A 10 BP deletion in the apolipoprotein ε gene causing apolipoprotein E deficiency and severe type III hyperlipoproteinemia

Feussner, Giso; Dobmeyer, Jürgen; Lohmer, Stefan; Wohlfeil, Stefan

doi:10.1016/0021-9150(95)96683-j

Cited by 20 publications

(32 citation statements)

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“…ApoE has also been proposed to have a variety of biological functions in addition to that in lipoprotein metabolism (1,3,4). Genetic deficiency of apoE in humans (5)(6)(7)(8) and in mice (9,10) results in a substantial increase in plasma levels of remnant lipoproteins. Certain rare mutations of apoE within the receptor binding region severely impair apoE binding and result in a dominant form of familial dysbetalipoproteinemia (Type III hyperlipoproteinemia) (11).…”

Section: Introductionmentioning

confidence: 99%

Liver-directed gene transfer and prolonged expression of three major human ApoE isoforms in ApoE-deficient mice.

Tsukamoto

Smith²,

Glick³

et al. 1997

J. Clin. Invest.

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Apolipoprotein E (apoE) plays a key role in lipoprotein metabolism and may have other important biological functions. In humans, there are three common, naturally occurring isoforms of apoE that are associated with differences in lipid levels and atherosclerosis. However, the direct in vivo effects of the apoE isoforms on lipoprotein metabolism and atherosclerosis are not yet fully understood. To investigate the effect of the apoE isoforms in vivo, we constructed second-generation recombinant adenoviruses encoding each of the apoE isoforms. These recombinant adenoviruses were injected intravenously into apoE-deficient mice fed a Western diet (mean baseline cholesterol level 1401 mg/dl) in order to study their effects in the absence of endogenous mouse apoE. Hepatic expression of apoE3 and apoE4 completely normalized the lipoprotein profile; 3 d after injection, mean plasma cholesterol levels were 194 and 217 mg/ dl, respectively, and this effect was maintained for at least 6 wk. Expression of apoE2 had much less effect on lipoprotein levels (mean cholesterol level 752 mg/dl 3 d after injection), despite much higher plasma levels of apoE2 compared with apoE3 and apoE4; by 6 wk after injection the cholesterol levels had returned to baseline levels in the apoE2-expressing mice. Expression of all three isoforms significantly increased HDL cholesterol levels by approximately threefold and was independent of the cholesterol-lowering effect. ApoE transgene expression was substantially prolonged compared with that achieved using a first generation adenovirus and apoE was readily detected in plasma 3 mo after virus injection. These studies demonstrate: ( a ) prolonged in vivo expression of human apoE isoforms in apoE deficient mice after second-generation recombinant adenovirus-mediated somatic gene transfer; and ( b ) significantly impaired ability of apoE2 in vivo to mediate clearance of remnant lipoproteins in apoE-deficient mice fed a Western diet compared with apoE3 and apoE4.

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Section: Introductionmentioning

confidence: 99%

Liver-directed gene transfer and prolonged expression of three major human ApoE isoforms in ApoE-deficient mice.

Tsukamoto

Smith²,

Glick³

et al. 1997

J. Clin. Invest.

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“…3 Altogether, these activities contribute to the regulation of circulating lipoprotein levels. Several population studies [3][4][5] associated apoE defects with lipoprotein disorders and increased cardiovascular risk, thus revealing the key role played in atheroprotection. This beneficial activity was further demonstrated by the generation of mice lacking the apoE gene, characterized by hypercholesterolemia and abnormal lipid deposition in the proximal aorta and liver, even when receiving a normal chow diet.…”

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confidence: 99%

Macrophage, But Not Systemic, Apolipoprotein E Is Necessary for Macrophage Reverse Cholesterol Transport In Vivo

Zanotti

Pedrelli

Potì

et al. 2011

ATVB

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Objective-To assess the role of apolipoprotein (apo) E in macrophage reverse cholesterol transport (RCT) in vivo. Methods and Results-ApoE exerts an antiatherosclerotic activity by regulating lipoprotein metabolism and promoting cell cholesterol efflux. We discriminated between macrophage and systemic apoE contribution using an assay of macrophage RCT in mice. The complete absence of apoE lead to an overall impairment of the process and, similarly, the absence of apoE exclusively in macrophages resulted in the reduction of cholesterol mobilization from macrophages to plasma, liver, and feces. Conversely, expression of apoE in macrophages is sufficient to promote normal RCT even in apoE-deficient mice. The mechanisms accounting for these results were investigated by evaluating the first step of RCT (ie, cholesterol efflux from cells). Macrophages isolated from apoE-deficient mice showed a reduced ability to release cholesterol into the culture medium, whereas the apoB-depleted plasma from apoE-deficient and healthy mice possessed a similar capacity to promote cellular lipid release from cultured macrophages. Conclusion-Our data demonstrate, for the first time to our knowledge, that apoE significantly contributes to macrophage RCT in vivo and that this role is fully attributable to apoE expressed in macrophages. A polipoprotein E (apoE) is a structural component of several lipoproteins, including very-low-density lipoproteins (LDLs) and their remnants, chylomicron remnants, and high-density lipoproteins (HDL). 1 ApoE is predominantly synthesized by the liver and accomplishes its physiological role by driving the hepatic clearance of the lipoproteins on which it resides through binding with very LDL and chylomicron-remnant receptors 2 and inhibiting triglyceride lipolysis. 3 Altogether, these activities contribute to the regulation of circulating lipoprotein levels. Several population studies 3-5 associated apoE defects with lipoprotein disorders and increased cardiovascular risk, thus revealing the key role played in atheroprotection. This beneficial activity was further demonstrated by the generation of mice lacking the apoE gene, characterized by hypercholesterolemia and abnormal lipid deposition in the proximal aorta and liver, even when receiving a normal chow diet. 6,7 Beyond the influence on lipoprotein metabolism, apoE atheroprotective activity is also related to the promotion of cholesterol efflux from macrophages. 8,9 Cholesterol efflux is the first ratelimiting step of reverse cholesterol transport (RCT), the process by which excess cholesterol is delivered from peripheral tissues to the liver for final excretion into the feces. 10 Macrophage is the primary cell type overloaded with cholesterol within atherosclerotic lesions, and this cholesterol pool is the most important for atherosclerosis development and progression. 11 Thus, the RCT that involves macrophage-derived cholesterol became fundamental concerning atheroprotection. Macrophage RCT can be estimated with a radioisotope-based assay, whose appli...

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“…4,13 An apo E of 228 amino acids, resulting from a deletion of amino acids 209±212 and premature termination of the protein, was associated with a dominant form of HLP in a subject homozygous…”

Section: Discussionmentioning

confidence: 99%

“…10,11 Single nucleotide substitutions 4,12 and a 10-base pair (bp) nucleotide deletion 13 have been reported that introduce a premature stop codon and lead to the synthesis of nonfunctional, truncated forms of apo E. Indigenous Australians have a high cardiovascular mortality rate 14,15 and a high prevalence of cardiovascular risk factors, including hypercholesterolaemia, 16 smoking, 17 non-insulindependent diabetes mellitus, 17 central adiposity associated with hyperinsulinaemia, hypertriglyceridaemia, low HDL-cholesterol levels 18 and hyperhomocysteinaemia. 17 Apo E allele frequency is likely to be another factor contributing to cardiovascular disease in this ethnic group.…”

Section: Introductionmentioning

confidence: 99%

Identification of an apolipoprotein(e) variant associated with type III hyperlipoproteinaemia in an indigenous Australian

Tate

Hoffmann²,

Lovelock³

et al. 2001

Ann Clin Biochem

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SUMMARY.As a result of testing for lipid and apolipoprotein(e) (apo E) phenotype status of an indigenous Australian community, an apo E variant associated with type III hyperlipoproteinaemia has been identi®ed. Apo E phenotype was determined by analysis of VLDL by isoelectric focusing, and genotype on DNA ampli®ed by polymerase chain reaction, using two different restriction enzyme isotyping assays. Phenotypes and genotypes were discordant in samples from two subjects and an abnormal-sized restriction fragment was also observed in their genotyping gel patterns. DNA sequencing studies revealed this was due to a single nucleotide deletion, 3817delC, at amino acid 136 on apo E. This resulted in a new reading frame and the premature termination of the apo E protein due to a stop codon (TGA) at nucleotide 4105. The variant apo E null allele showed a recessive mode of inheritance and, in combination with the E2 allele, resulted in the type III hyperlipoproteinaemic phenotype but when inherited with the E4 allele had no marked effect on plasma lipids.

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A 10 BP deletion in the apolipoprotein ε gene causing apolipoprotein E deficiency and severe type III hyperlipoproteinemia

Cited by 20 publications

References 0 publications

Liver-directed gene transfer and prolonged expression of three major human ApoE isoforms in ApoE-deficient mice.

Liver-directed gene transfer and prolonged expression of three major human ApoE isoforms in ApoE-deficient mice.

Macrophage, But Not Systemic, Apolipoprotein E Is Necessary for Macrophage Reverse Cholesterol Transport In Vivo

Identification of an apolipoprotein(e) variant associated with type III hyperlipoproteinaemia in an indigenous Australian

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