DEFECTIVE PEROXISOMAL CATABOLISM OF BRANCHED FATTY ACYL-COENZYME-A INMICE LACKING THE STEROL CARRIER PROTEIN-2 STEROL CARRIER PROTEIN-X GENE-FUNCTION

Gene targeting in mice was used to investigate the unknown function of Scp2, encoding sterol carrier protein-2 (SCP2; a peroxisomal lipid ca rrier) and sterol carrier protein-x (SCPx; a fusion protein between SC P2 and a peroxisomal thiolase). Complete deficiency of SCP2 and SCPx w as associated with marked alterations in gene expression, peroxisome p roliferation, hypolipidemia, impaired. body weight control, and neurop athy. Along with these abnormalities, catabolism of methyl-branched fa tty acyl CoAs was impaired. The defect became evident from up to 10-fo ld accumulation of the tetramethyl-branched fatty acid phytanic acid i n Scp2(-/-) mice. Further characterization supported that the gene dis ruption led to inefficient import of phytanoyl-CoA into peroxisomes an d to defective thiolytic cleavage of 3-ketopristanoyl-CoA. These resul ts corresponded to high-affinity binding of phytanoyl-CoA to the recom binant rat SCP2 protein, as well as high 3-ketopristanoyl-CoA thiolase activity of the recombinant rat SCPx protein.