Hyperlipidemia in APOE2 transgenic mice is ameliorated by a truncated apoE variant lacking the C-terminal domain
| Autor: | Gerritsen, G., Kypreos, K.E., Zee, A. van der, Teusink, B., Zannis, V.I., Havekes, L.M., Dijk, K.W. van |
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| Přispěvatelé: | Gaubius Instituut TNO |
| Jazyk: | angličtina |
| Rok vydání: | 2003 |
| Předmět: |
Apolipoprotein E2
Lipoproteins Apolipoprotein E4 Hyperlipidemias Mice Transgenic Lipoproteins VLDL Lipids Adenoviridae Protein Structure Tertiary Mice Apolipoproteins E Cholesterol Liver mental disorders Animals Humans Protein Isoforms lipids (amino acids peptides and proteins) human activities Biology Triglycerides |
| Zdroj: | Journal of Lipid Research, 2, 44, 408-414 |
| Popis: | 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. Chemicals/CAS: Apolipoprotein E2; Apolipoprotein E4; Apolipoproteins E; Cholesterol, 57-88-5; Lipids; Lipoproteins; Lipoproteins, VLDL; Protein Isoforms; Triglycerides; very low density lipoprotein triglyceride |
| Databáze: | OpenAIRE |
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