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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1800.)
© 2000 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Apolipoprotein E2 (Lys146Gln) Causes Hypertriglyceridemia due to an Apolipoprotein E Variant–Specific Inhibition of Lipolysis of Very Low Density Lipoproteins–Triglycerides

Femke de Beer; Ko Willems van Dijk; Miek C. Jong; Leonie C. van Vark; Andre van der Zee; Marten H. Hofker; Frits J. Fallaux; Rob C. Hoeben; Augustinus H. M. Smelt; Louis M. Havekes

From TNO-Prevention and Health (F.d.B., M.C.J., L.C.v.V., L.M.H.), Gaubius Laboratory, Leiden, the Netherlands, and the Departments of Internal Medicine (F.d.B., M.C.J., L.C.v.V., A.H.M.S., L.M.H.), Human Genetics (K.W.v.D., A.v.d.Z., M.H.H.), Molecular Cell Biology (F.J.F., R.C.H.), and Cardiology (L.M.H.), Leiden University Medical Center, Leiden, the Netherlands.

Correspondence to Prof Dr L.M. Havekes, TNO-Prevention and Health, Gaubius Laboratory, Zernikedreef 9, 2333 CK Leiden, Netherlands, or PO Box 2215, 2301 CE Leiden, Netherlands. E-mail LM.Havekes{at}PG.TNO.NL

Abstract—The apolipoprotein E2 (Lys146Gln) variant is associated with a dominant form of familial dysbetalipoproteinemia. Heterozygous carriers of this variant have elevated levels of plasma triglycerides, cholesterol, and apolipoprotein E (apoE). It was hypothesized that the high amounts of triglycerides in the very low density lipoprotein (VLDL) fraction are due to a disturbed lipolysis of VLDL. To test this hypothesis, apoE knockout mice were injected with an adenovirus containing the human APOE*2 (Lys146Gln) gene, Ad-E2(146), under the control of the cytomegalovirus promoter. ApoE knockout mice injected with an adenovirus vector encoding human apoE3 (Ad-E3) were used as controls. Five days after adenovirus injection, plasma cholesterol levels of mice injected with a high dose of Ad-E2(146) (2x10⁹ plaque-forming units) were not changed compared with preinjection levels, whereas in the group who received a low dose of Ad-E2(146) (5x10⁸ plaque-forming units) and in the groups injected with a low or a high dose of Ad-E3, plasma cholesterol levels were decreased 5-, 6-, and 12-fold, respectively. Plasma triglycerides were not affected in mice injected with Ad-E3. In contrast, a 7-fold increase in plasma triglycerides was observed in mice injected with the low dose of Ad-E2(146) compared with mice injected with Ad-E3. Injection with the high dose of Ad-E2(146) resulted in a dramatic increase of plasma triglycerides (50-fold compared with Ad-E3 injection). In vitro lipolysis experiments showed that the lipolysis rate of VLDLs containing normal amounts of apoE2 (Lys146Gln) was decreased by 54% compared with that of VLDLs containing comparable amounts of apoE3. The in vivo VLDL-triglyceride production rate of Ad-E2(146)–injected mice was not significantly different from that of Ad-E3–injected mice. These results demonstrate that expression of apoE2 (Lys146Gln) causes hypertriglyceridemia due to an apoE variant–specific inhibition of the hydrolysis of VLDL-triglycerides.

Key Words: adenovirus-mediated gene transfer • apolipoprotein E • familial dysbetalipoproteinemia • lipolysis

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