Inactivation of the peroxisomal multifunctional protein-2 in mice impedes the degradation of not only 2-methyl-branched fatty acids and bile acid intermediates but also of very long chain fatty acids

According to current views, peroxisomal beta-oxidation is organized as two parallel pathways: the classical pathway that is responsible for the degrad ation of straight chain fatty acids and a more recently identified pathway that degrades branched chain fatty acids and bile acid intermediates. Multi functional protein-2 (MFP-2), also called D-bifunctional protein, catalyzes the second (hydration) and third (dehydrogenation) reactions of the latter pathway. In order to further clarify the physiological role of this enzyme in the degradation of fatty carboxylates, MFP-2 knockout mice were generat ed. MFP-S deficiency caused a severe growth retardation during the first we eks of life, resulting in the premature death of one-third of the MFP-2(-/- ) mice. Furthermore, MFP-2-deficient mice accumulated VLCFA in brain and li ver phospholipids, immature C-27 bile acids in bile, and, after supplementa tion with phytol, pristanic and phytanic acid in liver triacylglycerols. Th ese changes correlated with a severe impairment of peroxisomal beta-oxidati on of very long straight chain fatty acids (C-24), 2-methyl-branched chain fatty acids, and the bile acid intermediate trihydroxycoprostanic acid in f ibroblast cultures or liver homogenates derived from the MFP-2 knockout mic e. In contrast, peroxisomal beta-oxidation of long straight chain fatty aci ds (C-16) was enhanced in liver tissue from MFP-2(-/-) mice, due to the up- regulation of the enzymes of the classical peroxisomal beta-oxidation pathw ay, The present data indicate that MFP-2 is not only essential for the degr adation of 2-methyl-branched fatty acids and the bile acid intermediates di - and trihydroxycoprostanic acid but also for the breakdown of very long ch ain fatty acids.