Abnormalities of lipoprotein metabolism in patients with the nephrotic syndrome

BACKGROUND AND METHODS. Patients with the nephrotic syndrome characteristically have multiple abnormalities of lipoprotein metabolism, but the cause and exact nature of these abnormalities are uncertain. In this study, we measured serum lipids and apoproteins in 57 patients with the nephrotic syndrome. We also determined the kinetic indexes of low-density lipoprotein (LDL) metabolism in six patients, and again in three of the six after recovery. RESULTS. The patients with the nephrotic syndrome had elevated serum concentrations of cholesterol, triglycerides, and phospholipids, which were confined to the lipoproteins containing apoprotein B. The serum concentrations of high-density lipoproteins and the associated A-I and A-II apoproteins were similar in the patients with the nephrotic syndrome and normal subjects. The relative proportions of lipids and their positive association with the increased serum concentrations of apoproteins B, C-II, C-III, and E suggest quantitative rather than qualitative differences in the lipoproteins. All the patients had lipiduria, which probably reflected the excretion of high-density lipoproteins, although no intact immunoreactive apoprotein A-I was found in urine. Serum albumin concentrations were inversely related to serum lipid concentrations in the patients, the severity of the hypoalbuminemia corresponding to the degree of change in serum lipoprotein concentrations. The kinetic studies of lipoprotein metabolism revealed an overproduction of LDL apoprotein B that returned to normal after recovery. CONCLUSIONS. The elevated serum concentrations of LDL cholesterol, other lipids, and apoprotein B in patients with uncomplicated nephrotic syndrome are due to reversible increases in lipoprotein production.     

Reduced plasma concentrations of total, low density lipoprotein and high density lipoprotein cholesterol in patients with Gaucher type I disease

Plasma lipid and serum apoprotein concentrations were determined in twenty-nine individuals with Gaucher type I disease. Plasma total cholesterol, low density lipoprotein (LDL) cholesterol and high density lipoprotein (HDL) cholesterol were all significantly reduced in the patients with Gaucher disease compared to a group of matched control subjects. Total, LDL and HDL cholesterol were lower in males than in females with Gaucher disease. These sex differences appeared to be inversely correlated with the severity of disease manifestations which were greater in the males. Serum levels of apoprotein-B and apoprotein-AI, the major structural apoproteins of LDL and HDL, respectively, were decreased in the subjects with Gaucher disease. Thus, the reductions in LDL and HDL cholesterol were associated with reduced numbers of lipoprotein particles in plasma. In contrast, apoprotein-E, a protein which is secreted by several tissues, including activated macrophages and which may mediate hepatic catabolism of lipoproteins, was elevated in the patients. Since macrophages may also catabolize lipoproteins, Gaucher disease may serve as a model for the effect of activated macrophages upon human lipoprotein metabolism.
This work was supported by the following grants: USPHS HL 23077, HD 07105, HL 25752, CA 31656 and RR-71 from the National Institutes of Health; 1–273 and 1–578 from the March of Dimes Birth Defects Foundation; grant from the New York Heart Assocation. Dr. Ginsberg is a recipient of a Research Career Development Award HL 00949 and is an Irma T. Hirschl Career Scientist. Dr. Grabowski is a recipient of a Clinical Investigator Award HD 00386.     

Use of transgenic mice to study the role of apolipoprotein E in lipid metabolism and atherosclerosis

Insight into the role of apolipoprotein (apo) E in lipoprotein metabolism and atherosclerosis has increased dramatically with the generation and analysis of novel transgenic, knockout and knockin mouse models. Moreover, the recent development and application of somatic gene and cell transfer technologies which can express (or delete) apoE in specific tissues of virtually any mouse model have further added to this increase in knowledge. It is now well established that apoE plays a role in virtually every step in the metabolism of very low-density lipoproteins and in the efflux of cholesterol from macrophages. In this review we will discuss recent insights into the role of apoE in these processes with particular emphasis on the specific effects of variation in apoE structure and quantity.     

What's new in the pathology of atherosclerosis?

Intimal smooth muscle cell proliferation has been known to be the key event in the development of advanced lesions of atherosclerosis. Since the important role of macrophages in the lipoprotein metabolism has been detected, however, current interest focuses on the macrophage reaction in the arterial wall. Animal experiments have shown that blood monocytes become attached to certain endothelial areas and enter the intima, where they are transformed to macrophages. Subendothelial infiltration of monocytes is the earliest cellular event in the formation of fatty streaks. Transformed to macrophages, they incorporate LDL by receptor-mediated endocytosis and are thus transformed to foam cells. The majority of foam cells in the atherosclerotic plaque is derived from macrophages. Furthermore, the importance of macrophages in the regulation of the lipoprotein metabolism and cholesterol homeostasis is increasingly attributed to their secretory capacities. It has been shown in vitro that they can secrete apolipoprotein E which associates with cholesterol and HDL to form a lipoprotein complex, which targets resecreted cholesterol to the liver cells. Recently, apolipoprotein E secretion of macrophages has also been demonstrated immunohistologically in the human atherosclerotic plaque. Cell culture investigations revealed that macrophages secrete different growth factors for fibroblasts and smooth muscle cells. So they are probably able, among other factors, to initiate smooth muscle cell proliferation in the intima. While smooth muscle cell proliferation and matrix components in the arterial wall had occupied the center of interest in previous investigations, the current focus on the cellular reactions of endothelial cells and monocytes/macrophages, especially in the early stages of atherosclerotic plaque formation, seems well justified.     

载脂蛋白E在ABCA1和ABCG1介导的胆固醇流出中的作用

目的:探讨载脂蛋白E(ApoE)在ATP结合盒转运蛋白A1(ABCA1)和ATP结合盒转运蛋白G1(ABCG1)介导的胆固醇流出中的作用及可能机制。方法:将RAW264.7细胞随机分为3组:空白对照组:用单纯培养基培养;低密度脂蛋白受体基因敲除(LDLr^-/-)组:用20mg/LLDLr^-/-小鼠脂蛋白处理细胞;ApoE基因敲除(ApoE^-/-)组:用20mg/LApoE^-/-小鼠脂蛋白处理细胞。采用透射电镜和酶法检测细胞内脂质含量,用液闪仪技术检测胆固醇流出变化,用免疫印迹技术和实时定量PCR技术检测ABCA1和ABCG1的表达水平。结果:与对照组相比,LDLr^-/-小鼠脂蛋白处理后细胞内脂质含量并未明显改变,而ApoE^-/-小鼠脂蛋白处理48h后,细胞内胆固醇酯增加了60%;同时,与LDLr^-/-小鼠脂蛋白处理组相比,用ApoE^-/-小鼠脂蛋白处理后,巨噬细胞胆固醇流出至载脂蛋白A-I(ApoA-I)和高密度脂蛋白(HDL)的量均明显降低。与对照组相比,LDLr^-/-小鼠脂蛋白和ApoE^-/-小鼠脂蛋白处理显著增加ABCA1和ABCG1的蛋白和mRNA水平,但是ApoE^-/-小鼠脂蛋白对ABCA1和ABCG1蛋白和mRNA水平的诱导程度明显低于LDLr^-/-小鼠脂蛋白。结论:ApoE在介导巨噬细胞胆固醇流出中发挥重要作用,该作用与其调节ABCA1和ABCG1的表达水平有关。     

Defective high-density lipoprotein composition in patients on chronic hemodialysis. A possible mechanism for accelerated atherosclerosis.

We determined serum high-density lipoprotein cholesterol content and analyzed the approtein structure of the various lipoprotein fractions in 21 patients on chronic hemodialysis. High-density lipoprotein cholesterol was significantly reduced in all patients as compared with 11 normal persons (mean +/-1 standard deviation: 26 +/- 13 vs. 52 +/- 9 mg per 100 ml; P less than 0.001) whether or not triglyceride levels were raised. In seven of those with Type IV hyperlipoproteinemia, protein content of high-density lipoprotein and its subfractions 1, 2 and 3 were also reduced (P less than 0.001) in parallel with reductions in cholesterol in these fractions. Apoprotein electrophoresis showed an increase in "arginine-rich" peptide in very-low-density lipoprotein and high-density lipoprotein fraction 1, and a reduction in apoprotein Cll in very-low-density and high-density lipoprotein. In addition to their reduced high-density lipoprotein cholesterol levels, a major factor in the atherosclerosis of these patients may be their abnormal high-density lipoprotein composition. Their raised triglyceride levels could be due to defective lipoprotein lipase activation by the reduced very-low-density lipoprotein apoprotein.     

ABCA1, from pathology to membrane function

The ABCA1 transporter is the prototype of the A class of mammalian adenosine triphosphate binding cassette transporters and one of the largest members of this family. ABCA1 has been originally identified as an engulfment receptor on macrophages and, more recently, it has been shown to play an essential role in the handling of cellular lipids. Indeed by promoting the effluxes of membrane phospholipids and cholesterol to lipid-poor apoprotein acceptors, ABCA1 controls the formation of high-density lipoproteins and thus the whole process of reverse cholesterol transport. A number of additional phenotypes have been found in the mouse model of invalidation of the ABCA1 gene. In spite of their clinical diversity, they all are extremely sensitive to variations in the physicochemical properties of the cell membrane, which ABCA1 controls as a lipid translocator.     

Mice transgenic for the human LCAT gene

The enzyme LCAT (Lecithin:cholesterol acyltransferase E.C. 2.3.1.43.) plays a central role in lipoprotein metabolism. It is secreted by the liver and catalyzes the transfer of a fatty acid from the 2-position of lecithin to the 3-beta-OH group of free cholesterol to produce cholesterol ester and lysolecithin.     

A case of systemic lupus erythematosus showing abnormal lipoproteins due to accompanied drug induced hepatitis

We describe here a 28-years-male with AIHA and SLE who had lipid and lipoprotein abnormalities during cholestasis induced by PGE1 administration. High free cholesterol level, 792 mg/dl was found in his serum, and markedly elevated, phospholipid level 1,614 mg/dl. But, LCAT activity was within normal range in this case. An agarose gel electrophoresis of lipoproteins showed abnormal bands which were located in slow alpha 2, pre beta and slow beta, and between beta and origin point. Moreover, it was detected formation of Lp-X from serum of the patient. Serum levels of apoprotein B, C-II, C-III, and E were higher, while apoprotein A-I, A-II were very lower than reference value. From these results, it was suspected that the patient might occur transient abnormal lipid metabolism according to the drug induced hepatic injury.     

ApoAI deficiency results in marked reductions in plasma cholesterol but no alterations in amyloid-beta pathology in a mouse model of Alzheimer's disease-like cerebral amyloidosis

Epidemiological studies suggest links between cholesterol metabolism and Alzheimer's disease (AD), with hypercholesterolemia associated with increased AD risk, and use of cholesterol-lowering drugs associated with decreased risk. Animal models using cholesterol-modifying dietary or pharmacological interventions demonstrate similar findings. Proposed mechanisms include effects of cholesterol on the metabolism of amyloid-beta (Abeta), the protein that deposits in AD brain. To investigate the effect of genetic alterations in plasma cholesterol on Abeta pathology, we crossed the PDAPP transgenic mouse model of AD-like cerebral amyloidosis to apolipoprotein AI-null mice that have markedly reduced plasma cholesterol levels due to a virtual absence of high density lipoproteins, the primary lipoprotein in mice. Interestingly and in contrast to models using non-physiological high fat diets or cholesterol-lowering drugs to modify plasma cholesterol, we observed no differences in Abeta pathology in PDAPP mice of the various apoAI genotypes despite robust differences in plasma cholesterol levels between the groups. Absence of apoAI also resulted in reductions in brain but not cerebrospinal fluid cholesterol, but had no effect on brain apolipoprotein E levels. These and other data suggest that it is perhaps the level of brain apolipoprotein E, not cholesterol per se, that plays a primary role in brain Abeta metabolism.     

Effects on lipids and lipoproteins in women treated with oestradiol and progesterone

Thirty women with climacteric symptoms were treated for 4 months with 2 mg 17β-oestradiol and different doses of progesterone (50, 100 or 200 mg). The concentrations of total and free cholesterol, phospholipids, triglycerides (TG), apoprotein A1 and apoprotein B were determined in high-density lipoprotein (HDL), low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) fractions and in serum. HDL levels increased and LDL levels decreased, while TG levels in VLDL remained unchanged, which indicates that the lipoprotein pattern is oestrogen-induced and that progesterone exerts little or no influence.     

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

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

The study of serum apoprotein levels as indicators for the severity of angiographically assessed coronary artery disease

Serum apoprotein A-I (Apo A-I) and B (Apo-B) concentrations were determined in 40 subjects undergoing coronary angiography for past myocardial infarction and angina pectoris, and the authors studied the relationship between the apoprotein concentrations and the severity of coronary artery disease (CAD). During this study, serum total cholesterol, triglyceride, and high-density lipoprotein, low-density lipoprotein, and very low density lipoprotein cholesterol concentrations were determined to control analysis. The results showed that the decrease in serum Apo A-I levels was the best indicator distinguishing CAD from non-coronary artery disease; the Apo B/Apo A-I ratio had the most consistent association with the severity of CAD as assessed by angiography; Apo B/Apo A-I values ranging from 0.98 to 1.00 might be considered critical values for early CAD.     

Lipoprotein and apoprotein levels in different types of dialysis

Cardiovascular disease is common in chronic renal failure and its progression during dialysis has been described. We evaluated lipoprotein and apoprotein profiles in 30 male and 28 female uremic patients on dialysis in order to compare the results with 30 male and 19 female non-uremic controls and to detect any differences in lipemic pattern due to different types of dialysis. The dyslipidemic picture typical of uremia was observed in both sexes, coupled with significant hypertriglyceridemia and an increase in the lipid components of the very low density lipoprotein (VLDL). There was also a significant reduction in high density lipoproteins (HDL) cholesterol and HDL2 cholesterol. Apo C levels were increased, whereas Apo AI and AII were diminished. Apo B levels were unchanged. We also evaluated their lipid profile in relation to three types of dialysis: hemodialysis, hemofiltration and continuous ambulatory peritoneal dialysis. Analysis of variance of three different types of dialysis performed for comparable periods of time showed that the parameters typically altered in uremia (Tg, VLDL, ApoC, ApoE) were uniform, whereas differences were observed in the variables indicative of cholesterol and phospholipid metabolism. The alterations of cholesterol metabolism in some subjects, in addition to the specific alterations of Tg metabolism, help explain the elevated prevalence of atherosclerotic complications in dialysed uremic patient.     

Lipids and theirs carriers in sportsmen: the lipoprotein particles

This study presents an original approach to the effect of regular sporting activity on the metabolism of lipids. We have examined the physiological variations of lipoparticles (Lp) AI, Lp B:CIII, Lp B:E, Lp (a) and the principal lipid markers in 21 high-level rugby players and men of the same age group who take part in no sporting activity (reference group; n=35). The analysis showed a paradoxical decrease in the high-density lipoprotein fraction of cholesterol (P<0.05) and in apolipoprotein AI (P<0.0001), and an increase in the apoprotein B/apoprotein AI ratio in the sportsmen, compared with the reference group. According to these results, physical activity seems to have only a slight influence on anti-atherogenic serum markers. However, the drop in Lp B:E (P<0.0001) and the static level of Lp AI in the sportsmen indicate a favourable effect of sport on these lipoparticles. The results of this study also highlight the importance of triglycerides and their metabolism. In fact, the lower triglyceride levels (P<0.05) of the sportsmen justify special attention to diet, especially during a period of competition. Electronic Publication     

Effects of medrogestone and conjugated oestrogens on serum lipid and lipoprotein concentrations

Twenty patients, aged 30–60 yr, who had undergone bilateral ovariectomy, were treated orally with 5 mg medrogestone (6,17-dimethylpregna-4,6-diene-3,20-dione) and 1.25 mg conjugated oestrogens per day, according to a constant dosage pattern during the cycle (22 + 6 days). The lipids and lipoproteins were determined twice before the start of therapy and 3, 6 and 12 mth thereafter. The lipids were quantified enzymatically and the lipoproteins by quantitative lipoprotein electrophoresis. Whilst cholesterol and triglyceride concentrations showed no detectable change, a slight but significant increase was seen in the high-density alphalipoprotein (HDL) cholesterol concentrations. The low-density beta-lipoprotein (LDL) cholesterol level showed a moderate fall. There was a resultant reduction in the beta/alpha-lipoprotein ratio. Accordingly, the apoprotein A1 concentrations were found to be elevated, while apoprotein B tended to fall to lower levels during therapy. When these changes are measured by the lipid metabolism risk criterion for the occurrence of coronary heart disease applicable to post-menopausal patients, the effects of the above-mentioned combination may be regarded as entirely favourable.     

Morphological detection and quantification of lipoprotein(a) deposition in atheromatous lesions of human aorta and coronary arteries

Summary Lipoprotein(a), as an atherogenic particle, represents an independent risk factor for coronary heart disease. In the present study the morphological distribution of apoprotein (a) and apoprotein B within the arterial wall is described. Apoprotein B, a constituent of very low-density lipoprotein, low-density lipoprotein and lipoprotein(a) has previously been demonstrated in atheromatous lesions. Lipoprotein(a) possesses an additional protein, designated apoprotein (a). Autopsy material (n=74) from the left coronary artery and from the thoracic aorta has been examined by means of immunohistochemistry and both apoprotein (a) and apoprotein B were detected, primarily associated with the extracellular matrix and accumulating in lesions in the arterial wall. The staining pattern for both antigens was almost always found to be congruent, suggesting that the detection of (a)-antigen has to be attributed at least in part to the presence of lipoprotein(a). It is concluded that both low-density lipoprotein and lipoprotein(a) have an important role in the pathogenesis of atherosclerosis.     

Serum lipids and apolipoprotein E phenotypes in identical twins reared apart1

Lipid and lipoprotein metabolism is controlled by genes, the environment and the gene-environment interaction. We studied monozygotic twin pairs reared apart (MZA) and an age-sex matched group of twins reared together (MZT) to evaluate the effects of the genotype and the rearing environment on lipids. The intraclass correlations for low density lipoprotein (LDL) cholesterol were 0.21 and 0.50 for the MZA and MZT groups, respectively, suggesting that the rearing environment possibly had an impact on the variability in LDL cholesterol later in life. The intraclass correlations for total cholesterol (0.26 and 0.47 for the MZA and MZT groups, respectively) reflected those for LDL cholesterol. The intraclass correlations for high density lipoprotein (HDL) cholesterol did not show any difference between the twin groups, suggesting that the rearing environment does not have major long-term effects on the variability of HDL levels. The intrapair differences for LDL cholesterol were smallest in the twins heterozygous for the apolipoprotein E allele ε2 (E2/3 and E2/4 phenotypes), intermediate in the pairs with the common E3/3 phenotype and enhanced in the pairs with E4/3 phenotype. To conclude, these data suggest that the rearing environment may play a role in the variability of LDL cholesterol levels, although variance difference between MZAs and MZTs, and the small number of available monozygotic twins reared apart limits the generalizability of the results.     

Macrophage scavenger receptors and foam cell formation

Scavenger receptors bind and internalize modified low-density lipoprotein (LDL) and high-density lipoprotein (HDL). Because the expression of scavenger receptors is not down-regulated by cholesterol, macrophages (Mphi) expressing scavenger receptors can internalize substantial quantities of cholesteryl ester from oxidized LDL and HDL, leading to foam cell formation. Mphi express several different classes of the growing scavenger receptor family on their cell surface and their relative contribution to Mphi cholesterol physiology and atherogenesis is the subject of intense investigation. We focus on the potential role of two scavenger receptors, macrosialin and SR-BI/II in Mphi cholesterol metabolism. Macrosialin is a predominantly Mphi-specific oxidized LDL-binding protein and an atherogenic diet markedly up-regulates its hepatic expression in atherosclerosis-susceptible and atherosclerosis-resistant mouse strains. The HDL receptor, SR-BI and its splicing variant SR-BII, colocalize with caveolin in caveolae in Mphi. Caveolae are initial acceptor sites for cholesteryl esters and these findings indicate a possible role for caveolae and SR-BI in Mphi-selective lipid uptake and in regulating Mphi cholesterol flux in the vascular wall.