Hyperlipidemia in APOE2 transgenic mice is ameliorated by a truncated apoE variant lacking the C-terminal domain
Familial dysbetalipoproteinemia associated with the apolipoprotein E2 (APOE2) genotype is a recessive disorder with low penetrance. We have investigated whether additional expression of full-length APOE3, APOE4, or a truncated variant of APOE4 (APOE4-202) can reduce APOE2- associated hyperlipidemia....
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Language: | English |
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Elsevier
2003-02-01
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Series: | Journal of Lipid Research |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520312281 |
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doaj-18f7be5fe8a84f5d9bf96b3dc9ce7bd9 |
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Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Gery Gerritsen Kyriakos E. Kypreos André van der Zee Bas Teusink Vassilis I. Zannis Louis M. Havekes Ko Willems van Dijk |
spellingShingle |
Gery Gerritsen Kyriakos E. Kypreos André van der Zee Bas Teusink Vassilis I. Zannis Louis M. Havekes Ko Willems van Dijk Hyperlipidemia in APOE2 transgenic mice is ameliorated by a truncated apoE variant lacking the C-terminal domain Journal of Lipid Research familial dysbetalipoproteinemia adenovirus-mediated gene transfer hypertriglyceridemia apolipoprotein E |
author_facet |
Gery Gerritsen Kyriakos E. Kypreos André van der Zee Bas Teusink Vassilis I. Zannis Louis M. Havekes Ko Willems van Dijk |
author_sort |
Gery Gerritsen |
title |
Hyperlipidemia in APOE2 transgenic mice is ameliorated by a truncated apoE variant lacking the C-terminal domain |
title_short |
Hyperlipidemia in APOE2 transgenic mice is ameliorated by a truncated apoE variant lacking the C-terminal domain |
title_full |
Hyperlipidemia in APOE2 transgenic mice is ameliorated by a truncated apoE variant lacking the C-terminal domain |
title_fullStr |
Hyperlipidemia in APOE2 transgenic mice is ameliorated by a truncated apoE variant lacking the C-terminal domain |
title_full_unstemmed |
Hyperlipidemia in APOE2 transgenic mice is ameliorated by a truncated apoE variant lacking the C-terminal domain |
title_sort |
hyperlipidemia in apoe2 transgenic mice is ameliorated by a truncated apoe variant lacking the c-terminal domain |
publisher |
Elsevier |
series |
Journal of Lipid Research |
issn |
0022-2275 |
publishDate |
2003-02-01 |
description |
Familial dysbetalipoproteinemia associated with the apolipoprotein E2 (APOE2) genotype is a recessive disorder with low penetrance. We have investigated whether additional expression of full-length APOE3, APOE4, or a truncated variant of APOE4 (APOE4-202) can reduce APOE2- associated hyperlipidemia. This was achieved using adenovirus-mediated gene transfer to mice transgenic for human APOE2 and deficient for endogenous Apoe (APOE2.Apoe−/− mice). The hyperlipidemia of APOE2.Apoe−/− mice was readily aggravated by APOE3 and APOE4 overexpression. Only a very low dose of APOE4 adenovirus was capable of reducing the serum cholesterol and triglyceride (TG) levels. Expression of higher doses of APOE4 was associated with an increased VLDL-TG production rate and the accumulation of TG-rich VLDL in the circulation. In contrast, a high dose of adenovirus carrying APOE4-202 reduced both the cholesterol and TG levels in APOE2.Apoe−/− mice. Despite the absence of the C-terminal lipid-binding domain, APOE4-202 is apparently capable of binding to lipoproteins and mediating hepatic uptake. Moreover, overexpression of APOE4-202 in APOE2.Apoe−/− mice does not aggravate their hypertriglyceridemia. These results extend our previous analyses of APOE4-202 expression in Apoe−/− mice and demonstrate that apoE4-202 functions even in the presence of clearance-defective apoE2.Thus, apoE4-202 is a safe and efficient candidate for future therapeutic applications. |
topic |
familial dysbetalipoproteinemia adenovirus-mediated gene transfer hypertriglyceridemia apolipoprotein E |
url |
http://www.sciencedirect.com/science/article/pii/S0022227520312281 |
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doaj-18f7be5fe8a84f5d9bf96b3dc9ce7bd92021-04-27T11:49:11ZengElsevierJournal of Lipid Research0022-22752003-02-01442408414Hyperlipidemia in APOE2 transgenic mice is ameliorated by a truncated apoE variant lacking the C-terminal domainGery Gerritsen0Kyriakos E. Kypreos1André van der Zee2Bas Teusink3Vassilis I. Zannis4Louis M. Havekes5Ko Willems van Dijk6Department of Human Genetics, Leiden University Medical Center, The Netherlands; TNO Prevention and Health, Gaubius Laboratory, Leiden, The Netherlands; Boston University School of Medicine, Boston, MA; Department of General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands; Department of Cardiology, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Human Genetics, Leiden University Medical Center, The Netherlands; TNO Prevention and Health, Gaubius Laboratory, Leiden, The Netherlands; Boston University School of Medicine, Boston, MA; Department of General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands; Department of Cardiology, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Human Genetics, Leiden University Medical Center, The Netherlands; TNO Prevention and Health, Gaubius Laboratory, Leiden, The Netherlands; Boston University School of Medicine, Boston, MA; Department of General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands; Department of Cardiology, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Human Genetics, Leiden University Medical Center, The Netherlands; TNO Prevention and Health, Gaubius Laboratory, Leiden, The Netherlands; Boston University School of Medicine, Boston, MA; Department of General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands; Department of Cardiology, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Human Genetics, Leiden University Medical Center, The Netherlands; TNO Prevention and Health, Gaubius Laboratory, Leiden, The Netherlands; Boston University School of Medicine, Boston, MA; Department of General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands; Department of Cardiology, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Human Genetics, Leiden University Medical Center, The Netherlands; TNO Prevention and Health, Gaubius Laboratory, Leiden, The Netherlands; Boston University School of Medicine, Boston, MA; Department of General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands; Department of Cardiology, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Human Genetics, Leiden University Medical Center, The Netherlands; TNO Prevention and Health, Gaubius Laboratory, Leiden, The Netherlands; Boston University School of Medicine, Boston, MA; Department of General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands; Department of Cardiology, Leiden University Medical Center, Leiden, The NetherlandsFamilial dysbetalipoproteinemia associated with the apolipoprotein E2 (APOE2) genotype is a recessive disorder with low penetrance. We have investigated whether additional expression of full-length APOE3, APOE4, or a truncated variant of APOE4 (APOE4-202) can reduce APOE2- associated hyperlipidemia. This was achieved using adenovirus-mediated gene transfer to mice transgenic for human APOE2 and deficient for endogenous Apoe (APOE2.Apoe−/− mice). The hyperlipidemia of APOE2.Apoe−/− mice was readily aggravated by APOE3 and APOE4 overexpression. Only a very low dose of APOE4 adenovirus was capable of reducing the serum cholesterol and triglyceride (TG) levels. Expression of higher doses of APOE4 was associated with an increased VLDL-TG production rate and the accumulation of TG-rich VLDL in the circulation. In contrast, a high dose of adenovirus carrying APOE4-202 reduced both the cholesterol and TG levels in APOE2.Apoe−/− mice. Despite the absence of the C-terminal lipid-binding domain, APOE4-202 is apparently capable of binding to lipoproteins and mediating hepatic uptake. Moreover, overexpression of APOE4-202 in APOE2.Apoe−/− mice does not aggravate their hypertriglyceridemia. These results extend our previous analyses of APOE4-202 expression in Apoe−/− mice and demonstrate that apoE4-202 functions even in the presence of clearance-defective apoE2.Thus, apoE4-202 is a safe and efficient candidate for future therapeutic applications.http://www.sciencedirect.com/science/article/pii/S0022227520312281familial dysbetalipoproteinemiaadenovirus-mediated gene transferhypertriglyceridemiaapolipoprotein E |