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At least 19 recordsLinked to original sources

PubMed1998

Reversal of hypercholesterolemia in apolipoprotein E2 and apolipoprotein E3-Leiden transgenic mice by adenovirus-mediated gene transfer of the VLDL receptor.

We have investigated the interaction of apolipoprotein E2(Arg158-Cys) (apoE2) and apolipoprotein E3-Leiden (apoE3-Leiden) with the very low density lipoprotein (VLDL) receptor in vivo and in vitro to define the possible role of this receptor in lipoprotein metabolism and atherosclerosis. The in vivo binding specificity of the VLDL receptor for apoE2 and apoE3-Leiden was investigated by adenovirus-mediated gene transfer of the VLDL receptor in apoE2 and apoE3-Leiden transgenic mice lacking endogenous mouse apoE (Apoe-/-). Ectopic overexpression of the VLDL receptor gene in the liver resulted in a >50% decrease of plasma cholesterol levels in both apoE2 and apoE3-Leiden transgenic mice compared with liver expression of the beta-galactosidase gene. This reduction in plasma cholesterol was mainly due to a reduction in the VLDL level. Overexpression of the VLDL receptor did not affect the hepatic VLDL triglyceride production, indicating that the hypocholesterolemic effect is due to an increased level of plasma clearance mediated by the VLDL receptor. In vitro binding analysis showed that both apoE2 and apoE3-Leiden VLDL compete efficiently with rabbit beta-VLDL for binding to the VLDL receptor expressed on LDL receptor-deficient Chinese hamster ovary cells. We conclude from these data that both apoE2 and apoE3-Leiden function as proper ligands for the VLDL receptor in vitro and in vivo. This finding substantiates a possible role for the VLDL receptor in atherosclerosis in hyperlipidemic subjects homozygous for apoE2 or carrying apoE3-Leiden and indicates that the VLDL receptor expressed on the liver has therapeutic potential as an alternative route for clearance of binding-defective lipoproteins.

Adenoviridae↗

PubMed2002

Possible association between genetic variability at the apolipoprotein(a) locus and Alzheimer's disease in apolipoprotein E2 carriers.

Apolipoprotein(a) (Apo(a)) is a glycoprotein that is linked by a disulfide bond to apolipoprotein B on low density lipoprotein particles to form lipoprotein(a) (Lp(a)). High plasma levels of Lp(a) are thought to contribute directly to the development of atherosclerosis. We tested a variant (T3888P) located in the Kringle-IV region of Apo(a) in a case-control series. Overall, there were no differences between case and controls. However, in the apoE2 positive subgroup, we noticed that the mutant allele is over-represented in the cases (P=0.005). We suggest that this polymorphism and others at the Apo(a) locus be further studied in relation to Alzheimer's disease.

Alzheimer Disease↗

PubMed2002

Remnant-like lipoprotein particles in type 2 diabetic patients with apolipoprotein E3/3 and apolipoprotein E2 genotypes.

Apolipoprotein (apo) E2 and diabetes mellitus are known to be associated with an accumulation of remnant lipoproteins in plasma. In this study, effects of type 2 diabetes mellitus and/or apo E2 genotypes on remnant-like lipoprotein particles (RLP) were assessed. Thirty-three subjects were divided into 6 groups: 7 apo E3/3 nondiabetic subjects, 6 apo E3/3 diabetic patients, 5 apo E3/2 nondiabetic subjects, 6 apo E3/2 diabetic patients, 5 apo E2/2 nondiabetic subjects, and 4 apo E2/2 diabetic patients. First, the effect of diabetes mellitus on RLP were estimated by comparing the apo E3/3 nondiabetic group with the apo E3/3 diabetic group. Plasma levels of RLP-cholesterol (chol) in the apo E3/3 diabetic group and the uptake of RLP from the apo E3/3 diabetic group by macrophages were significantly greater compared with the apo E3/3 nondiabetic group. Second, the effect of apo E2 on RLP was estimated in nondiabetic subjects. Apo E2/2 nondiabetic subjects had type III hyperlipoproteinemia (HLP). Plasma levels of RLP-chol in the apo E2/2 nondiabetic group and the uptake of RLP from the apo E2/2 nondiabetic group by macrophages were significantly greater compared with the apo E3/3 and apo E3/2 nondiabetic groups. Third, the effects of both apo E2 and diabetes on RLP were estimated. Plasma levels of RLP-chol in the apo E2 (E3/2 and E2/2) diabetic groups and the uptake of RLP from apo E2 (E3/2 and E2/2) diabetic groups by macrophages were significantly greater compared with apo E3/3 nondiabetic and diabetic groups or the apo E3/2 nondiabetic group. In diabetes, a gene dose effect of apo E2 on plasma levels of RLP-chol and uptake of RLP by macrophages was present (apo E3/3 < apo E3/2 < apo E2/2). The apo E2/2 diabetic group had type III HLP. Furthermore, uptake of RLP from the apo E2/2 diabetic group with type III HLP was significantly greater compared with the apo E2/2 nondiabetic group with type III HLP. In conclusion, type 2 diabetes was associated with increased RLP-chol in plasma and atherogenic RLP. In nondiabetes, apo E2/2 contributes to increased plasma RLP-chol and atherogenic RLP. In diabetes, additional effects of apo E2 to increase RLP-chol in plasma and to enhance the uptake of RLP by macrophages are present. RLP from apo E2/2 diabetes with type III HLP are more atherogenic than those from apo E2/2 nondiabetes with type III HLP.

Adult↗

PubMed2000

Apolipoprotein E2 (Lys146-->Gln) causes hypertriglyceridemia due to an apolipoprotein E variant-specific inhibition of lipolysis of very low density lipoproteins-triglycerides.

The apolipoprotein E2 (Lys146-->Gln) variant is associated with a dominant form of familial dysbetalipoproteinemia. Heterozygous carriers of this variant have elevated levels of plasma triglycerides, cholesterol, and apolipoprotein E (apoE). It was hypothesized that the high amounts of triglycerides in the very low density lipoprotein (VLDL) fraction are due to a disturbed lipolysis of VLDL. To test this hypothesis, apoE knockout mice were injected with an adenovirus containing the human APOE*2 (Lys146-->Gln) gene, Ad-E2(146), under the control of the cytomegalovirus promoter. ApoE knockout mice injected with an adenovirus vector encoding human apoE3 (Ad-E3) were used as controls. Five days after adenovirus injection, plasma cholesterol levels of mice injected with a high dose of Ad-E2(146) (2x10(9) plaque-forming units) were not changed compared with preinjection levels, whereas in the group who received a low dose of Ad-E2(146) (5x10(8) plaque-forming units) and in the groups injected with a low or a high dose of Ad-E3, plasma cholesterol levels were decreased 5-, 6-, and 12-fold, respectively. Plasma triglycerides were not affected in mice injected with Ad-E3. In contrast, a 7-fold increase in plasma triglycerides was observed in mice injected with the low dose of Ad-E2(146) compared with mice injected with Ad-E3. Injection with the high dose of Ad-E2(146) resulted in a dramatic increase of plasma triglycerides (50-fold compared with Ad-E3 injection). In vitro lipolysis experiments showed that the lipolysis rate of VLDLs containing normal amounts of apoE2 (Lys146-->Gln) was decreased by 54% compared with that of VLDLs containing comparable amounts of apoE3. The in vivo VLDL-triglyceride production rate of Ad-E2(146)-injected mice was not significantly different from that of Ad-E3-injected mice. These results demonstrate that expression of apoE2 (Lys146-->Gln) causes hypertriglyceridemia due to an apoE variant-specific inhibition of the hydrolysis of VLDL-triglycerides.

Adenoviridae↗

PubMed1996

Apolipoprotein E2 (Arg-136-->Cys), a variant of apolipoprotein E associated with late-onset dominance of type III hyperlipoproteinaemia.

Type III hyperlipoproteinaemia (HLP) is usually associated with homozygosity for apolipoprotein (apo) E2 (arg-158-->Cys). We identified a 46-year-old white female with severe hyperlipidaemia and the heterozygous apo E3/2* phenotype. Typical clinical characteristics of type III HLP, i.e. palmar xanthomas (orange-yellowish discolorations of the palmar creases) and tuberoeruptive xanthomas, were present in the patient. Without therapy the patient's serum triglycerides (1.098 mg dL(-1)), cholesterol (546 mg dL(-1)), very low-density lipoprotein (VLDL) cholesterol (372 mg dL(-1)) and the apo E concentration (25.0 mg dL(-1)) were distinctly elevated as well as her VLDL cholesterol to serum triglyceride (TG) ratio at 0.34 (normal ratio about 0.2). Direct sequencing of polymerase chain reaction (PCR)-amplified segments of the apo epsilon gene identified a thymine for cytosine (C-->T) exchange in the first base of codon 136 that is predictive for a Cys (TGC) for Arg (CGC) substitution in the encoded amino acid sequence. Two children, an 18-year-old female with the heterozygous apo E4/2* phenotype, a 25-year-old female with the heterozygous apo E3/2* phenotype and the 73-year-old father of the proband with the heterozygous apo E3/2* phenotype are also carriers of the rare mutant. The father has severe atherosclerosis and lipid values compatible with the diagnosis of type III HLP. The affected children have hyper/dyslipidaemia but as yet no clinical expression of the disease. We propose that in the analysed family this rare apo E2 (Arg-136-->Cys) variant is associated with late-onset dominance of type III HLP.

Adolescent↗

PubMed1998

The carboxyl terminus in apolipoprotein E2 and the seven amino acid repeat in apolipoprotein E-Leiden: role in receptor-binding activity.

Both apolipoprotein (apo) E2 and apoE-Leiden (tandem repeat of amino acids 121-127) are associated with type III hyperlipoproteinemia and bind defectively to low density lipoprotein receptors. Removing the carboxyl terminus of both variants (residues 192-299) increases receptor-binding activity, suggesting that the carboxyl terminus modulates activity. To identify the region(s) that modulated binding activity, we produced carboxyl-terminal truncations in apoE2 and apoE-Leiden (terminating at positions 191, 223, 244, and 272) and in apoE3 (terminating at positions 191, 223, and 244) and compared their receptor-binding activities as dimyristoylphosphatidylcholine (DMPC) discs. The results suggest that the entire carboxyl terminus up to residue 272, not a discrete smaller segment, is responsible for the modulation in apoE2. Intact apoE-Leiden and the 223 and 244 variants displayed similar activities (approximately 25% of apoE3's), but the 191 variant's activity was identical to that of intact apoE3. ApoE-Leiden and its truncated variants formed larger DMPC discs than did intact or truncated apoE3 or apoE2. These discs contained more apoE molecules than apoE3 discs, suggesting that the apparently normal binding activity of the apoE-Leiden 191 variant results from an increased number of apoE molecules and that the binding activity is actually defective. Direct comparison in a solid-phase assay revealed that the binding activity of the apoE-Leiden fragment was defective (51.4+/-9.4%). Thus, the defective binding of apoE-Leiden results from a direct effect of the seven amino acid repeat on receptor-binding activity rather than from an indirect effect operating through the carboxyl terminus as previously believed.

Apolipoprotein E2↗

PubMed1984

Normalization of receptor binding of apolipoprotein E2. Evidence for modulation of the binding site conformation.

Apolipoprotein (apo-) E3, when combined with the phospholipid dimyristoylphosphatidylcholine (DMPC), binds avidly to apo-B,E (low density lipoprotein) receptors on human fibroblasts. Apolipoprotein E2 isolated from type III hyperlipoproteinemic subjects, which differs from apo-E3 by the presence of cysteine instead of arginine at residue 158, possesses only about 1% of the receptor binding activity of apo-E3. Modification of apo-E2 with cysteamine, which converts the cysteine at position 158 to a positively charged lysine analogue, activates receptor binding approximately 13-fold. In the present experiments, thrombin was used to cleave apo-E2 into two fragments (Mr = 22,000 and Mr = 10,000). The larger fragment, which has been shown to possess the receptor binding domain, displayed binding activity up to 12-fold greater than intact apo-E2 or equivalent to apo-E2 treated with cysteamine. When the Mr = 22,000 fragment was modified with cysteamine and combined with DMPC, receptor binding was further enhanced, attaining the level of activity of normal apo-E3 X DMPC, a 100-fold increase over apo-E2 X DMPC binding. When the cysteamine modification was reversed by incubation with beta-mercaptoethanol, the Mr = 22,000 fragment retained most of its binding activity. However, when the same sample was tested 24 h later, the level of binding activity dropped significantly. The receptor binding of apo-E2-containing beta-very low density lipoproteins could also be activated by cysteamine treatment, with the same retention of enhanced binding activity occurring after the reversal of the modification. These results indicate that apo-E2 can attain full binding activity by the removal of the carboxyl-terminal one-third of the molecule and the addition of a positive charge at residue 158 of the molecule. The retention of enhanced binding after the reversal of the cysteamine modification indicates that the enhanced binding is probably due to conformational changes induced in the binding domain (and maintained by the phospholipid) and not merely to the presence of the positive charge at residue 158.

Apolipoprotein E2↗

PubMed1984

Genetic polymorphism of apolipoprotein E: a variant form of apolipoprotein E2 distinguished by sodium dodecyl sulfate--polyacrylamide gel electrophoresis.

The apolipoprotein E2 ( apoE2 ) variant that possesses a cysteine substituted for an arginine at residue 158 in the amino acid sequence E2( Arg158 ----Cys) can be distinguished by sodium dodecyl sulfate-polyacrylamide gel electrophoresis from other forms of apoE, including E3 (the parent form), E4( Cys112 ----Arg), E2( Arg145 ----Cys), and E2( Lys146 ----Gln). The E2( Arg158 ----Cys) migrates as a distinctly separable band with a higher apparent molecular weight than the other forms. Chemical modification of apoE2 ( Arg158 ----Cys) with sulfhydryl reagents (2-bromoethyl)-trimethylammonium bromide or cysteamine, which convert cysteine to arginyl or lysyl analogues, respectively, abolishes the difference in apparent molecular weight and results in the co-electrophoresis of E2( Arg158 ----Cys) with other apoE forms. The mobilities of the other apoE variants are not affected by these modifications. These results suggest that the substitution site at residue 158 is a key location, important in modifying the behavior of apoE and in modulating its apparent molecular weight on sodium dodecyl sulfate-polyacrylamide gels. Furthermore, the technique used in this study may be very helpful in distinguishing specific mutant forms of apoE2 .

Amino Acid Sequence↗

PubMed1987

Increased prevalence of apolipoprotein E2 in patients with retinitis pigmentosa.

Apolipoprotein E isoforms were determined in 139 unrelated patients with retinitis pigmentosa (RP). When compared to prevalence rates for the general population in Germany, an increased prevalence was observed for phenotypes E2/E2: 10.1 vs. 1.0% (p less than 0.001), E2/E3: 19.4 vs. 12.0% (p less than 0.05), and E2/E4: 5.8 vs. 1.5% (n.s.), while the prevalence appeared to be reduced for phenotypes E3/E3: 48.9 vs. 59.8% (n.s.) E3/E4: 13.7 vs. 22.9% (p less than 0.05), and E4/E4: 2.2 vs. 2.8% (n.s.). These findings suggest that genetically determined abnormalities of plasma lipoprotein metabolism may be associated with some forms of RP.

Apolipoprotein E2↗

PubMed1989

Apolipoprotein-E2 and hyperlipoproteinemia in noninsulin-dependent diabetes mellitus.

The association of apolipoprotein-E2 (apoE2) with hyperlipoproteinemia (HLP) was investigated in 23 noninsulin-dependent diabetes mellitus patients with apoE2 and 24 nondiabetic controls with apoE2. The frequency of HLP was significantly higher in diabetic subjects with apoE2 (73.9%) than in nondiabetic controls (37.5%). HLP in nondiabetic subjects with apoE2 included only type IV (n = 9), whereas HLP in diabetic subjects with apoE2 included type IIb (n = 1), type III (n = 7), and type IV (n = 9). Diabetic patients with apoE2 were characterized by increased levels of plasma triglyceride, total cholesterol (chol), very low density lipoprotein (VLDL)-chol, and apoE and an increased VLDL-chol/VLDL-triglyceride ratio, i.e. the accumulation of remnants. In addition, fasting plasma glucose and hemoglobin-A1 levels were significantly higher in hyperlipoproteinemic diabetic patients with apoE2 than in normolipidemic diabetic patients with apoE2. It is concluded that diabetes (poor metabolic control) predisposes apoE2 (epsilon 2)-carrying subjects to HLP (particularly type III) and that apoE2 may be one factor linking diabetes with HLP and cardiovascular disease.

Adult↗

PubMed2002

Comparative in vivo metabolism of apolipoproteins E2 and E4 in heterozygous apoE2/4 subjects.

Apolipoprotein E (apoE) exists in three common forms in humans: the wild-type apoE3 and two common genetic variants, apoE2 and apoE4. Although previous studies have examined the metabolism of the different apoE isoforms in human subjects, they have not involved direct comparison of two different isoforms in subjects heterozygous for the same two isoforms. We conducted this study to directly compare the catabolism of apoE2 and apoE4 in heterozygous E2/4 subjects in vivo. Iodine 131-labeled apoE2 and iodine 125-labeled apoE4 were simultaneously injected into three E4/2 heterozygous subjects. The mean residence time of apoE4 (0.40 +/- 0.01 day) was found to be one-third that of apoE2 (1.20 +/- 0.18 day). ApoE2 was present primarily in high-density lipoprotein, whereas apoE4 was present equally in very low density and high-density lipoprotein. In all lipoprotein subfractions, apoE4 was catabolized at a much faster rate than apoE2. In conclusion, E4 is catabolized three times faster than apoE2 in heterozygous E2/4 subjects, indicating that these two apoE isoproteins have distinct metabolic pathways.

Adult↗

PubMed2002

Expression of type III hyperlipoproteinemia in apolipoprotein E2 (Arg158 --> Cys) homozygotes is associated with hyperinsulinemia.

Type III hyperlipoproteinemia (HLP) is mainly found in homozygous carriers of apolipoprotein E2 (apoE2, Arg158-->Cys). Only a small percentage (< 5%) of these apoE2 homozygotes develops hyperlipidemia, indicating that additional environmental and genetic factors contribute to the expression of type III HLP. In the present study, first, the prevalence of type III HLP among apoE2 homozygotes was estimated in a Dutch population sample of 8888 participants. Second, 68 normocholesterolemic and 162 hypercholesterolemic apoE2 homozygotes (type III HLP patients) were collected to investigate additional factors influencing type III HLP expression. In the Dutch population sample, apoE2 homozygosity occurred with a frequency of 0.6% (57 of 8888 individuals). Among the 57 E2/2 subjects, 10 type III HLP patients were identified (prevalence 18%). Comparison of normocholesterolemic E2/2 subjects and type III HLP patients showed that the latter had a significantly increased body mass index (25.6 +/- 4.0 versus 26.9 +/- 3.8 kg/m(2), respectively; P=0.03) and prevalence of hyperinsulinemia (26% versus 63%, respectively; P<0.001). Multiple linear regression analysis demonstrated that most of the variability in type III HLP expression can be explained by fasting insulin levels (partial correlation coefficient approximately 0.50, P<0.001). In contrast to men, apoE2 homozygous women aged > or = 50 years had significantly higher plasma lipid levels than their counterparts aged < 50 years. These data demonstrate that the expression of type III HLP in E2/2 subjects is elicited to a large extent by hyperinsulinemia. In addition, in female apoE2 homozygotes, the expression increases with age; this increase is most likely due to the loss of estrogen production.

Adult↗

PubMed2001

Diminished LDL receptor and high heparin binding of apolipoprotein E2 Sendai associated with lipoprotein glomerulopathy.

Variants of apolipoprotein E (apoE) have been linked to lipoprotein glomerulopathy, a new glomerular disease characterized by the deposition of lipoproteins in mesangial capillaries. One third of affected patients are heterozygous for apoE2 Sendai (Arg(145) Pro). Variants of apoE can also produce type III hyperlipoproteinemia (HLP). Recessive type III HLP is caused by apoE2 (Arg(158) Cys), a mutant with diminished low-density lipoprotein (LDL) receptor binding but halfnormal heparin binding. Dominant type III HLP is caused by mutations that markedly alter heparin binding but modestly reduce receptor binding. This study examined whether apoE2 Sendai (Arg(145) Pro) was functionally different from type III HLP-producing apoE variants by expressing apoE3, apoE2 (Arg(158) Cys), apoE1 (Arg(146) Glu), a dominant apoE variant, and apoE2 Sendai (Arg(145) Pro) in the baculovirus system. LDL receptor binding was studied using recombinant apoE complexed to phospholipid vesicles and to very lowdensity lipoprotein from a patient with familiar apoE deficiency. Compared with apoE3, receptor-binding activities of apoE2 (Arg(158) Cys), apoE1 (Arg(146) Glu), and apoE2 Sendai (Arg(145) Pro) all were less than 5%. Heparin-binding activities were 53%, 23%, and 66%, respectively, of apoE3. The distribution of apoE2 Sendai among the major plasma lipoprotein fractions was similar to that of apoE3 and apoE2 (Arg(158) Cys). ApoE2 Sendai (Arg(145) Pro) represents the only known mutation within the heparin-binding domain of apoE (residues 142 through 147), revealing diminished receptor binding and almost normal heparin binding. These unique characteristics of apoE2 Sendai (Arg(145) Pro) may relate to the development of lipoprotein glomerulopathy.

Apolipoprotein E2↗

PubMed1997

Isoform-specific effects of apolipoproteins E2, E3, and E4 on cerebral capillary sequestration and blood-brain barrier transport of circulating Alzheimer's amyloid beta.

Cerebral capillary sequestration and blood-brain barrier (BBB) permeability to apolipoproteins E2 (apoE2), E3 (apoE3), and E4 (apoE4) and to their complexes with sA beta(1-40), a peptide homologous to the major form of soluble Alzheimer's amyloid beta, were studied in perfused guinea pig brain. Cerebrovascular uptake of three apoE isoforms was low, their blood-to-brain transport undetectable, but uptake by the choroid plexus significant. Binding of all three isoforms to sA beta(1-40) in vitro was similar with a K(D) between 11.8 and 12.9 nM. Transport into brain parenchyma and sequestration by BBB and choroid plexus were negligible for sA beta(1-40)-apoE2 and sA beta(1-40)-apoE3, but significant for sA beta(1-40)-apoE4. After 10 min, 85% of sA beta(1-40)-apoE4 taken up at the BBB remained as intact complex, whereas free sA beta(1-40) was 51% degraded. Circulating apoE isoforms have contrasting effects on cerebral capillary uptake of and BBB permeability of sA beta. ApoE2 and apoE3 completely prevent cerebral capillary sequestration and blood-to-brain transport of sA beta(1-40). Conversely, apoE4, by entering brain microvessels and parenchyma as a stable complex with sA beta, reduces peptide degradation and may predispose to cerebrovascular and possibly enhance parenchymal amyloid formation under pathological conditions.

Amino Acid Sequence↗

PubMed2000

Apolipoprotein E polymorphism: automated determination of apolipoprotein E2, E3, and E4 isoforms.

Apolipoprotein E (apo E) plays an essential role in lipoprotein metabolism, where it is involved in the clearance of chylomicrons and very low density lipoproteins. Apart from some rare variants, apo E exists in three common isoforms (E2, E3, and E4). The different isoforms have not only been associated with different plasma lipid levels but have also been correlated with certain pathological conditions, such as lipid disorders (dysbetalipoproteinemia, hypercholesterolemia), cardiovascular diseases, and Alzheimer's disease. Here we describe a rapid, automated test for the determination of the most frequent polymorphisms (E2, E3, and E4). This polymerase chain reaction-based test allows the reliable discrimination of all six genotypes. The assay has been developed especially for the nonspecialized routine clinical laboratory by employing an analyzer and chemistry often present in this type of laboratory. Because of its low costs and easy handling, the assay can be performed on a daily basis.

Apolipoprotein E2↗

PubMed1996

Novel mechanism for defective receptor binding of apolipoprotein E2 in type III hyperlipoproteinemia.

The defective binding of apolipoprotein (apo) E2 to lipoprotein receptors, an underlying cause of type III hyperlipoproteinemia, results from replacement of Arg 158 with Cys, disrupting the naturally occurring salt bridge between Asp 154 and Arg 158. A new bond between Asp 154 and Arg 150 is formed, shifting Arg 150 out of the receptor binding region. Elimination of the 154-150 salt bridge by site-directed mutagenesis of Asp 154 to Ala restored the receptor binding activity to near normal levels. The X-ray crystal structure of apoE2 Ala 154 demonstrated that Arg 150 was relocated within the receptor binding region. Our results demonstrate that defective binding of apoE2 occurs by a novel mechanism of the replacement of one salt bridge with another.

Apolipoprotein E2↗

PubMed2005

Combination of apolipoprotein E2 and lipoprotein lipase heterozygosity causes severe hypertriglyceridemia during pregnancy.

Pregnancy is a physiological condition where plasma triglyceride levels are moderately increased. This results from raised synthesis of very-low-density lipoproteins (VLDL) in response to elevated estrogen levels. The occurrence of marked hypertriglyceridemia (HTG) is rare and may result from combination of heterozygote mutation in the lipoprotein lipase (LPL) gene and apolipoprotein E2 isoform, as reported in this case. This observation illustrates the interaction between genetic and environmental factors, since pregnancy may disclose a silent LPL deficiency. The risk of acute pancreatitis threatens both the mother and fetus lives. Early recognition of severe HTG and appropriate management are essential for a successful pregnancy outcome.

Apolipoprotein E2↗

PubMed1997

Characterization of the binding of amyloid-beta peptide to cell culture-derived native apolipoprotein E2, E3, and E4 isoforms and to isoforms from human plasma.

The epsilon 4 allele of apolipoprotein E (apoE, protein; APOE, gene) is a major risk factor for Alzheimer's disease (AD). Genetically, the frequency of the epsilon 4 allele is enriched in early-onset sporadic, late-onset familial, and common late-onset sporadic AD. ApoE is found in the extracellular amyloid-beta (A beta) deposits that are characteristic features of AD. In this study, we examined the interaction between A beta and apoE isoforms. The apoE isoforms used in this study were either produced by stably transfected Chinese hamster ovary cells (CHO) or were from human plasma. We report that when similar concentrations of the apoE isoforms were used, native nonpurified apoE3 from recombinant CHO-derived sources bound A beta, but apoE4 did not. In fact, in our system, binding of recombinant apoE4 to A beta was never detectable, even after incubation for 4 days. Furthermore, using the same assay conditions, native apoE2, like apoE3, binds A beta avidly. Furthermore, when human plasma apoE isoforms are tested in A beta binding experiments, apoE3 bound A beta more avidly than apoE4, and a major apoE/A beta complex (the 40-kDa form) was observed with plasma apoE3 but not apoE4. These data extend our understanding of apoE isoform-dependent binding of A beta by associating apoE2 with efficient apoE/A beta complex formation and demonstrate that native apoE3 (whether recombinant or derived from human plasma) forms sodium dodecyl sulfate-stable apoE/A beta complexes more readily than native apoE4. The different A beta-binding properties of native apoE4 versus native apoE3 provide insight into the molecular mechanisms by which the APOE epsilon 4 allele exerts its risk factor effects in AD.

Amyloid beta-Peptides↗