The Niemann-Pick C1 gene is downregulated by feedback inhibition of the SREBP pathway in human fibroblasts.
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.
Garver
William S
WS
Department of Pediatrics, University of Arizona, Tucson, AZ 85724-5037, USA. wgarver@peds.arizona.edu
Jelinek
David
D
Francis
Gordon A
GA
Murphy
Bruce D
BD
D002352:Carrier Proteins / Q000235:genetics*; D018929:Cell Culture Techniques; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism; D017931:DNA Primers; D011992:Endosomes / Q000378:metabolism; D005246:Feedback; D005347:Fibroblasts / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008247:Lysosomes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics*; D000077296:Niemann-Pick C1 Protein; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics
D002352:Carrier Proteins; D002788:Cholesterol Esters; D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D012333:RNA, Messenger; C497387:SREBF1 protein, human; C497390:SREBF2 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol