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Apolipoprotein E2 (Lys146→Gln) causes hypertriglyceridemia due to an apolipoprotein E variant-specific inhibition of lipolysis of very low density lipoproteins-triglycerides

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Author: Beer, F. de · Dijk, K.W. van · Jong, M.C. · Vark, L.C. van · Zee, A. van der · Hofker, M.H. · Fallaux, F.J. · Hoeben, R.C. · Smelt, A.H.M. · Havekes, L.M.
Type:article
Date:2000
Institution: Gaubius Instituut TNO
Source:Arteriosclerosis, Thrombosis, and Vascular Biology, 7, 20, 1800-1806
Identifier: 235596
Keywords: Adenoviridae · Alleles · Animals · Apolipoprotein E2 · Apolipoprotein E3 · Apolipoproteins E · Gene Expression · Gene Transfer Techniques · Humans · Hydrolysis · Hyperlipoproteinemia Type III · Hypertriglyceridemia · Lipolysis · Lipoproteins, VLDL · Liver · Male · Mice · Mice, Knockout · Point Mutation · RNA, Messenger · Triglycerides

Abstract

The apolipoprotein E2 (Lys146→Gln) 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 (Lys146→Gln) 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) (2 x 109 plaque-forming units) were not changed compared with preinjection levels, whereas in the group who received a low dose of Ad-E2(146) (5 x 108 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 (Lys146→Gln) 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 (Lys146→Gln) causes hypertriglyceridemia due to an apoE variant-specific inhibition of the hydrolysis of VLDL-triglycerides. Chemicals/CAS: Apolipoprotein E2; Apolipoprotein E3; Apolipoproteins E; Lipoproteins, VLDL; RNA, Messenger; Triglycerides