Peroxisomal multifunctional protein 2 is essential for lipid homeostasis in Sertoli cells and male fertility in mice.
Inactivation of peroxisomal beta-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 beta-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 beta-oxidation product, was reduced. The testicular defects were also present in double MFP-2/peroxisome proliferator-activated receptor-alpha 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 beta-oxidation is essential for lipid homeostasis in the testis and for male fertility.
Laboratory of Clinical Chemistry, Faculty of Pharmacy, Katholieke Universiteit, Leuven, Belgium.
Steven
S
Huyghe
Henning
H
Schmalbruch
Karel
K
De Gendt
Guido
G
Verhoeven
Florian
F
Guillou
Paul P
PP
Van Veldhoven
Myriam
M
Baes
D015067:17-Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D000818:Animals; D002788:Cholesterol Esters / Q000737:chemistry; D004746:Enoyl-CoA Hydratase / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D005298:Fertility; D006579:Heterozygote; D006706:Homeostasis; D006720:Homozygote; D007150:Immunohistochemistry; D007248:Infertility, Male; D007985:Leydig Cells; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics; D064029:Peroxisomal Multifunctional Protein-2; D020675:Peroxisomes / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012671:Seminiferous Tubules / Q000378:metabolism; D012708:Sertoli Cells / Q000378:metabolism*; D013737:Testis / Q000378:metabolism
D002788:Cholesterol Esters; D005227:Fatty Acids; D005231:Fatty Acids, Unsaturated; D008055:Lipids; D009097:Multienzyme Complexes; D047493:PPAR alpha; C002844:pristanic acid; D012313:RNA; D015067:17-Hydroxysteroid Dehydrogenases; C491288:Hsd17b4 protein, mouse; C491286:Hsd17b4 protein, rat; D064029:Peroxisomal Multifunctional Protein-2; D004746:Enoyl-CoA Hydratase; C026219:docosapentaenoic acid; D010100:Oxygen