Mutant Apo Research Articles

The relationship of the apolipoprotein E gene polymorphism in Turkish Type 2 diabetic patients with and without nephropathy

Apolipoprotein E (ApoE) genetic variation which is a major constituent of plasma lipoproteins causes diabetic nephropathy progress. Chronic kidney disease is associated with increased E2 allele and the decreased E4 allele risk. The aim of this study was to investigate the association between ApoE gene polymorphism in the development of diabetic nephropathy in Type 2 diabetes Turkish patients. The objective of the study is to investigate the influence of ApoE gene polymorphism in the development of diabetic nephropathy in Turkish Type 2 diabetes. The ApoE genotypes were determined retrospectively in 46 patients with nephropathy and 56 without nephropathy and a control group of 35 healthy individuals. Genomic DNA was extracted from peripheral leukocytes of the subjects using the High Pure PCR Template Preparation Kit. For the detection of the presence of the three ApoE E alleles epsilon2, epsilon3, and epsilon4 (codon 112 and 158) were analyzed by the commercial LightCycler ApoE Mutation Detection Kit. No differences in ApoE genotype or the allelic frequencies of epsilon2, epsilon3 or epsilon4 were found between the Type 2 diabetic patient group (with and without nephropathy) and a control group. We conclude that the ApoE gene polymorphism is not associated with the development of diabetic nephropathy in Turkish Type 2 diabetic patients. Lack of association between ApoE gene polymorphism and Type 2 diabetic nephropathy might be due to ethnic differences.

A novel mutation of the apolipoprotein A-I gene in a family with familial combined hyperlipidemia

We report a large family in which four members showed a plasma lipid profile consistent with the clinical diagnosis of familial combined hyperlipidemia (FCHL). One of these patients was found to have markedly reduced HDL cholesterol (HDL-C) (0.72 mmol/l) and Apo A-I (72 mg/dl) levels, a condition suggestive of the presence of a mutation in one of the HDL-related genes. The analysis of APOA1 gene revealed that this patient was heterozygous for a cytosine insertion in exon 3 (c.49–50 ins C), resulting in a frame-shift and premature stop codon at position 26 of pro-Apo A-I (Q17PFsX10). This novel mutation, which prevents the synthesis of Apo A-I, was also found in four family members, including three siblings and the daughter of the proband. Carriers of Apo A-I mutation had significantly lower HDL-C and Apo A-I than non-carriers family members (0.77 ± 0.15 mmol/l vs. 1.15 ± 0.20 mmol/l, P < 0.005; 71.4 ± 9.1 mg/dl vs. 134.0 ± 14.7 mg/dl, P < 0.005, respectively). Two of the APOA1 mutation carriers, who were also heavy smokers, had fibrous plaques in the carotid arteries causing mild stenosis (20%). The intimal-media thickness in the two other adult carriers was within the normal range. The other non-carriers family members with FCHL had either overt vascular disease or carotid atherosclerosis at ultrasound examination. This observation suggests that the low HDL-C/low Apo A-I phenotype may result from a genetic defect directly affecting HDL metabolism, even in the context of a dyslipidemia which, like FCHL, is associated with low plasma HDL-C.

A novel apolipoprotein E mutation, ApoE Tsukuba (Arg 114 Cys), in lipoprotein glomerulopathy

Lipoprotein glomerulopathy (LPG) is considered a type of renal lipidosis, characterized by the presence of lipoprotein thrombi in markedly dilated capillary lumina of the affected glomeruli [1]. LPG is a rare disease; approximately 65 cases have been reported to date [2]. Patients with LPG exhibit proteinuria and progressive renal dysfunction. In most of the LPG patients, levels of intermediate-density lipoproteins are elevated, resembling type III hyperlipoproteinaemia; moreover, apolipoprotein E (ApoE) levels are also elevated. Recent genetic studies have revealed that several ApoE gene mutations are associated with LPG [3]. In this study, we report a LPG patient with a novel ApoE mutation, without plasma lipid and lipoprotein abnormalities or elevated ApoE level.

Residues Leu261, Trp264, and Phe265 Account for Apolipoprotein E-Induced Dyslipidemia and Affect the Formation of Apolipoprotein E-Containing High-Density Lipoprotein

Overexpression of apolipoprotein E (apoE) induces hypertriglyceridemia in apoE-deficient mice, which is abrogated by deletion of the carboxy-terminal segment of residues 260-299. We have used adenovirus-mediated gene transfer in apoE-/- and apoA-I-/- mice to test the effect of three sets of apoE mutations within the region of residues 261-265 on the induction of hypertriglyceridemia, the esterification of cholesterol of very low-density lipoprotein (VLDL) and high-density lipoprotein (HDL), and the formation of spherical or discoidal apoE-containing HDL. A single-amino acid substitution (apoE4[Phe265Ala]) induced hypertriglyceridemia in apoE-/- or apoA-I-/- mice, promoted the accumulation of free cholesterol in the very low-density lipoprotein (VLDL) and HDL region, and decreased HDL cholesterol levels. A double substitution (apoE4[Leu261Ala/Trp264Ala]) induced milder hypertriglyceridemia and increased HDL cholesterol levels. A triple substitution (apoE4[Leu261Ala/Trp264Ala/Phe265Ala] or apoE2[Leu261Ala/Trp264Ala/Phe265Ala]) did not induce hypertriglyceridemia and increased greatly the HDL cholesterol levels. Electron microscopy (EM) analysis of the HDL fractions showed that apoE4[Leu261Ala/Trp264Ala/Phe265Ala] and apoE2[Leu261Ala/Trp264Ala/Phe265Ala] contained spherical HDL, apoE4[Leu261Ala/Trp264Ala] contained mostly spherical and few discoidal HDL particles, and apoE4[Phe265Ala] contained discoidal HDL. We conclude that residues Leu261, Trp264, and Phe265 play an important role in apoE-induced hypertriglyceridemia, the accumulation of free cholesterol in VLDL and HDL, and the formation of discoidal HDL. Substitution of these residues with Ala improves the apoE functions by preventing hypertriglyceridemia and promoting formation of spherical apoE-containing HDL.

HDL and the progression of atherosclerosis: new insights

Aims Lowering low-density lipoprotein (LDL) cholesterol or raising high-density lipoprotein (HDL) cholesterol can result in significant cardiovascular benefit, both in terms of reduction of events and also, to a variable extent, of atheromatous lesions. LDL and HDL have opposite roles in body cholesterol regulation and, both reduced deposition (LDL reduction) and increased removal (raised HDL) can improve vascular disease. Very recently, studies using recombinant apolipoprotein AI liposomes (in particular with the mutant apo AIMilano) have shown that direct infusion can effectively remove cellular cholesterol and dramatically reduce established atheromatous plaques in animals and in coronary patients. It has thus become of growing interest, the possibility of raising HDL by pharmacological treatments. This review will attempt to investigate existing and novel methodologies for HDL raising. Methods and results HDL raising can be achieved by using drugs active on the peroxisome proliferator activated receptor α (PPAR α) system, particularly using fibrates or n-3 fatty acids and, possibly more effectively, by using nicotinic acid. The activity of this agent has been traditionally linked to a reduced free fatty acid (FFA) mobilization from adipose tissue. More recently, it has been noted that nicotinic acid can activate the PPAR system, by stimulating all three PPAR isoforms (α, γ, δ). This mode of action seems to more effectively explain the striking HDL-raising properties of the drug. Conclusions Newly discovered mechanisms of nicotinic acid can explain, on the one hand, reduced atherosclerosis progression in secondary prevention patients treated with statins and, on the other hand, improved body cholesterol mobilization, effectively reducing cholesterol pool sizes.

Properties of human and rabbit cytosolic serine hydroxymethyltransferase are changed by single nucleotide polymorphic mutations

Serine hydroxymethyltransferase (SHMT) is a key enzyme in the formation and regulation of the folate one-carbon pool. Recent studies on human subjects have shown the existence of two single nucleotide polymorphisms that may be associated with several disease states. One of these mutations results in Ser394 being converted to an Asn (S394N) and the other in the change of Leu474 to a Phe (L474F). These mutations were introduced into the cDNA for both human and rabbit cytosolic SHMT and the mutant enzymes expressed and purified from an Escherichia coli expression system. The mutant enzymes show normal values for k cat and K m for serine. However, the S394N mutant enzyme has increased dissociation constant values for both glycine and tetrahydrofolate (tetrahydropteroylglutamate) and its pentaglutamate form compared to wild-type enzyme. The L474F mutant shows lowered affinity (increased dissociation constant) for only the pentaglutamate form of the folate ligand. Both mutations result in decreased rates of pyridoxal phosphate addition to the mutant apo enzymes to form the active holo enzymes. Neither mutation significantly affects the stability of SHMT or the rate at which it converts 5,10-methenyl tetrahydropteroyl pentaglutamate to 5-formyl tetrahydropteroyl pentaglutamate. Analysis of the structures of rabbit and human SHMT show how mutations at these two sites can result in the observed functional differences.

The apoE isoform binding properties of the VLDL receptor reveal marked differences from LRP and the LDL receptor

Apolipoprotein E (apoE) associates with lipoproteins and mediates their interaction with members of the LDL receptor family. ApoE exists as three common isoforms that have important distinct functional and biological properties. Two apoE isoforms, apoE3 and apoE4, are recognized by the LDL receptor, whereas apoE2 binds poorly to this receptor and is associated with type III hyperlipidemia. In addition, the apoE4 isoform is associated with the common late-onset familial and sporadic forms of Alzheimer's disease. Although the interaction of apoE with the LDL receptor is well characterized, the specificity of other members of this receptor family for apoE is poorly understood. In the current investigation, we have characterized the binding of apoE to the VLDL receptor and the LDL receptor-related protein (LRP). Our results indicate that like the LDL receptor, LRP prefers lipid-bound forms of apoE, but in contrast to the LDL receptor, both LRP and the VLDL receptor recognize all apoE isoforms. Interestingly, the VLDL receptor does not require the association of apoE with lipid for optimal recognition and avidly binds lipid-free apoE. It is likely that this receptor-dependent specificity for various apoE isoforms and for lipid-free versus lipid-bound forms of apoE is physiologically significant and is connected to distinct functions for these receptors.

Screening for Dysbetalipoproteinemia by Plasma Cholesterol and Apolipoprotein B Concentrations

Dysbetalipoproteinemia (type III hyperlipidemia) is a highly atherogenic mixed hyperlipidemia characterized by the accumulation of remnants of triglyceride-rich lipoproteins (chylomicrons and VLDL) (1). The binding of these remnants to hepatic lipoprotein receptors is mediated by apolipoprotein E (apoE). At the apoE gene locus, there are three common alleles: e2, e3, and e4 (2). ApoE2 binds poorly to hepatic lipoprotein receptors, leading to impaired remnant clearance. Consequently, remnants become enriched with cholesterol and migrate abnormally on electrophoresis. More than 90% of dysbetalipoproteinemic patients are homozygous for apoE2, but only a minority (1 in 20) of apoE2 homozygotes will be overtly hyperlipidemic. Remnant accumulation sufficient to cause hyperlipidemia usually occurs only when a second metabolic hit increases lipoprotein production (e.g., diabetes) or further decreases remnant clearance (e.g., hypothyroidism) (3). Dysbetalipoproteinemia is highly atherogenic but responds well to lifestyle changes and lipid-modifying medications. Genetic counseling is important, particularly in areas where there is a high local prevalence of autosomal dominant apoE mutations (4)(5). Dysbetalipoproteinemia is often suspected when both the total cholesterol (TC) and triglyceride (TG) concentrations are increased and the TC/TG molar ratio approximates 2:1. Clinically, pathognomonic palmar crease xanthomata are found in only ∼20% of patients (4)(6)(7). There are no simple diagnostic tests for dysbetalipoproteinemia. Diagnostic tests are based either on the demonstration of remnant accumulation or characterization of apoE. Electrophoretic techniques include serum agarose gel electrophoresis, but a broad β band is found in less than one half of patients (8)(9). Ultracentrifugation is required to demonstrate β-migrating VLDL. Nondenaturing polyacrylamide gradient gel electrophoresis is an effective screening technique (9). Cholesterol-enriched VLDL is diagnostic of dysbetalipoproteinemia (10)(11)(12), but sample preparation requires ultracentrifugation, which is not available in routine diagnostic laboratories. ApoE phenotyping requires isoelectric focusing, and genotyping is …

W06-O-002 Apolipoprotein AV accelerates plasma hydrolysis of triglyceride-rich lipoproteins by interaction with proteoglycan bound lipoprotein lipase

Dyslipidemia is a commonly encountered clinical condition and is an important determinant of cardiovascular disease. Although secondary factors play a role in clinical expression, dyslipidemias have a strong genetic component. Familial hypercholesterolemia is usually due to loss-of-function mutations in LDLR, the gene coding for low density lipoprotein receptor and genes encoding for proteins that interact with the receptor: APOB, PCSK9 and LDLRAP1. Monogenic hypertriglyceridemia is the result of mutations in genes that regulate the metabolism of triglyceride rich lipoproteins (eg LPL, APOC2, APOA5, LMF1, GPIHBP1). Conversely familial hypobetalipoproteinemia is caused by inactivation of the PCSK9 gene which increases the number of LDL receptors and decreases plasma cholesterol. Mutations in the genes APOB, and ANGPTL3 and ANGPTL4 (that encode angiopoietin-like proteins which inhibit lipoprotein lipase activity) can further cause low levels of apoB containing lipoproteins. Abetalipoproteinemia and chylomicron retention disease are due to mutations in the microsomal transfer protein and Sar1b-GTPase genes, which affect the secretion of apoB containing lipoproteins. Dysbetalipoproteinemia stems from dysfunctional apoE and is characterized by the accumulation of remnants of chylomicrons and very low density lipoproteins. ApoE deficiency can cause a similar phenotype or rarely mutations in apoE can be associated with lipoprotein glomerulopathy. Low HDL can result from mutations in a number of genes regulating HDL production or catabolism; apoAI, lecithin: cholesterol acyltransferase and the ATP-binding cassette transporter ABCA1. Patients with cholesteryl ester transfer protein deficiency have markedly increased HDL cholesterol. Both common and rare genetic variants contribute to susceptibility to dyslipidemias. In contrast to rare familial syndromes, in most patients, dyslipidemias have a complex genetic etiology consisting of multiple genetic variants as established by genome wide association studies. Secondary factors, obesity, metabolic syndrome, diabetes, renal disease, estrogen and antipsychotics can increase the likelihood of clinical presentation of an individual with predisposed genetic susceptibility to hyperlipoproteinemia. The genetic profiles studied are far from complete and there is room for further characterization of genes influencing lipid levels. Genetic assessment can help identify patients at risk for developing dyslipidemias and for treatment decisions based on ‘risk allele’ profiles. This review will present the current information on the genetics and pathophysiology of disorders that cause dyslipidemias.

Mutations in MTP gene in abeta- and hypobeta-lipoproteinemia

Familial hypobetalipoproteinemia (FHBL) and abetalipoproteinemia (ABL) are inherited disorders of apolipoprotein B (apo B)-containing lipoproteins that result from mutations in apo B and microsomal triglyceride transfer protein (MTP) genes, respectively. Here we report three patients with severe deficiency of plasma low-density lipoprotein (LDL) and apo B. Two of them (probands F.A. and P.E.) had clinical and biochemical phenotype consistent with ABL. Proband F.A. was homozygous for a minute deletion/insertion (c.1228delCCCinsT) in exon 9 of MTP gene predicted to cause a truncated MTP protein of 412 amino acids. Proband P. E. was heterozygous for a mutation in intron 9 (IVS9-1G>A), previously reported in an ABL patient. We failed to find the second pathogenic mutation in MTP gene of this patient. No mutations were found in apo B gene. The third proband (D.F.) had a less severe lipoprotein phenotype which was similar to that of heterozygous FHBL and appeared to be inherited as a co-dominant trait. However, he had no mutations in apo B gene. He was found to be a compound heterozygote for two missense mutations (D384A and G661A), involving highly conserved regions of MTP. Since this proband was also homozygous for ɛ2 allele of apolipoprotein E (apo E), it is likely that his hypobetalipoproteinemia derives from a combined effect of a mild MTP deficiency and homozygosity for apo E2 isoform.

40 Severe familial hypobetalipoproteinemia due to combined mutations of apo B gene

40 Severe familial hypobetalipoproteinemia due to combined mutations of apo B gene

Apolipoprotein E Is Required for Cell Proliferation and Survival in Ovarian Cancer

Apolipoprotein E (ApoE) has been recently identified as a potential tumor-associated marker in ovarian cancer by serial analysis of gene expression. ApoE has long been known to play a key role in lipid transport, and its specific isoforms may participate in atherosclerogenesis. However, its role in human cancer is not known. In this study, apoE expression was frequently detected in ovarian serous carcinomas, the most common and lethal type of ovarian cancer. It was not detected in serous borderline tumors and normal ovarian surface epithelium. Inhibition of apoE expression using an apoE-specific siRNA led to G(2) cell cycle arrest and apoptosis in an apoE-expressing ovarian cancer cell line, OVCAR3, but not in apoE-negative cell lines. Furthermore, the phenotype of apoE siRNA-treated OVCAR3 cells was reversed by expressing engineered mutant apoE with introduced silent mutations in the siRNA target sequence. Expression of apoE in nuclei was significantly associated with a better survival in patients who presented peritoneal effusion at the time of diagnosis (5-year follow-up, P = 0.004). This study suggests a new role of apoE in cancer as apoE expression is important for the proliferation and survival in apoE-expressing ovarian cancer cells.

Two mutations in APO B and ABCA1 genes causing hypercholesterolemia and hypoalphalipoproteinemia in a patient with premature coronary artery disease; study of proband's family

Two mutations in APO B and ABCA1 genes causing hypercholesterolemia and hypoalphalipoproteinemia in a patient with premature coronary artery disease; study of proband's family

Gene-drug interaction: additive influence of mutant APOA1 and testosterone on plasma HDL-cholesterol

Objectives: Factors associated with decreased plasma high-density lipoprotein (HDL) cholesterol concentration, or hypoalphalipoproteinemia, include androgenic steroids and mutations in APOA1, encoding apolipoprotein (apo) A-I, the main structural protein of HDL. However, there is little information regarding the extent of plasma HDL lowering when exogenous testosterone is used in subjects with monogenic low HDL. Design and methods: A man with coronary heart disease (CHD) had been receiving exogenous testosterone post-orchidectomy. He had marked hypoalphalipoproteinemia, which was not responsive to diet or medication. To identify a possible genetic contribution to his biochemical phenotype, we sequenced the LCAT and APOA1 genes. Results: There were no sequence abnormalities in LCAT, but we found that he was a heterozygote for a novel APOA1 mutation in codon 107 (AAG->TGG), which predicted the replacement of lysine by tryptophan (K107W). Serial biochemical measurements over 11 years showed that plasma HDL cholesterol on either intramuscular or oral testosterone was 0.19 ± 0.06 mmol/L, while plasma HDL cholesterol on transdermal testosterone was significantly higher at 0.52 ± 0.18 mmol/L ( p = 0.015, unpaired t-test). Conclusions: The findings suggest that the low plasma HDL cholesterol associated with heterozygosity for mutant APOA1 can become extremely depressed during treatment with oral or intramuscular androgens. The findings also suggest that transdermal testosterone may perturb HDL to a lesser extent than other routes of delivery in such patients.

Apolipoprotein E structural requirements for the formation of SDS-stable complexes with beta-amyloid-(1-40): the role of salt bridges.

Of the three major isoforms of human apolipoprotein E (apoE), apoE4 is a risk factor for the development of Alzheimer's disease. Among possible neurologically relevant differences in the properties of apoE3 and apoE4 is the fact that apoE3 forms an SDS-stable complex with beta-amyloid-(1-40) (Abeta40) with greater avidity than does apoE4. This interaction may sequester potentially toxic species of Abeta or facilitate clearance. To understand more about this difference, we examined whether differences in salt bridges between apoE domains influence the capacity of apoE isoforms to form complexes with Abeta. In apoE3 there is a salt bridge between Arg-61 and Asp-65, while in apoE4 there are salt bridges between Arg-61 and Glu-255, and Arg-112 and Glu-109. Mutation of position 112, which is Cys in apoE3 and Arg in apoE4, to Ala or Lys abolished complex formation, while mutant apoE with Ser at this position retained the capacity to form complex. Substituting Ala for Glu-109 had no effect on the ability of either apoE4 or apoE3 to form complexes. On the other hand, substitution of Thr for Arg-61 in apoE3 abolished, and truncation of apoE3 at position 201 substantially lowered, but did not abolish, complex formation. Neither of these mutations within apoE4 had any affect on its complex formation with Abeta. These results suggest that the nature of the cysteine residue in apoE3 and interactions between the N-terminal and C-terminal domains of human apoE are important for the ability of apoE3 to form an SDS-stable complex with Abeta40.

Asociación de factores lipídicos, genotipo de APOE y tipos de mutación del gen del receptor de LDL con el infarto agudo de miocardio en sujetos con hipercolesterolemia familiar heterocigota

Our goal was to analyze the relationship of lipids and lipoproteins, APOE genotype and mutations of the LDL receptor gene with the prevalence of myocardial infarction (MI) in patients with familial hypercholesterolemia (FH) from a Southern European FH population. We studied 108 heterozygous FH subjects aged > 35 years (41 males). It was a cross-sectional study comparing individuals with FH and MI with individuals with FH without MI. In 88 FH subjects, a mutation of the LDL receptor gene was detected. These FH subjects were divided in carriers of null mutation or no null mutations. We compared lipids and lipoproteins and prevalences of LDL receptor type mutation and APOE genotype. Parameters associated with MI were: age, presence of xanthomas and arcus cornealis, plasma concentrations of total cholesterol (TC), LDLc, TC/HDLc ratio > 5.3 and *4 genotype of the APOE gene. Odds ratio for MI were as follows: presence of xanthomas and arcus cornealis, 1.36 (CI 95%, 1.08-1.71; P = 0.01), age > 54 years (50 th of FH group), 1.56 (CI 95%, 1.19-2.04; P = 0.001) and plasma TC values > 332 mg/dl (50 th of FH group), 1.34 (CI 95%, 1.05-1.71; P = 0.019). In the logistic regression model, only age and TC were significantly associated with MI. In FH subjects aged over 35 years from a Southern European population, MI is associated with age, plasma TC and LDLc values, TC/HDLc ratio and the *4 genotype. In addition, MI is related with age and TC plasma levels on an independent basis.

Analysis of apolipoprotein A-I, lecithin:cholesterol acyltransferase and glucocerebrosidase genes in hypoalphalipoproteinemia

Hypoalphalipoproteinemia (HALP) is a dyslipidemia characterized by low HDL-cholesterol (HDL-C) levels with important genetic contribution. However, no common genetic mutations have been found to be associated with this disorder. We screened the promoter and coding sequence of apolipoprotein (apo) A-I and lecithin:cholesterol acyltransferase (LCAT) genes and the 5′ apo C-III region by SSCP and heteroduplex analysis, and DNA sequencing in 66 unrelated subjects with recurrent low HDL-C levels. We also analyzed the N370S and L444P variants, in the glucocerebrosidase (GBA) gene by restriction fragment analysis. Three mutations in the apo A-I gene (L144R, W108R, g.1833C>T) and 3 mutations in the LCAT gene (S208T, I178T, IVS3-23C>A) were detected, in six heterozygous subjects. In addition, a novel polymorphic site in LCAT gene (g.4886C>T) has been identified. Allelic frequencies of polymorphisms g.(−636)C>A, g.(−625)G>A, g.(−620)T>del, g.(−479C>T and g.(−452)T>C, located upstream of the apo C-III gene, were in normal range, and no other mutation was found in this region. Two HALP subjects were found to carry the N370S mutation at GBA locus. In conclusion, 12% of HALP subjects were found to carry mutations in apo A-I, LCAT, or GBA genes, which could explain this phenotype. Our results confirm the molecular, genetic and phenotypic heterogeneity of HALP.

Role of apolipoprotein E variants in lipoprotein glomerulopathy and other renal lipidoses

Lipoprotein glomerulopathy (LPG) is a new renal lipidosis entity, characterized by peculiar histology and abnormal lipoprotein profiles mimicking type III hyperlipoproteinemia. Recently, it has been clarified that LPG is associated with novel apolipoprotein E (apoE) mutations. In particular, ApoE-Sendai, which substitutes arginine 145 with proline, is observed in most Japanese patients with LPG, although isoelectric focusing polyacrylamide gel electrophoresis has shown that it is consistent with the apoE2 isoform. To confirm the etiological role of these apoE mutations, we established an animal model of LPG. The model was created by the introduction of recombinant adenovirus containing human apoE-Sendai into apoE knockout mice. Both clinical and experimental findings indicate that LPG is caused not only by hyperlipoproteinemia but also by an in situ interaction between apoE variants and glomerular elements. In addition, several studies suggest that the apoE2 mutation is responsible for the development of diabetic nephropathy and IgA nephropathy, as well as renal lipidosis with type III hyperlipoproteinemia. In this review, we present the clinical and histological features of LPG and its pathogenesis, and discuss the role of apoE abnormalities, especially apoE-Sendai and apoE2, in LPG and other renal lipidoses.

Virus-mediated Transduction of Apolipoprotein E (ApoE)-Sendai Develops Lipoprotein Glomerulopathy in ApoE-deficient Mice

Lipoprotein glomerulopathy (LPG) is a unique renal disease characterized by thrombus-like substances in markedly dilated glomerular capillaries, dysbetalipoproteinemia, and elevated plasma concentrations of apoE. Recent studies identified several apoE mutations in patients with LPG, including apoE2(R145P) Sendai (apoE-Sendai). Virus-mediated transduction of apoE-Sendai in apoE-deficient hypercholesterolemic mice resulted in insufficient correction of hypercholesterolemia and a marked and temporal induction of plasma triglyceride levels. In vitro binding studies showed that apoE-Sendai has a reduced affinity for the low density lipoprotein receptor, suggesting that dysbetalipoproteinemia in LPG is caused by the apoE mutation. Furthermore, histological examination revealed marked intraglomerular depositions of apoE-containing lipoproteins in mice injected with apoE-Sendai virus. These LPG-like depositions were detected 6 days after virus injection and were sustained for at least 60 days. Our results demonstrated that apoE-Sendai is an etiological cause of LPG.

Molecular Belt Models for the Apolipoprotein A-I Paris and Milano Mutations

Models for the binding of the 200-residue carboxy-terminal domain of two mutants of apolipoprotein A-I (apo A-I), apo A-I(R173C) Milano and apo A-I(R151C) Paris, to lipid in discoidal high-density lipoprotein (HDL) particles are presented. In both models, two monomers of the mutant apo A-I molecule bind to lipid in an antiparallel manner, with the long axes of their helical repeats running perpendicular to the normal of the lipid bilayer to form a single disulfide-linked homodimer. The overall structures of the models of these two mutants are very similar, differing only in helix-helix registration. Thus these models are consistent with experimental observations that reconstituted HDL particles containing apo A-I Milano and apo A-I Paris are very similar in diameter to reconstituted HDL particles containing wild-type apo A-I, and they support the belief that apo A-I binds to lipid in discoidal HDL particles via the belt conformation.