TY - JOUR
T1 - Cholesterol substrate pools and steroid hormone levels are normal in the face of mutational inactivation of NPC1 protein
AU - Xie, Chonglun
AU - Richardson, James A.
AU - Turley, Stephen D.
AU - Dietschy, John M.
PY - 2006/5
Y1 - 2006/5
N2 - 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 (∼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.
AB - 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 (∼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.
KW - Adrenal gland
KW - Corticosterone
KW - Lipoprotein receptors
KW - Niemann Pick type C 1
KW - Ovary
KW - Progesterone
KW - Testis
KW - Testosterone
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U2 - 10.1194/jlr.M500534-JLR200
DO - 10.1194/jlr.M500534-JLR200
M3 - Article
C2 - 16461760
AN - SCOPUS:33646787783
SN - 0022-2275
VL - 47
SP - 953
EP - 963
JO - Journal of lipid research
JF - Journal of lipid research
IS - 5
ER -