title: Dysregulation of testicular cholesterol metabolism following spontaneous mutation of the niemann-pick c1 gene in mice.
abstract: The Niemann-Pick-type C1 (Npc1) protein mobilizes LDL-derived cholesterol from lysosomes. Npc1 deficiency disease is a panethnic autosomal recessive disorder of intracellular cholesterol trafficking, leading to accumulation of cholesterol in endosomes/lysosomes. This report assesses the effects of a spontaneous inactivating mutation of the Npc1 gene on spermatogenesis and cholesterol homeostasis in mice. We quantified 1) free and esterified cholesterol levels by enzymatic analysis, 2) cholesterol enzymes and transporter protein expression by Western blotting, and 3) the number of Apostain-labeled apoptotic germ cells and apoptosis levels by ELISA in seminiferous tubule-enriched fractions. In wild-type (WT) mice, esterified cholesterol was elevated when Npc1 expression was low during puberty, while in adulthood, the levels were low (P < 0.05) when Npc1 expression was high (P < 0.01). In Npc1-/- mice, free and esterified cholesterol were significantly elevated. The abundance of cholesterol regulatory proteins, HMGR ACAT1, ACAT2, SR-BI, and ABCA1 was significantly higher in Npc1-/- than in WT mice. The level of apoptosis determined by ELISA and the number of Apostain-labeled cells/tubule were higher in Npc1-/- than in WT mice. Circulating testosterone levels in the Npc1-/- males were threefold lower than those observed in the WT. Deleting the Npc1 gene is accompanied by an increase in germ cell apoptosis and compensatory imbalances in the expression of cholesterol enzymatic and transporter factors and is associated with esterified cholesterol accumulation in seminiferous tubules.
authors.affiliation: Département de Pathologie et Biologie Cellulaire, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Casimir D
authors.initials: CD
authors.lastname: Akpovi
authors.affiliation: Centre de Recherche en Reproduction Animale, Faculté de Médecine Vétérinaire, Université de Montréal, St.-Hyacinthe, Québec, Canada.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Murphy
authors.affiliation: Department of Pediatrics, University of Arizona College of Medicine, Tucson, Arizona.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Erickson
authors.affiliation: Département de Pathologie et Biologie Cellulaire, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada marc.pelletier@umontreal.ca.
authors.forename: R-Marc
authors.initials: RM
authors.lastname: Pelletier
mesh_terms: D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D005854:Germ Cells / Q000166:cytology / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009154:Mutation; D000077296:Niemann-Pick C1 Protein; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D013091:Spermatogenesis / Q000502:physiology; D013737:Testis / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D013739:Testosterone / Q000097:blood; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D001786:Blood Glucose; D051242:Caveolin 1; D002784:Cholesterol; D053222:Fas Ligand Protein; D047908:Intracellular Signaling Peptides and Proteins; D051907:Lysosomal Membrane Proteins; D008565:Membrane Proteins; D000077296:Niemann-Pick C1 Protein; D011506:Proteins; D013739:Testosterone; D019014:fas Receptor; C491899:Fas protein, mouse; C052255:Lamp1 protein, mouse; D052118:Lysosomal-Associated Membrane Protein 1; C106831:Npc1 protein, mouse; C106354:flotillins
keywords: Niemann-Pic C1; Npc1 mutation; apoptosis; cholesterol metabolism