Genetic analysis of LDL receptor-related genes

The low density lipoprotein (LDL) receplor gene family consists of a growing number of structurally closely related endocytic cell surface receptors. Several members of the family are multifunctional and bind a variety of biologically diverse ligands including lipoproteins, enzymes involved in lipid metabolism, active proteases and protease inhibitors. Two family members which exhibit the hroadest ligand recognition specificity, the LI)L receptor-related l)rotein (LRP) and its close homologue gp330/megalin, are required for normal embryonic development. LRP-deficient embryos and newborn gp330/megalindeficient mice suffer from multiple pleiotropic abnormalities which makes it difficult to define the physiological roles of these receptors during development or post-natal life. To better define and dissect specific functions of the LRP in vivo we have employed tissue-specific and inducible gene targeting methods in mice. Somatic disruption of the LRP gene in hepatocytes has allowed us to unequivocally define an alternative, LI)I, receptor-independen! cholesterol clearance pathway in the liver. Experiments aiming at the disruption of the gene in other tissues and cell types, e.g. the vascular wall and neurons, are currently ongoing.