Functional Analysis of Sterol Carrier Protein-2 (SCP2) in the SCP2 Knockout Mouse

Sterol carrier protein-2 (SCP2) and sterol carrier protein-x (SCPx, peroxisomal 3-ketoacyl-CoA thiolase with intrinsic non-specific lipid transfer activity) are expressed from a fused gene (designated Scp2) which is similarly organized in all vertebrates and could be traced back to Drosophila melanogaster. Numerous in vitro studies were performed over the past two decades. They have led to the concept that SCP2 functions intracellularly in cholesterol transport to diverse subcellular locations. On the other hand, apparent lack of transport specificity and the well established localization of SCP2 within peroxisomes has made it difficult to understand how the protein might carry out this function in the intact cell. This chapter summarizes phenotypic abnormalities, that were detected in a murine strain harboring a targeted Scp2 null mutation. Whereas the SCP2/SCPx-deficient strain revealed no major abnormality in cholesterol trafficking, profound effects were found with regard to the metabolism of several methyl-branched acyl-CoAs that are metabolized in peroxisomes. Along with the metabolic abnormalities, the gene disruption led to diet-dependent alterations in gene expression, peroxisome proliferation, hypolipidemia, impaired body weight control and neuropathy.