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Journal of Lipid Research, Vol. 49, 1090-1102, May 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

The Niemann-Pick C1 gene is downregulated by feedback inhibition of the SREBP pathway in human fibroblasts^*

William S. Garver^1,*, David Jelinek^*, Gordon A. Francis and Bruce D. Murphy

^* Department of Pediatrics, University of Arizona, Tucson, AZ 85724-5037
Department of Medicine, James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, University of British Columbia, Vancouver, British Columbia, Canada V6Z 1Y6
Centre de Recherche en Reproduction Animale, Faculté de Médecine Vétérinaire, Université de Montréal, St. Hyacinthe, Québec, Canada J2S 7C6

^* This work was supported in part by National Institutes of Health Grant R21 DK-071544, an investigator award from the Ara Parseghian Medical Research Foundation, a grant from the Father's Day Council of Tucson, and other private donations (to W.S.G.), by Canadian Institutes of Health Research Grant MOP-79532 (to G.A.F.), and by Canadian Institutes of Health Research Grant MOP-117373 (to B.D.M.).

Published, JLR Papers in Press, February 13, 2008.

¹ To whom correspondence should be addressed. e-mail: wgarver{at}peds.arizona.edu

The Niemann-Pick C1 (NPC1) protein regulates the transport of cholesterol from late endosomes/lysosomes to other compartments responsible for maintaining intracellular cholesterol homeostasis. The present study examined the expression of the NPC1 gene and the distribution of the NPC1 protein that resulted from the transport of LDL-derived cholesterol through normal human fibroblasts. A key finding was that the transport of cholesterol from late endosomes/lysosomes to the sterol-regulatory pool at the endoplasmic reticulum, as determined by feedback inhibition of the sterol-regulatory element binding protein (SREBP) pathway, was associated with the downregulation of the NPC1 gene. Consistent with these results, fibroblasts incubated with LDL had decreased amounts of SREBP protein that interacted with sterol-regulatory element (SRE) sequences positioned within the NPC1 gene promoter region. Finally, partial colocalization of the NPC1 protein with late endosomes/lysosomes and distinct regions of the endoplasmic reticulum suggested that the NPC1 protein may facilitate the transport of cholesterol directly between these two compartments. Together, these results indicate that the transport of LDL-derived cholesterol from late endosomes/lysosomes to the sterol-regulatory pool, known to be regulated by the NPC1 protein, is responsible for promoting feedback inhibition of the SREBP pathway and downregulation of the NPC1 gene.

Supplementary key words cholesterol homeostasis • coated-pit pathway • late endosomes/lysosomes • low density lipoprotein-derived cholesterol • sterol-regulatory element binding protein

Abbreviations: ChIP, chromatin immunoprecipitation; CREB, cAMP response element binding protein; FAFA, fatty acid-free albumin; FCS, fetal calf serum; INSIG, insulin-induced gene; LAMP-1, lysosome-associated membrane protein-1; LPDS, lipoprotein-deficient serum; NPC1, Niemann-Pick C1; PDI, protein disulfide isomerase; P/S, penicillin/streptomycin; SCAP, SREBP-cleavage-activating protein; SRE, sterol-regulatory element; SREBP, sterol-regulatory element binding protein

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