Mice expressing only the mutant APOE3Leiden gene show impaired VLDL secretion

Apolipoprotein E (apoE)-deficient mice develop hepatic steatosis and show i mpaired very low density lipoprotein (VLDL)-triglyceride (TG) secretion. Th ese effects are normalized on the introduction of the human APOE3 gene. To assess whether this apoE effect is isoform. specific, we studied hepatic li pid metabolism in mice expressing either APOE3 or the mutant APOE3Leiden on apoe-/- or apoe+/- backgrounds. The transgenes were expressed mainly in pe riportal hepatocytes, as revealed by in situ hybridization. Mice expressing APOE3Leiden, on the apoe-/- and apoe+/- backgrounds, had fatty livers, whi ch were absent in APOE3/apoe-/- mice. APOE3Leiden/apoe-/- mice showed a str ongly reduced V-LDL-TG secretion compared with APOE3/apoe-/- mice (48 +/- 1 4 versus 82 +/- 10 mu mol/kg per hour, respectively). The presence of a sin gle mouse apoe allele increased VLDL-TG secretion in APOE3Leiden/apoe+/- mi ce(121 +/- 43 mu mol/kg per hour) compared with APOE3Leiden/apoe-/- mice. T hese results show that APOE3Leiden does not prevent development of a fatty Liver and does not normalize VLDL-TG secretion in mice with an apoE-deficie nt background. The presence of a single mouse apoe allele is sufficient to normalize the APOE3Leiden-associated reduction of VLDL-TG secretion but doe s not prevent steatosis. We conclude that apoE-mediated stimulation of VLDL secretion is isoform specific.