or TgL mice. Twenty-four hour incubation of aortic rings isolated from control mice with recombinant human apo(a) or native Lp(a) (up to 300 microg/ml) caused no impairment of endothelium-dependent relaxations. In contrast, incubation with oxidized Lp(a) (50 microg/ml) or oxidized LDL (250 microg/ml) caused significant suppression of acetylcholine-induced endothelium-dependent vasorelaxation. These results show for the first time that elevated plasma levels of apo(a) and Lp(a) do not cause endothelial dysfunction in transgenic mice.

Twenty-four hours of insulin infusion does not lower plasma lipoprotein(a) in healthy men

The effect of 24-h exogenous hyperinsulinaemia on the plasma level of the atherogenic lipoprotein(a) (Lp(a)) is unknown. We evaluated the responses of plasma cholesterol, triglycerides, apolipoprotein (apo) B and Lp(a) during 24-h insulin infusion (180 pmol/kg/h) in 6 healthy men. Plasma total cholesterol (p < 0.01) and triglycerides (p < 0.05) decreased after 24 h of hyperinsulinaemia. Apo B was unchanged after 8 h (-2.4 +/- 3.0%, n.s.) and decreased by 10.9 +/- 4.8% (p<0.025) after 24 h of insulin. In contrast, Lp(a) did not decrease (+28.4 +/- 18.4%, n.s., and +/- 49.1 +/- 22.0%, n.s., after 8 and 24 h of insulin, respectively). This experiment supports the hypothesis that moderate hyperinsulinaemia has a different effect on the plasma level of triglyceride-rich lipoproteins compared to Lp(a).

Plasma and Lp(a)-associated PAF-acetylhydrolase activity in uremic patients undergoing different dialysis procedures

Plasma and Lp(a)-associated PAF-acetylhydrolase activity in uremic patients undergoing different dialysis procedures. Platelet-activating factor (PAF) is a potent inflammatory mediator associated with several physiopathological conditions, including renal diseases. PAF is degraded to the inactive metabolite lyso-PAF by PAF-acetylhydrolase (PAF-AH), which is considered as a potent anti-inflammatory and anti-atherogenic enzyme associated with lipoproteins. In this study, we evaluated the plasma- and lipoprotein(a) [Lp(a)]-associated PAF-AH activity in relationship to plasma lipid parameters and Lp(a) isoform size in patients with mild/moderate chronic renal failure (CRF), as well as in hemodialysis (HD) and chronic ambulatory peritoneal dialysis (CAPD) patients. We studied 74 patients undergoing maintenance HD, 44 patients undergoing CAPD, 56 patients with mild/moderate CRF, and 98 healthy subjects whose lipid profile, as well as plasma and high-density lipoprotein (HDL)-associated PAF-AH activity, was determined. Moreover, the effect of Lp(a) plasma levels on the distribution of PAF-AH among plasma lipoproteins, as well as the specific activity and kinetic properties of PAF-AH on two different Lp(a) isoforms, was measured in each studied group. The plasma PAF-AH activity in all studied groups was significantly higher than in controls, and the increase was more profound in CAPD patients. The HDL-associated PAF-AH activity, expressed per milliliter of plasma, was similar among all studied groups; however, when it was expressed as either per milligrams of HDL cholesterol or per milligrams of plasma apolipoprotein (apo) AI, the PAF-AH activity was significantly higher in all patient groups compared with controls. All patient groups had significantly elevated plasma Lp(a) levels, which altered the distribution of PAF-AH among the plasma lipoproteins compared with that observed in subjects with very low plasma Lp(a) levels (<8 mg/dl). Additionally, in each studied group, the specific activity as well as the apparent Km and Vmax values of the 19K4 apo(a) isoform were significantly higher (P < 0.01) compared with the values of the 23K4 isoform. However, the specific activity, as well as the Km and Vmax values on either the 19K4 apo(a) isoform or the 23K4 isoform, was significantly higher in CAPD patients compared with the other three groups. Plasma PAF-AH activity is increased in uremic patients. This elevation is more profound in CAPD patients, who also exhibit a more atherogenic lipid profile and more pronounced alterations in the specific activity and the kinetic constants of Lp(a)-associated PAF-AH.

Renal disease as a determinant of increased lipoprotein(a) concentrations in diabetic patients.

This study examined the hypothesis that kidney function is an independent determinant of lipoprotein(a) [Lp(a)] concentrations in people with diabetes. Lp(a) concentrations were measured in plasma samples from 273 type 2 and 223 type 1 diabetic patients recruited from a diabetes clinic. Kidney function was categorized as normal or pathological according to plasma creatinine levels and creatinine clearance rates. Macroalbuminuria was uniformly associated with significantly raised plasma concentrations of Lp(a) regardless of the marker used to identify kidney dysfunction. In contrast, in patients with microalbuminuria, significantly raised plasma Lp(a) levels were observed only when creatinine clearance rates or plasma creatinine levels indicated pathological kidney function. These conclusions were independent of diabetes type. In microalbuminuria and apparently in normoalbuminuria, altered kidney function determined by creatinine clearance rates or creatinine levels appears to be a major determinant of raised Lp(a) levels in both type 1 and type 2 diabetic patients. In contrast, Lp(a) concentrations were uniformly raised in patients with macroalbuminuria.