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Journal of Lipid Research, Vol. 47, 953-963, May 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Cholesterol substrate pools and steroid hormone levels are normal in the face of mutational inactivation of NPC1 protein

Chonglun Xie^*, James A. Richardson, Stephen D. Turley^* and John M. Dietschy^*,1

^* Department of Internal Medicine, University of Texas Southwestern Medical School, Dallas, TX 75390-8887
Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX 75390-8887

Published, JLR Papers in Press, February 3, 2006.

¹ To whom correspondence should be addressed. e-mail: john.dietschy{at}utsouthwestern.edu

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.

Supplementary key words adrenal gland • ovary • testis • lipoprotein receptors • corticosterone • testosterone • progesterone • Niemann Pick type C 1

Abbreviations: apolipoprotein B₁₀₀, apoB₁₀₀; CE, cholesteryl ester; LDLR, LDL receptor; NPC, Niemann-Pick disease type C; NPCIL1, Niemann-Pick type C1 Like 1; NPC1, Niemann-Pick type C1; SR-BI, scavenger receptor class B type I; TC, total cholesterol

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