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Hyperlipidemia in APOE2 transgenic mice is ameliorated by a truncated apoE variant lacking the C-terminal domain

Author: Gerritsen, G. · Kypreos, K.E. · Zee, A. van der · Teusink, B. · Zannis, V.I. · Havekes, L.M. · Dijk, K.W. van
Type:article
Date:2003
Institution: Gaubius Instituut TNO
Source:Journal of Lipid Research, 2, 44, 408-414
Identifier: 236960
doi: doi:10.1194/jlr.M200313-JLR200
Keywords: Biology · 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

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