title: Cholesterol substrate pools and steroid hormone levels are normal in the face of mutational inactivation of NPC1 protein.
abstract: Mutational inactivation of NPC1 largely blocks the movement of LDL-derived cholesterol from the lysosome to the metabolically active, cytosolic pool of sterol that is the substrate for steroid hormone production. Such a block might, in theory, lead to deficiencies in circulating levels of testosterone, progesterone, and corticosterone. However, there are at least two other sources for cellular cholesterol, de novo synthesis and scavenger receptor class B type I-mediated uptake of HDL cholesteryl ester (CE). In this study, we measured the rates of net cholesterol acquisition by these three pathways in the adrenal, ovary, and testis. In all three organs, the majority (81-98%) of cholesterol acquisition came from the selective uptake of CE from HDL and de novo synthesis. Furthermore, in the npc1(-/-)mouse, the cytosolic storage pool of CE in a tissue such as the adrenal remained constant (approximately 25 mg/g). As a result of these alternative pathways, the plasma concentrations of testosterone (3.5 vs. 2.5 ng/ml), progesterone (8.5 vs. 6.7 ng/ml), and corticosterone (391 vs. 134 ng/ml) were either the same or elevated in the npc1(-/-)mouse, compared with the control animal. Thus, impairment of cholesterol acquisition through the NPC1-dependent, clathrin-coated pit pathway did not limit the availability of cholesterol substrate for steroid hormone synthesis in the steroidogenic cells.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical School, Dallas, 75390-8887, USA.
authors.forename: Chonglun
authors.initials: C
authors.lastname: Xie
authors.forename: James A
authors.initials: JA
authors.lastname: Richardson
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Turley
authors.forename: John M
authors.initials: JM
authors.lastname: Dietschy
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D002788:Cholesterol Esters / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism; D003345:Corticosterone / Q000097:blood*; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins; D008075:Lipoproteins, HDL / Q000378:metabolism; D008297:Male; D051379:Mice; D009154:Mutation; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000235:genetics*; D010053:Ovary / Q000378:metabolism; D011374:Progesterone / Q000097:blood*; D011506:Proteins / Q000235:genetics* / Q000502:physiology*; D011973:Receptors, LDL / Q000235:genetics / Q000502:physiology; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000502:physiology; D013737:Testis / Q000378:metabolism; D013739:Testosterone / Q000097:blood*
chemical_list: D002788:Cholesterol Esters; D008078:Cholesterol, LDL; C059714:HDL cholesteryl ester; D047908:Intracellular Signaling Peptides and Proteins; D008075:Lipoproteins, HDL; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D011973:Receptors, LDL; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D013739:Testosterone; D011374:Progesterone; D003345:Corticosterone