Type III hyperlipoproteinemia and spontaneous atherosclerosis in mice resulting from gene replacement of mouse Apoe with human Apoe*2.

Sullivan, Patrick M.; Mezdour, Hafid; Quarfordt, Steven H.; Maeda, Nobuyo

doi:10.1172/jci2673

Cited by 224 publications

(201 citation statements)

References 29 publications

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“…These mice exhibit full penetrance of the type III HLP phenotype, regardless of age or gender in the presence of normal murine LDL receptor expression (8). This suggested to us that genetic factors that trigger the type III HLP phenotype in some humans are already present in mice.…”

Section: Type III Hyperlipoproteinemia (Type Iii Hlp)mentioning

confidence: 79%

Doubling Expression of the Low Density Lipoprotein Receptor by Truncation of the 3′-Untranslated Region Sequence Ameliorates Type III Hyperlipoproteinemia in Mice Expressing the Human ApoE2 Isoform

Knouff

Malloy

Wilder

et al. 2001

Journal of Biological Chemistry

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The primary receptor mediating clearance of apolipoprotein (apo)E-and apoB100-containing lipoproteins from the circulation is the low density lipoprotein (LDL) receptor. Reduced expression of the LDLR is believed to be a precipitating factor in the pathogenesis of type III hyperlipoproteinemia (HLP) in some humans homozygous for the apoE2 allele (APOE*2). To test the effect of genetic changes in LDL receptor expression on the pathogenesis of type III HLP, we have generated a variant allele at the endogenous mouse Ldlr locus that expresses the human LDL receptor transcript. Transcription of the human LDLR minigene is regulated by the endogenous mouse promoter sequence, but a truncation of 3-untranslated region results in increased mRNA stability. Consequently, in liver of heterozygotes, steady state levels of mouse and human LDLR transcripts are 50 and 180% the levels of total transcript in wild type mice, respectively. Overall, the 2.3-fold normal level of LDLR message in heterozygotes completely ameliorates type III HLP caused by the homozygosity for the human APOE*2 allele, normalizing their plasma lipoprotein profile. We conclude that a modest increase in expression of the LDLR through message stabilization is sufficient to prevent precipitation of type III HLP in mice. Type III hyperlipoproteinemia (type III HLP)1 is a disorder of lipoprotein metabolism that leads to elevated plasma cholesterol and triglyceride concentrations due mainly to an increase of apoB-containing remnant lipoproteins. These particles are the product of lipolytic processing of chylomicrons and very low density lipoproteins (VLDL) derived from the intestine and liver, respectively. Like low density lipoproteins (LDL), these are atherogenic lipoproteins, and subjects with type III hyperlipoproteinemia are predisposed to atherosclerosis and premature death from myocardial infarction (1).Type III HLP is a genetic disease associated with the expression of a metabolically impaired apoE protein (2, 3) or apoE deficiency (4). It is most commonly associated with individuals homozygous for the APOE*2 allele, the product of which has decreased affinity for the LDL receptor compared with other common isoforms. However, homozygosity of APOE*2 is necessary but not sufficient for the common form of type III hyperlipoproteinemia, as only 5-10% of adult homozygotes develop this disorder. In fact, most APOE*2 homozygotes have mild hypocholesterolemia and reduced atherosclerosis risk (5).It has long been appreciated that other genetic and environmental factors besides possession of two APOE*2 alleles are required for development of type III HLP. Type III HLP rarely manifests before adulthood, is more prevalent in men than women, and has an earlier age of onset in men than women (6). Women tend to express type III hyperlipoproteinemia only after menopause. Earlier onset is also associated with obesity, excessive alcohol consumption, diabetes mellitus, and hypothyroidism (1). The mechanism by which these conditions induce type III HLP is unclear. One possi...

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Section: Type III Hyperlipoproteinemia (Type Iii Hlp)mentioning

confidence: 79%

Doubling Expression of the Low Density Lipoprotein Receptor by Truncation of the 3′-Untranslated Region Sequence Ameliorates Type III Hyperlipoproteinemia in Mice Expressing the Human ApoE2 Isoform

Knouff

Malloy

Wilder

et al. 2001

Journal of Biological Chemistry

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“…APOE knock-in mice expressing human apoE2, apoE3, or apoE4 (homozygous) under the control of the endogenous mouse apoE promoter were generated by a gene replacement strategy (Knouff et al, 1999;Sullivan et al, 1997Sullivan et al, , 1998. These mice were used to produce immortalized astrocytes.…”

Section: Animalsmentioning

confidence: 99%

Production and characterization of astrocyte-derived human apolipoprotein E isoforms from immortalized astrocytes and their interactions with amyloid-β

Morikawa

Fryer

Sullivan

et al. 2005

Neurobiology of Disease

122

127

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The apolipoprotein E (apoE) genotype is an important genetic risk factor for Alzheimer's disease (AD). In the central nervous system (CNS), most apoE is produced by astrocytes and is present in unique high-density lipoprotein (HDL)-like particles that have distinct properties from apoE derived from other sources. To develop an efficient system to produce astrocyte-derived apoE in large quantities, we produced and characterized immortalized cell lines from primary astrocyte cultures derived from human APOE knock-in mice. APOE2, APOE3, and APOE4 expressing cell lines were established that secrete apoE in HDL-like particles at similar levels, cholesterol composition, and size as those produced by primary astrocytes. In physiological buffers, astrocyte-secreted apoE3 and E4 associated equally well with amyloid-B. Under the same conditions, only a small fraction of AB formed sodium dodecyl sulfate (SDS)-stable complexes with apoE (E3 N E4). These immortalized astrocytes will be useful for studying mechanisms underlying the isoform-specific effects of apoE in the CNS. D 2004 Elsevier Inc. All rights reserved.

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“…The presence of apo E2 allele/alleles results in a delayed uptake of chylomicron remnants, and patients with type III hyperlipidaemia who are homozygous for the apo E2 allele have a severely retarded elimination of chylomicron remnants [48]. The severe hyperlipidaemia found in apo E knockout mice [49,50] is only marginally attenuated in mice made transgenic for the human apo E2 gene variant [51]. Furthermore, apo E2 has recently been assigned an antilipolytic role which might add to the hyperlipidaemic potential of this gene variant [52].…”

Section: Intravascular Metabolism Of Trlmentioning

confidence: 99%

Postprandial lipoprotein metabolism and atherosclerosis

Karpe

1999

Journal of Internal Medicine

361

242

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Type III hyperlipoproteinemia and spontaneous atherosclerosis in mice resulting from gene replacement of mouse Apoe with human Apoe*2.

Cited by 224 publications

References 29 publications

Doubling Expression of the Low Density Lipoprotein Receptor by Truncation of the 3′-Untranslated Region Sequence Ameliorates Type III Hyperlipoproteinemia in Mice Expressing the Human ApoE2 Isoform

Doubling Expression of the Low Density Lipoprotein Receptor by Truncation of the 3′-Untranslated Region Sequence Ameliorates Type III Hyperlipoproteinemia in Mice Expressing the Human ApoE2 Isoform

Production and characterization of astrocyte-derived human apolipoprotein E isoforms from immortalized astrocytes and their interactions with amyloid-β

Postprandial lipoprotein metabolism and atherosclerosis

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