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. 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.
Gerritsen
Gery
G
Department of Human Genetics, Leiden University Medical Center, The Netherlands.
Kypreos
Kyriakos E
KE
van der Zee
André
A
Teusink
Bas
B
Zannis
Vassilis I
VI
Havekes
Louis M
LM
van Dijk
Ko Willems
KW
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D053329:Apolipoprotein E2; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood; D006801:Humans; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism*; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008079:Lipoproteins, VLDL / Q000737:chemistry / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D014280:Triglycerides / Q000737:chemistry / Q000378:metabolism
D053329:Apolipoprotein E2; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D008055:Lipids; D008074:Lipoproteins; D008079:Lipoproteins, VLDL; D020033:Protein Isoforms; D014280:Triglycerides; C030106:very low density lipoprotein triglyceride; D002784:Cholesterol