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Mice expressing only the mutant APOE3Leiden gene show impaired VLDL secretion

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Author: Mensenkamp, A.R. · Teusink, B. · Baller, J.F.W. · Wolters, H. · Havinga, R. · Dijk, K.W. van · Havekes, L.M. · Kuipers, F.
Type:article
Date:2001
Institution: Gaubius Instituut TNO
Source:Arteriosclerosis, Thrombosis, and Vascular Biology, 8, 21, 1366-1372
Identifier: 236332
Keywords: Animals · Apolipoprotein E3 · Apolipoproteins B · Apolipoproteins E · Fatty Liver · Lipid Metabolism · Lipoproteins, VLDL · Liver · Mice · Mice, Transgenic · Protein Isoforms · RNA, Messenger · Triglycerides

Abstract

Apolipoprotein E (apoE)-deficient mice develop hepatic steaatosis and show impaired very low density lipoprotein (VLDL)-triglyceride (TG) secretion. These effects are normalized on the introduction of the human APOE3 gene. To assess whether this apoE effect is isoform specific, we studied hepatic lipid metabolism in mice expressing either APOE3 or the mutant APOE3Leiden on apoe-/- or apoe+/- backgrounds. The transgenes were expressed mainly in periportal hepatocytes, as revealed by in situ hybridization. Mice expressing APOE3Leiden, on the apoe-/and apoe+/- backgrounds, had fatty livers, which were absent in APOE3/apoe-/- mice. APOE3Leiden/apoe-/mice showed a strongly reduced VLDL-TG secretion compared with APOE3/apoe-/- mice (48± 14 versus 82± 10 μmol/kg per hour, respectively). The presence of a single mouse apoe allele increased VLDL-TG secretion in APOE3Leiden/apoe +/- mice (121±43 μmol/kg per hour) compared with APOE3Leiden/apoe-/- mice. These results show that APOE3Leiden does not prevent development of a fatty liver and does not normalize VLDL-TG secretion in mice with an apoE-deficient background. The presence of a single mouse apoe allele is sufficient to normalize the APOE3Leiden-associated reduction of VLDL-TG secretion but does not prevent steatosis. We conclude that apoE-mediated stimulation of VLDL secretion is isoform specific. Chemicals/CAS: apolipoprotein E3 (Leidein); Apolipoprotein E3; Apolipoproteins B; Apolipoproteins E; Lipoproteins, VLDL; Protein Isoforms; RNA, Messenger; Triglycerides; very low density lipoprotein triglyceride