title: The role and regulation of the Niemann-Pick C1 gene in adrenal steroidogenesis.
abstract: The Niemann-Pick C-1 (NPC-1) gene codes for an intracellular membrane glycoprotein that processes low density lipoprotein (LDL)-imported cholesterol. Its absence is characterized by pathologic accumulation of cholesterol in endosomes and lysosomes. Niemann-Pick C-1 is involved in steroidogenesis in the adrenal, ovary, testis, and placenta. We investigated adrenal morphology of the BALB/c NPC-1(-/-) mutant mouse. Adrenals of mutant and wild type mice were similar at three weeks, but were substantially smaller in NPC-1(-/-) mice at eight weeks. The major histological difference was reduction in the thickness of the zona fasciculata, due to decreased cell volume. Lipid accumulation, revealed by Oil Red-O staining, was restricted to the zona fasciculata in wild type mice, but was found throughout the cortex in NPC-1 mutants. The 5'-flanking region of the mouse NPC-1 gene was cloned and sequenced. Comparison of the proximal promoter region revealed a CpG island and two consensus sequences for the cAMP response element (CRE). The role of the PKA pathway in transactivation of the NPC-1 promoter was probed by transient transfection of a 2.2 kb fragment of the 5'-flanking region fused to the luciferase reporter into mouse adrenal Y-1 and Leydig tumor cells and into nonsteroidogenic monkey kidney CV-1 cells. This promoter fragment displayed significant constitutive transcription, which was enhanced 3-5 fold in steroidogenic cells by treatment with 1 mM cAMP. The cAMP response was muted in CV-1 cells. We conclude that the NPC-1 gene is regulated by cAMP. It plays a role in normal cholesterol homeostasis and is essential for normal adrenal development and function.
authors.affiliation: Centre de Recherche en Reproduction Animale, Faculté de Médecine Vétérinaire, Université de Montréal, St. Hyacinthe, QC, Canada J2S7C6.
authors.forename: Nicolas Y
authors.initials: NY
authors.lastname: Gévry
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Murphy
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001483:Base Sequence / Q000235:genetics; D003994:Bucladesine / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D005786:Gene Expression Regulation; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology; D000077296:Niemann-Pick C1 Protein; D011401:Promoter Regions, Genetic / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D013256:Steroids / Q000096:biosynthesis*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D013256:Steroids; D003994:Bucladesine; D000242:Cyclic AMP