Type III Hyperlipoproteinemia Associated with Apolipoprotein E Deficiency

Ghiselli, Giancarlo; Ej, Schaefer; Gascón, Pedro; Breser, HB

doi:10.1126/science.6795720

Cited by 259 publications

(117 citation statements)

References 26 publications

(13 reference statements)

Supporting

Mentioning

111

Contrasting

Unclassified

Order By: Relevance

“…Plasma was obtained from normolipidemic individuals and an apolipoprotein E-deficient patient [20] by plasmapheresis, and LDL (d = 1.030-1.050 g/ml) was isolated by preparative ultracentrifugation [21]. LDL was radiolabeled by the iodine monochloride method [22] as modified for lipoproteins [23].…”

Section: Lipoprotein Preparationmentioning

confidence: 99%

See 1 more Smart Citation

Metabolism of low-density lipoproteins by cultured hepatocytes from normal and homozygous familial hypercholesterolemic subjects

Hoeg

Edge

Demosky

et al. 1986

Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metaboli

View full text Add to dashboard Cite

The profoundly elevated concentrations of low-density lipoproteins (LDL) present in homozygous familial hypercholesterolemia lead to symptomatic cardiovascular disease and death by early adulthood. Studies conducted in nonhepatic tissues demonstrated defective cellular recognition and metabolism of LDL in these patients. Since mammalian liver removes at least half of the LDL in the circulation, the metabolism of LDL by cultured hepatocytes isolated from familial hypercholesterolemic homozygotes was compared to hepatocytes from normal individuals. Fibroblast studies demonstrated that the familial hypercholesterolemic subjects studied were LDL receptor-negative (less than 1% normal receptor activity) and LDL receptor-defective (18% normal receptor activity). Cholesterol-depleted hepatocytes from normal subjects bound and internalized 125 I-labeled LDL (B max = 2.2 μg LDL/mg cell protein). Preincubation of normal hepatocytes with 200 μg/ml LDL reduced binding and internalization by approx. 40%. In contrast, 125 I-labeled LDL binding and internalization by receptor-negative familial hypercholesterolemic hepatocytes was unaffected by cholesterol loading and considerably lower than normal. This residual LDL uptake could not be ascribed to fluid phase endocytosis as determined by [ 14 C]sucrose uptake. The residual LDL binding by familial hypercholesterolemia hepatocytes led to a small increase in hepatocyte cholesterol content which was relatively ineffective in reducing hepatocyte 3-hydroxy-3-methylglutaryl-CoA reductase activity. Receptordefective familial hypercholesterolemia hepatocytes retained some degree of regulatable 125 Ilabeled LDL uptake, but LDL uptake did not lead to normal hepatocyte cholesterol content or 3-hydroxy-3-methylglutaryl-CoA reductase activity. These combined results indicate that the LDL receptor abnormality present in familial hypercholesterolemia fibroblasts reflects deranged hepatocyte LDL recognition and metabolism. In addition, a low-affinity, nonsaturable uptake process for LDL is present in human liver which does not efficiently modulate hepatocyte cholesterol content or synthesis.

show abstract

Section: Lipoprotein Preparationmentioning

confidence: 99%

“…Fibroblast and hepatocyte 125 I-labeled LDL-binding assays were conducted identically, utilizing LDL isolated from a patient with apolipoprotein E deficiency [20]. From 0.5 to 5 · 10 5 cells were incubated for 24 h in 2 cm 2 wells containing 1 ml serum-free medium.…”

Section: Cellular Lipoprotein-binding Studiesmentioning

confidence: 99%

Metabolism of low-density lipoproteins by cultured hepatocytes from normal and homozygous familial hypercholesterolemic subjects

Hoeg

Edge

Demosky

et al. 1986

Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metaboli

View full text Add to dashboard Cite

show abstract

“…The presence of immunoreactive apoE in other organs such as the tubular epithelia ofthe kidney and the glandular epithelia of the stomach also suggests potentially important functions of apoE in these highly differentiated tissues. The fact that a single patient with plasma apoE deficiency has been described (28,29) should not negate these other potential roles for this protein, since such functions may be assumed by other proteins. A similar situation is noted in the case of analbuminemia where the absence of a major physiological serum protein is consistent with relatively normal health (30-32).…”

Section: Bmentioning

confidence: 99%

Immunoreactive apolipoprotein E is a widely distributed cellular protein. Immunohistochemical localization of apolipoprotein E in baboon tissues.

Lin¹,

Xu²,

Wu³

et al. 1986

J. Clin. Invest.

110

View full text Add to dashboard Cite

“…1993). Apo E is also at the center of interest, because patients with apo E deficiency have a lipoprotein pattern resembling that seen in type III hyperlipoproteinemia and also develop atherosclerosis and xanthomas (Ghiselli et al 1981, Schaeffer et al 1986, Mabuchi et al 1989, Mahley & Rall 1989. Moreover, a common genetic variation of apo E in human populations is also known (Zannis et al 1982).…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E-deficient mice created by systemic administration of antisense oligodeoxynucleotides: a new model for lipoprotein metabolism studies

Morishita

Gibbons²,

Kaneda³

et al. 2002

Journal of Endocrinology

View full text Add to dashboard Cite

Atherosclerotic cardiovascular disease results from complex interactions among multiple genetic and environmental factors. Thus, it is important to elucidate the influence of each factor on cholesterol metabolism. For this purpose, transgenic/gene-targeting technology is a powerful tool for studying gene functions. However, this technology has several disadvantages such as being time consuming and expensive. Accordingly, we established new animal models using in vivo gene transfer technology. In this study, we examined the feasibility of the creation of a new animal model for the study of atherosclerosis. We hypothesized that apolipoprotein (apo) E-deficient mice can be created by systemic administration of antisense apo E oligodeoxynucleotides (ODN) coupled to the HVJliposome complex. Initially, we examined the localization and cellular fate of FITC-labeled antisense ODN administered intravenously. FITC-labeled ODN transfection by the HVJ-liposome method resulted in fluorescence in the liver, spleen and kidney, but not in other organs such as brain. Moreover, fluorescence with the HVJ-liposome method was sustained for up to 2 weeks after transfection, which resulted in a striking difference from transfection of ODN alone or ODN in liposomes without HVJ, which showed rapid disappearance of fluorescence (within 1 day). Given these unique characteristics of the HVJ-liposome method, we next examined transfection of antisense apo E ODN by intravenous administration. Transfection of antisense apo E ODN resulted in a marked reduction of apo E mRNA levels in the liver, but no change in apo B and -actin mRNA levels. In mice fed a normal diet, a transient increase in cholesterol and triglyceride levels was observed in the antisense apo E-treated group, but they returned to normal levels by 6 days after transfection. Similar findings were also found in mice fed a high cholesterol diet. Neither scrambled nor mismatched ODN resulted in any increase in cholesterol. To make chronic hypercholesterolemic mice, we therefore performed repeated injections of apo E antisense ODN. Whenever antisense apo E ODN were injected, mice showed a transient increase in cholesterol and triglyceride. Cumulative administration of antisense apo E ODN resulted in a sustained increase in cholesterol for up to 3 weeks after the last transfection. Finally, mice treated with repeated injections of antisense apo E every week developed sustained hypercholesterolemia and hypertriglyceridemia until withdrawal of injections. Apolipoprotein-deficient mice created by intravenous administration of antisense ODN are a promising new animal model to help understand the role of apolipoprotein in vivo and develop a new drug therapy targeting apolipoprotein.

show abstract

Type III Hyperlipoproteinemia Associated with Apolipoprotein E Deficiency

Cited by 259 publications

References 26 publications

Metabolism of low-density lipoproteins by cultured hepatocytes from normal and homozygous familial hypercholesterolemic subjects

Metabolism of low-density lipoproteins by cultured hepatocytes from normal and homozygous familial hypercholesterolemic subjects

Immunoreactive apolipoprotein E is a widely distributed cellular protein. Immunohistochemical localization of apolipoprotein E in baboon tissues.

Apolipoprotein E-deficient mice created by systemic administration of antisense oligodeoxynucleotides: a new model for lipoprotein metabolism studies

Contact Info

Product

Resources

About