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

Abstract

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, W. S.,

Cholesterol supply and SREBPs modulate transcription of the Niemann-Pick C-1 gene in steroidogenic tissues

“…The ensemble of data we present here demonstrates that intracellular cholesterol and the SREPB transcriptional pathway modulate, at least in part, the expression of NPC-1 in steroidogenic cells. This view, along with results indicating the SREBP regulation of NPC-1 expression in human fibroblasts (16), contrast with the constitutive expression scenario.…”

“…From subsequent measurement of NPC-1 mRNA and protein in this experimental paradigm, it was concluded that cholesterol entering cells via the coated-pit, endosomal pathway does not regulate NPC-1 expression (15). In contrast, a more recent investigation using human fibroblasts demonstrated that LDL cholesterol does, in fact, downregulate NPC-1 expression via SREBP (16). We undertook parallel experimentation in the porcine model to examine this question.…”

Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease

“…Downregulation of this pathway may induce the sequestration of cholesterol within late endosomes and lysosomes, 168 and the transcriptional activity of SREBF1 is enhanced in models of lysosomal storage disorders, leading to increased transcription of LDLR (low density lipoprotein receptor). 169 These findings suggest that SREBF1 has a role in mitophagy, as well as in regulation of lysosomal lipid accumulation, and more studies of its potential interactions with PARK2, PARK7, and PINK1 are necessary.…”

Cellular cholesterol substrate pools for adenosine-triphosphate cassette transporter A1-dependent high-density lipoprotein formation

“…Since the endoplasmic reticulum membrane cannot accommodate much cholesterol without inducing endoplasmic reticulum stress [59], late endosomes/lysosomes could serve as a holding pool for cholesterol between the plasma membrane and the endoplasmic reticulum for rapid transport to the endoplasmic reticulum for esterification by ACAT, or removal by ABCA1 in the process of HDL formation. Our recent observation of feedback inhibition by LDL of sterol regulatory element binding protein-regulated expression of NPC1 [60], which would result in reduced NPC1-mediated cholesterol egress out of late endosomes/lysosomes, is also consistent with this compartment being a storage pool to protect against cholesterol toxicity in the endoplasmic reticulum, as well as a substrate pool for ABCA1.…”