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Peroxisomal Multifunctional Protein 2 Is Essential for Lipid Homeostasis in Sertoli Cells and Male Fertility in Mice

Laboratory of Clinical Chemistry, Faculty of Pharmacy (S.H., M.B.); Department of Pharmacology, Faculty of Medicine (P.P.V.V.); and Laboratory for Experimental Medicine and Endocrinology, Department of Developmental Biology (K.D.G., G.V.), Katholieke Universiteit, B-3000 Leuven, Belgium; Department of Medical Physiology, Division of Neurophysiology, University of Copenhagen, The Panum Institute (H.S.), 2200 Copenhagen, Denmark; and Unité Mixte de Recherche 6175, Institut National de la Recherche Agronomique/Centre National de la Recherche Scientifique/Université de Tours/Haras Nationaux, Physiologie de la Reproduction et des Comportements (F.G.), 37380 Nouzilly, France

Address all correspondence and requests for reprints to: Dr. Myriam Baes, Laboratory of Clinical Chemistry, Campus Gasthuisberg, Onderwijs en Navorsing II bus 823, Herestraat 49, B-3000 Leuven, Belgium. E-mail: myriam.baes{at}pharm.kuleuven.be.

Inactivation of peroxisomal ß-oxidation in mice, by knocking out multifunctional protein-2 (MFP-2; also called D-bifunctional enzyme), causes male infertility. In the testis, extensive accumulations of neutral lipids were observed in Sertoli cells, beginning in prepubertal mice and evolving in complete testicular atrophy by the age of 4 months. Spermatogenesis was already severely affected at the age of 5 wk, and pre- and postmeiotic germ cells gradually disappeared from the tubuli seminiferi. Based on cytochemical stainings and biochemical analyses, the lipid droplets consisted of cholesteryl esters and neutral glycerolipids. Furthermore, peroxisomal ß-oxidation substrates, such as very-long-chain fatty acids and pristanic acid, accumulated in the testis, whereas the concentration of docosapentaenoic acid, a polyunsaturated fatty acid and peroxisomal ß-oxidation product, was reduced. The testicular defects were also present in double MFP-2/peroxisome proliferator-activated receptor- knockout mice, ruling out the possibility that they were mediated through the activation of this nuclear receptor. Immunoreactivity for peroxisomal proteins, including MFP-2, was detected in Sertoli cells as well as in germ cells and Leydig cells. The pivotal role of peroxisomal metabolism in Sertoli cells was also demonstrated by generating mice with a Sertoli cell-selective elimination of peroxisomes through cell type-specific inactivation of the peroxin 5 gene. These mice also developed lipid inclusions and were infertile, and their testes fully degenerated by the age of 4 months. In conclusion, the present data demonstrate that peroxisomal ß-oxidation is essential for lipid homeostasis in the testis and for male fertility.

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