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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1366.)
© 2001 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Mice Expressing Only the Mutant APOE3Leiden Gene Show Impaired VLDL Secretion

Arjen R. Mensenkamp; Bas Teusink; Julius F.W. Baller; Henk Wolters; Rick Havinga; Ko Willems van Dijk; Louis M. Havekes; Folkert Kuipers

From the Groningen University Institute for Drug Exploration (A.R.M., J.F.W.B., H.W., R.H., F.K.), Center for Liver, Digestive, and Metabolic Diseases, Faculty of Medical Sciences and University Hospital Groningen, Groningen, the Netherlands; the Gaubius Laboratory TNO-PG (B.T., L.M.H.), Leiden, the Netherlands; and the Departments of Human Genetics (K.W.v.D.) and General Internal Medicine and Cardiology (L.M.H.), Leiden University, Leiden, the Netherlands.

Correspondence to Folkert Kuipers, PhD, Groningen University Institute for Drug Exploration, Center for Liver, Digestive, and Metabolic Diseases, University Hospital Groningen, CMC IV, Room Y2115, Hanzeplein 1, 9713 GZ Groningen, Netherlands. E-mail f.kuipers{at}med.rug.nl

Abstract—— Apolipoprotein E (apoE)-deficient mice develop hepatic steatosis 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 µ mol/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.

Key Words: very low density lipoproteins • apolipoprotein E • lipoprotein assembly • lipoprotein secretion • steatosis

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