Title
Hyperlipidemia in APOE2 transgenic mice is ameliorated by a truncated apoE variant lacking the C-terminal domain
Author
Gaubius Instituut TNO
Gerritsen, G.
Kypreos, K.E.
van der Zee, A.
Teusink, B.
Zannis, V.I.
Havekes, L.M.
van Dijk, K.W.
Publication year
2003
Abstract
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
Subject
Adenoviridae
Animals
Apolipoprotein E2
Apolipoprotein E4
Apolipoproteins E
Cholesterol
Humans
Hyperlipidemias
Lipids
Lipoproteins
Lipoproteins, VLDL
Liver
Mice
Mice, Transgenic
Protein Isoforms
Protein Structure, Tertiary
Triglycerides
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DOI
https://doi.org/10.1194/jlr.m200313-jlr200
TNO identifier
236960
ISSN
0022-2275
Source
Journal of Lipid Research, 44 (44), 408-414
Document type
article