Identical Structural and Receptor Binding Defects in Apolipoprotein E2 in Hypo-, Normo-, and Hypercholesterolemic Dysbetalipoproteinemia

Rall, S C; Weisgraber, Karl H.; Innerarity, Thomas L.; Mahley, Robert W.; Assmann, Gerd

doi:10.1172/jci110829

Cited by 84 publications

(44 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…78 ' ™ In addition it has been shown that apo E from hyper-, normoor hypocholesterolemic subjects with an E2/2 phenotype has equally defective binding to the LDL receptor in vitro. 80 The data are most consistent with the notion that the E2/2 phenotype is a necessary, but not sufficient, requirement for the expression of type III hyperiipoproteinemia in humans.…”

Section: Dysbetallpoprotelnemla and Type III Hyperiipoproteinemiasupporting

confidence: 77%

“…On the other hand, the estimate of the relative frequency of e4 for the Finnish population is 50% higher than the estimates for the other Caucasian populations and significantly different (p < 0.01) from all other samples in the group. There is no statistically significant evidence for heterogeneity of the relative allele frequencies among the Framingham, 80 Munster, 6162 Marburg, 3 Grampian, 57 Ottawa, 54 and Nijmegen 56 populations. The Nancy and Christchurch estimates are not significantly different from each other at the 0.10 level of probability.…”

Section: Relative Allele Frequenciesmentioning

confidence: 91%

See 1 more Smart Citation

Apolipoprotein E polymorphism and atherosclerosis.

1988

View full text Add to dashboard Cite

Lipoproteins play a central role in the development of atherosclerotic cardiovascular disease in humans. The plasma concentrations of lipoproteins and their metabolic fates are modulated by apolipoproteins on the surface of these lipid-rich particles. The hypothesis has been raised that genetic variation in apolipoproteins is a major determinant of the interindividual variation in susceptibility to coronary artery disease (CAD). In humans, the structural gene locus for plasma apolipoprotein E (apo E) is polymorphic:1 " 6 three common alleles, designated e4, e3, and e2, code for three major apo E isoforms in plasma, respectively designated apo E4, apo E3, and apo E2. Apo E is a key protein in the modulation of the metabolism of the highly atherogenic apo B-containing lipoproteins. Therefore, apo E provides a good model to test the above hypothesis.The existence of a polymorphism for such an important apolipoprotein has been a source of major interest in recent years and has raised many questions for clinicians, epidemiologists, geneticists, and biochemists. The similarities of the relative frequencies of the three common alleles among populations representing very different ethnic, cultural, and geographic settings; their different effects on •lipoprotein metabolism; and their association with certain lipid transport disorders have stimulated research aimed at a better understanding of their role in health and disease. A wealth of information 7 " 18 has accrued from studies on apolipoprotein E structure, metabolism, and function. These have considerably advanced our knowledge of the role of apo E in normal and abnormal lipoprotein metabolism, the complex interactions leading to hyperfipidemia and atherosclerosis, and the pathogenesis of type III hyperiipoproteinemia. Of major interest is the observation that the protein products of the e4 and E2 alleles have separate, and in some circumstances opposite, influences on plasma lipo- protein concentrations, a finding which leads to the hypothesis that the apo E polymorphism ranks among the major factors involved in determining interindividual differences in the initiation and progression of atherosclerosis. The evidence associating the apo E polymorphism with altered lipid and lipoprotein levels and atherosclerosis will be reviewed here. First, the apo E gene and gene product will be considered with a brief overview of molecular biology, protein chemistry, and methods for phenotyping. Second, the impact of variation at the apo E locus on plasma lipids and lipoproteins in health and disease will be discussed. Third, the metabolic interactions accounting for the various effects of the different alleles on lipids and lipoproteins will be considered to provide a unifying interpretation as to how apo E modulates the metabolism of apo B-containing lipoproteins and their remnants. Last, direct evidence associating the apo E polymorphism and atherosclerosis will be reviewed and discussed. This review is not intended to be all-inclusive, and the reader is referred to recent r...

show abstract

Section: Dysbetallpoprotelnemla and Type III Hyperiipoproteinemiasupporting

confidence: 77%

Section: Relative Allele Frequenciesmentioning

confidence: 91%

Apolipoprotein E polymorphism and atherosclerosis.

1988

View full text Add to dashboard Cite

show abstract

“…Collectively, these kinetic defects may account for the dyslipoproteinemia seen in our apoE2/E2 type III hyperlipidemic subjects. Whether downregulation of VLDL receptors or other extrahepatic receptors ( 31,32 ), or the inhibition of lipolytic enzymes by other apoproteins, such as apoC-III ( 33,34 ), contributes further to the impaired catabolism and accumulation of ␤ -VLDL particles in circulation requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

Effect of apolipoprotein E genotype on apolipoprotein B-100 metabolism in normolipidemic and hyperlipidemic subjects

Ooi

Janus

Grant

et al. 2010

Journal of Lipid Research

View full text Add to dashboard Cite

Apolipoprotein (apo) E is a 34.2 kDa glycoprotein synthesized by the liver and to a lesser extent by peripheral tissues ( 1 ). It is associated in plasma with triglyceride-rich lipoproteins (TRL) and HDL particles ( 2 ). ApoE plays a central role in mediating hepatic recognition and uptake of TRL and their remnants by acting as a ligand for lipoprotein binding to the LDL receptor, LDL receptorrelated protein, and glycosaminoglycans ( 3 ). ApoE may also activate enzymes involved in lipoprotein metabolism, including hepatic lipases, cholesteryl ester transfer protein, and lecithin cholesteryl:acytransferase ( 4 ). The apoE gene is polymorphic, with three common alleles coding for three major isoforms identifi ed as E2, E3, and E4 ( 5 ).Type III hyperlipidemia, also known as dysbetalipoproteinemia, is a rare form of genetic dyslipidemia characterized by elevated plasma cholesterol and triglycerides and the presence of cholesterol-enriched remnant particles, collectively known as ␤ -VLDL ( 6 ). The accumulation of ␤ -VLDL particles may be associated with impaired TRL catabolism ( 7 ). Type III hyperlipidemic subjects may have severe xanthomatosis and signifi cantly increased risk of developing premature atherosclerosis ( 8 ). The majority of type III hyperlipidemic subjects are homozygotes for the apoE2 allele of the apoE ( APOE ) gene. However, <10% of apoE2 homozygotes develop hyperlipidemia, and most apoE2/E2 subjects are either normolipidemic or hypocholesterolemic ( 6 ). The onset of hyperlipidemia may be associated with additional genetic factors and/or environmental factors such as obesity, diabetes, and menopausal status ( 6 ). The regulation of lipoprotein transport in subjects with the apoE2/E2 genotype, in particular those withAbstract The effect of apolipoprotein (apo) E genotype on apoB-100 metabolism was examined in three normolipidemic apoE2/E2, fi ve type III hyperlipidemic apoE2/E2, and fi ve hyperlipidemic apoE3/E2 subjects using simultaneous administration of 131 I-VLDL and 125 I-LDL, and multicompartmental modeling. Compared with normolipidemic apoE2/E2 subjects, type III hyperlipidemic E2/E2 subjects had increased plasma and VLDL cholesterol, plasma and VLDL triglycerides, and VLDL and intermediate density lipoprotein (IDL) apoB concentrations ( P < 0.05). These abnormalities were chiefl y a consequence of decreased VLDL and IDL apoB fractional catabolic rate (FCR). Compared with hyperlipidemic E3/E2 subjects, type III hyperlipidemic E2/E2 subjects had increased IDL apoB concentration and decreased conversion of IDL to LDL particles ( P < 0.05). In a pooled analysis, VLDL cholesterol was positively associated with VLDL and IDL apoB concentrations and the proportion of VLDL apoB in the slowly turning over VLDL pool, and was negatively associated with VLDL apoB FCR after adjusting for subject group. VLDL triglyceride was positively associated with VLDL apoB concentration and VLDL and IDL apoB production rates after adjusting for subject group. A defective apoE contributes to altered lipoprotein me...

show abstract

“…gous for cysteine at position 1S8, 23 and in the second, six of seven apo E2/2 type III patients from a New Zealand population were also found to be homozygous for this substitution. 20 The results are also consistent with the Funke et al study 29 in which DNAs from six apo E2/2 subjects and seven subjects heterozygous for apo E2 were examined with oligonucleotide probes.…”

mentioning

confidence: 90%

“…A limited screening of six German apo E2/2 subjects, who ranged from hypolipidemic to hyperlipidemic, showed that all were homozygous for apo E2(Arg 158 ->-Cys). 23 That study involved protein sequencing, which is not an effective method for screening large populations. One possible alternative method is sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of VLDL.…”

mentioning

confidence: 99%

Apolipoprotein E2(Arg158----Cys) frequency in a hyperlipidemic French-Canadian population of apolipoprotein E2/2 subjects. Determination by synthetic oligonucleotide probes.

et al. 1989

View full text Add to dashboard Cite

An underlying cause of type III hyperllpoproteinemia Is the presence of variant forms of apolipoprotein (apo) E that are defective in binding to apo B,E low density llpoprotein receptors. This disorder Is associated almost exclusively with the apo E2/ 2 phenotype. However, structural and functional heterogeneity have been demonstrated within this phenotype. The apo E2(Arg 1s8 -»Cys) variant, displaying 1 % of normal apo E3 binding activity, Is the most defective known form. In this study, we describe a method in which a pair of 19-mer synthetic oligonucleotide probes were used to distinguish between DNA coding for arglnlne or cystelne at position 158 In apo E. The specificity of the probes was demonstrated by using DNA from subjects whose apo E protein sequence or phenotype was known. The probes were used to screen a French-Canadian population of 34 apo E2/2 subjects to determine the frequency of the apo E2(Arg 1M ->Cys) variant All 34 subjects, most of whom displayed clinical or biochemical features of type III hyperllpoproteinemia, were found to be homozygous for apo E2(Arg 1sr ->Cys), strongly suggesting that this variant Is the most common form of apo E2 within this ethnic and clinical population. In addition, the utility of this approach In detecting new apo E mutants was demonstrated when DNA from one of the apo E3/3 control subjects, whose family has a history of hyperllpldemla and coronary artery disease, reacted with both probes. This result suggests that this subject Is heterozygous for normal apo E3 and a new apo E3 variant that Is likely to be functionally equivalent to apo E2(Arg 1M ->Cys). (Arteriosclerosis 9:50-57, January/February 1989) H uman apolipoprotein (apo) E is a component of several classes of plasma lipoproteins and, because of its ability to interact with lipoprotein receptors, apo E plays an important role in directing the metabolism of triglyceride-and cholesterol-containing lipoproteins.1 The structures of the protein and its gene are known. 2314 A combination of experimental approaches has demonstrated that a region of the protein in the vicinity of residues 140 to 160 is critical for interaction with apo B,E LDL receptors (for review, see Reference 5). Apo E, which exhibits a genetically determined polymorphism at the level of the structural gene, has several variants, 5 many of which display defective receptor binding activity. heterogeneity results in six phenotypes: E2/2, E3/3, E4/4, E4/2, E4/3, and E3/2. 6 The apo E3/3 phenotype is the most prevalent one in several different populations.7 - 13The most common variants differ by arginine-cysteine interchanges at positions 112 and 158. The apo E4, apo E3, and apo E2 variants contain Arg/Arg, Cys/Arg, and Cys/Cys, respectively, at positions 112/158.

show abstract

Identical Structural and Receptor Binding Defects in Apolipoprotein E2 in Hypo-, Normo-, and Hypercholesterolemic Dysbetalipoproteinemia

Cited by 84 publications

References 36 publications

Apolipoprotein E polymorphism and atherosclerosis.

Apolipoprotein E polymorphism and atherosclerosis.

Effect of apolipoprotein E genotype on apolipoprotein B-100 metabolism in normolipidemic and hyperlipidemic subjects

Apolipoprotein E2(Arg158----Cys) frequency in a hyperlipidemic French-Canadian population of apolipoprotein E2/2 subjects. Determination by synthetic oligonucleotide probes.

Contact Info

Product

Resources

About