Submitted on November 28, 2007
Revised on January 18, 2008
Accepted on February 12, 2008
The Niemann-Pick C1 gene is downregulated by feedback inhibition of the SREBP pathway in human fibroblasts
William S. Garver, David Jelinek, Gordon A. Francis, and Bruce D. Murphy
Pediatrics, The University of Arizona, Arizona Health Science Center, Tucson, AZ 85724
Corresponding Author: 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 expression of the NPC1 gene and 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 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.
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