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Papers In Press, published online ahead of print October 16, 2002
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Submitted on August 8, 2002
General Internal Medicine and Human Genetics, Leiden University Medical Center, Leiden 2333AL
Corresponding Author: kowvd{at}lumc.nl
Familial Dysbetalipoproteinemia (FD) associated with the apolipoprotein E2 (APOE2) genotype is a recessive disorder with low penetrance. Here we have investigated whether additional expression of full-length APOE3, APOE4 or a variant of APOE4 truncated at position 203 (APOE4-202) can reduce APOE2-associated hyperlipidemia in a mouse model for FD. This was achieved using adenovirus mediated gene transfer to mice transgenic for human APOE2 and deficient for endogenous Apoe (APOE2.Apoe-/- mice). Injection of 2x109 plaque forming units (pfu) of adenovirus encoding apoE3 and increasing doses of adenovirus encoding full-length apoE4 (2x108 – 1x109 pfu) indicated that the hyperlipidemia of APOE2.Apoe-/- mice is readily aggravated by APOE3 and APOE4 overexpression. Only a very low dose of APOE4 adenovirus (2x108 pfu) was capable of reducing the serum cholesterol levels from 13.8±1.7mM to 2.2±0.7mM (p<0.01) and the serum TG levels from 3.1±2.2 to 0.7±0.3mM (p<0.05) at day 5 after virus injection. Increasing the dose up to 5x108 pfu induced hypertriglyceridemia (9.1±6.3mM). Overexpression of APOE4 was associated with an increase in the VLDL-TG production rate and the accumulation of TG-rich VLDL in the circulation. In contrast, a high dose (2x109 pfu) of adenovirus carrying APOE4-202 reduced both the hypercholesterolemia and the hypertriglyceridemia (from 13.1±3.2 to 3.8±1.1 (p<0.01) and 4.4±1.5 to 2.2±0.8mM (p<0.05) resp.) in APOE2.Apoe-/- mice. Despite the absence of the C-terminal lipid-binding domain, APOE4-202 is apparently capable of binding to lipoproteins and mediate their uptake via hepatic receptors. 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 alternative to full-length apoE in therapeutic applications.
Revised on October 1, 2002
Accepted on October 1, 2002
Hyperlipidemia in APOE2 transgenic mice is ameliorated by a truncated apoE variant lacking the C-terminal domain
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