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

Myriam Baes,Steven Huyghe,Peter Carmeliet,Peter E Declercq,Désiré Collen,Guy P Mannaerts,Paul P Van Veldhoven

doi:10.1074/jbc.m001994200

Abstract

According to current views, peroxisomal beta-oxidation is organized as two parallel pathways: the classical pathway that is responsible for the degradation of straight chain fatty acids and a more recently identified pathway that degrades branched chain fatty acids and bile acid intermediates. Multifunctional 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 generated. MFP-2 deficiency caused a severe growth retardation during the first weeks 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 liver phospholipids, immature C(27) bile acids in bile, and, after supplementation with phytol, pristanic and phytanic acid in liver triacylglycerols. These changes correlated with a severe impairment of peroxisomal beta-oxidation of very long straight chain fatty acids (C(24)), 2-methyl-branched chain fatty acids, and the bile acid intermediate trihydroxycoprostanic acid in fibroblast cultures or liver homogenates derived from the MFP-2 knockout mice. In contrast, peroxisomal beta-oxidation of long straight chain fatty acids (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 pathway. The present data indicate that MFP-2 is not only essential for the degradation of 2-methyl-branched fatty acids and the bile acid intermediates di- and trihydroxycoprostanic acid but also for the breakdown of very long chain fatty acids.

Highlights

According to current views, peroxisomal ␤-oxidation is organized as two parallel pathways: the classical pathway that is responsible for the degradation of straight chain fatty acids and a more recently identified pathway that degrades branched chain fatty acids and bile acid intermediates
The substrates for peroxisomal ␤-oxidation known to date include very long straight chain fatty acids; 2-methylbranched chain fatty acids; prostanoids; dicarboxylic acids; and the C27 bile acid intermediates di- and trihydroxycoprostanic acid, which are converted to the mature C24 bile acids via peroxisomal ␤-oxidation
The present study demonstrates that straight very long chain fatty acids (VLCFA) accumulate, besides branched chain fatty acids and bile acid intermediates, in mice lacking MFP-2, an enzyme belonging to the second pathway

Summary

Introduction

Peroxisomal ␤-oxidation is organized as two parallel pathways: the classical pathway that is responsible for the degradation of straight chain fatty acids and a more recently identified pathway that degrades branched chain fatty acids and bile acid intermediates. The classical pathway catalyzed by palmitoyl-CoA oxidase, multifunctional protein-1 ( denoted as L-bifunctional protein because the hydrated species it generates has the L-configuration), and peroxisomal thiolase is generally accepted to be responsible for the oxidation of straight chain fatty acids. All enzymes of this pathway are found in different species and can be strongly induced in rodents by ligands of the peroxisome proliferator-activated receptor ␣ (PPAR␣)..

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