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Analysis of Expression of Genes Involved in Apolipoprotein E-Based Lipoprotein Metabolism in Pregnant Mice Deficient in the Receptor-Associated Protein, the Low Density Lipoprotein Receptor, or Apolipoprotein E¹

^a Experimental Genetics Group, Center for Human Genetics (CME), Flemish Institute for Biotechnology (VIB), Katholieke Universiteit Leuven, Campus Gasthuisberg, B-3000 Leuven, Belgium

Mice deficient in receptor-associated protein (RAP) were phenotypically normal, but in contrast to results previously reported in RAP^-;cl- mice, nearly 50% of the offspring died at or shortly after birth. To attempt to determine the reason for this, we analyzed the regulation of expression of genes involved in apolipoprotein E (apoE)-based mechanisms in RAP-deficient mice and compared this to results in mice deficient in low density lipoprotein receptor (LDLR) or apoE. The major finding concerned a large increase in hepatic lipoprotein receptor-related protein (LRP) mRNA and LDLR mRNA levels in pregnant RAP knockout mice. This is in contrast to the down-regulation of LRP mRNA and LDLR mRNA, which is normally seen in wild-type mice. Also in LDLR knockout mice, a significant up-regulation in expression of LRP mRNA was demonstrated. In apoE knockout mice, hepatic LRP mRNA did not change significantly, while hepatic LDLR mRNA expression was increased. In placenta and uterus, the deficiency of RAP did not markedly affect the expression of LRP and LDLR. Lipoprotein lipase mRNA and apoE mRNA increased during pregnancy in all mice, independent of their genetic status. The current study does not directly explain the increased mortality of RAP^-;cl- pups. The data demonstrate, however, important relative changes in expression of the genes analyzed, an indication that LRP and LDLR play an important role in lipid metabolism during pregnancy.

¹ This investigation was supported by the ‘Fonds voor Wetenschappelijk Onderzoek-Vlaanderen’ (FWO), by NFWO-Lotto, by the Interuniversity-network for Fundamental Research (IUAP) of the Belgian Government, by the Special Biotechnology Program of the Flemish government (IWT/VLAB/COT-008). L.U. and L.O. were postdoctoral research fellows of the Special Research Fund of the K.U.Leuven.

² Correspondence. FAX: 32 16 3458 71; fredvl{at}med.kuleuven.ac.be

³ Current address: Laboratory of Experimental Transplantation, Campus Gasthuisberg O&N 08, KULeuven, B-3000 Leuven, Belgium.

⁴ These authors contributed equally to this work.

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