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

We tested whether sterol-regulatory element binding proteins (SREBPs) mediate sterol-regulated transactivation of the Niemann-Pick C-1 (NPC-1) gene. Loading granulosa cells with 22- or 25-hydroxycholesterol decreased NPC-1 mRNA, whereas culturing in cholesterol-depleted medium or inhibition of cholesterol biosynthesis increased NPC-1 promoter activity and NPC-1 mRNA abundance. Cotransfection of SREBP1a, SREBP1c, and SREBP2 and the NPC-1 promoter-luciferase reporter into granulosa cell lines increased the transcriptional activity of porcine, human, and mouse NPC-1 promoters. Deletion analysis of the 5′ flanking region of the pig NPC-1 gene demonstrated significant promoter activity between fragments −934 and −636 bp upstream from the transcription initiation site. Sequence analysis revealed three sterol-regulatory elements (SREs) clustered between −558 and −650 bp. Each site, along with E-box sequences, bound recombinant SREBP in electromobility shift assays. Mutation of all three sites attenuated the SREBP induction of promoter activity. Chromatin immunoprecipitation (ChIP) assays revealed that cholesterol depletion enriched the association of both SREBP and acetylated histone H3 with the NPC-1 promoter fragment containing the three SREs. ChIP analysis confirmed that SREBP's association with SRE and the E-box was enriched in cells cultured in cholesterol-depleted medium. We conclude that NPC-1 is sterol-regulated, achieved by SREBP acting via SRE and the E-box sequences. We tested whether sterol-regulatory element binding proteins (SREBPs) mediate sterol-regulated transactivation of the Niemann-Pick C-1 (NPC-1) gene. Loading granulosa cells with 22- or 25-hydroxycholesterol decreased NPC-1 mRNA, whereas culturing in cholesterol-depleted medium or inhibition of cholesterol biosynthesis increased NPC-1 promoter activity and NPC-1 mRNA abundance. Cotransfection of SREBP1a, SREBP1c, and SREBP2 and the NPC-1 promoter-luciferase reporter into granulosa cell lines increased the transcriptional activity of porcine, human, and mouse NPC-1 promoters. Deletion analysis of the 5′ flanking region of the pig NPC-1 gene demonstrated significant promoter activity between fragments −934 and −636 bp upstream from the transcription initiation site. Sequence analysis revealed three sterol-regulatory elements (SREs) clustered between −558 and −650 bp. Each site, along with E-box sequences, bound recombinant SREBP in electromobility shift assays. Mutation of all three sites attenuated the SREBP induction of promoter activity. Chromatin immunoprecipitation (ChIP) assays revealed that cholesterol depletion enriched the association of both SREBP and acetylated histone H3 with the NPC-1 promoter fragment containing the three SREs. ChIP analysis confirmed that SREBP's association with SRE and the E-box was enriched in cells cultured in cholesterol-depleted medium. We conclude that NPC-1 is sterol-regulated, achieved by SREBP acting via SRE and the E-box sequences. Intracellular cholesterol is regulated by a negative feedback mechanism that senses sterol concentrations and modifies transcription and, by consequence, the expression of a diverse array of proteins that synthesize, import, and transport cholesterol (1.Goldstein J.L. DeBose-Boyd R.A. Brown M.S. Protein sensors for membrane sterols.Cell. 2006; 124: 35-46Abstract Full Text Full Text PDF PubMed Scopus (1188) Google Scholar, 2.Brown M.S. Goldstein J.L. Sterol regulatory element binding proteins (SREBPs): controllers of lipid synthesis and cellular uptake.Nutr. Rev. 1998; 56 (discussion 54–75).: 1-3PubMed Google Scholar). The key elements in this transcriptional regulation are the sterol-regulatory element binding proteins (SREBPs), members of a family of three membrane-bound transcription factors (3.Horton J.D. Goldstein J.L. Brown M.S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver.J. Clin. Invest. 2002; 109: 1125-1131Crossref PubMed Scopus (3632) Google Scholar). The SREBP1a and -1c isoforms result from alternate splicing of a single gene, whereas SREBP2, which bears 47% homology to SREBP1a, is derived from a second gene (3.Horton J.D. Goldstein J.L. Brown M.S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver.J. Clin. Invest. 2002; 109: 1125-1131Crossref PubMed Scopus (3632) Google Scholar). The SREBP cleavage-activating protein (SCAP), which contains a sterol-sensing domain, is the proximate regulator of SREBP-modulated transcription (1.Goldstein J.L. DeBose-Boyd R.A. Brown M.S. Protein sensors for membrane sterols.Cell. 2006; 124: 35-46Abstract Full Text Full Text PDF PubMed Scopus (1188) Google Scholar). At low intracellular sterol concentrations, SCAP translocates the inactive, membrane-bound form of SREBP to the Golgi, where two distinct proteolytic cleavage steps convert it to its nuclear and transcriptionally active form (4.Rawson R.B. The SREBP pathway—insights from Insigs and insects.Nat. Rev. Mol. Cell Biol. 2003; 4: 631-640Crossref PubMed Scopus (249) Google Scholar). Cholesterol is believed to act directly on SCAP via its sterol-sensitive domain, inducing conformational changes that interdict its translocation function (5.Adams C.M. Reitz J. De Brabander J.K. Feramisco J.D. Li L. Brown M.S. Goldstein J.L. Cholesterol and 25-hydroxycholesterol inhibit activation of SREBPs by different mechanisms, both involving SCAP and Insigs.J. Biol. Chem. 2004; 279: 52772-52780Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar). After activation, the SREBPs translocated to the nucleus dimerize and interact with cognate regulatory sequences, the sterol-regulatory elements (SREs), to transactivate genes (3.Horton J.D. Goldstein J.L. Brown M.S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver.J. Clin. Invest. 2002; 109: 1125-1131Crossref PubMed Scopus (3632) Google Scholar) in concert with coactivators (6.Toth J.I. Datta S. Athanikar J.N. Freedman L.P. Osborne T.F. Selective coactivator interactions in gene activation by SREBP-1a and -1c.Mol. Cell. Biol. 2004; 24: 8288-8300Crossref PubMed Scopus (88) Google Scholar). The Niemann-Pick C-1 (NPC-1) gene codes for a protein in the network of intracellular cholesterol homeostasis (7.Pentchev P.G. Niemann-Pick C research from mouse to gene.Biochim. Biophys. Acta. 2004; 1685: 3-7Crossref PubMed Scopus (69) Google Scholar). It is a late endosomal protein and is required for the delivery of low density lipoprotein-derived cholesterol to the endoplasmic reticulum (8.Ory D.S. The Niemann-Pick disease genes: regulators of cellular cholesterol homeostasis.Trends Cardiovasc. Med. 2004; 14: 66-72Crossref PubMed Scopus (66) Google Scholar). Humans and mice bearing spontaneous inactivating mutations of this gene have nearly ubiquitous pathological and fatal intracellular cholesterol accumulation (8.Ory D.S. The Niemann-Pick disease genes: regulators of cellular cholesterol homeostasis.Trends Cardiovasc. Med. 2004; 14: 66-72Crossref PubMed Scopus (66) Google Scholar). The NPC-1 protein has a sterol-sensing domain that mediates sterol binding (9.Chang T.Y. Reid P.C. Sugii S. Ohgami N. Cruz J.C. Chang C.C. Niemann-Pick type C disease and intracellular cholesterol trafficking.J. Biol. Chem. 2005; 280: 20917-20920Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar), and point mutation studies have shown that this domain is required for the transport of cholesterol imported by means of the LDL pathway (10.Millard E.E. Gale S.E. Dudley N. Zhang J. Schaffer J.E. Ory D.S. The sterol-sensing domain of the Niemann-Pick C1 (NPC1) protein regulates trafficking of low-density lipoprotein cholesterol.J. Biol. Chem. 2005; 280: 28581-28590Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar). Early studies of the sequence of the human NPC-1 gene suggested that that it was constitutively expressed rather than under active transcriptional regulation (11.Morris J.A. Zhang D. Coleman K.G. Nagle J. Pentchev P.G. Carstea E.D. The genomic organization and polymorphism analysis of the human Niemann- Pick C1 gene.Biochem. Biophys. Res. Commun. 1999; 261: 493-498Crossref PubMed Scopus (58) Google Scholar). By deletion analysis of the 5′-flanking region of the porcine promoter, it was shown that there is a requirement for a segment of 1.2 upstream of the initiation for transcriptional expression of Niemann-Pick C1 gene expression by the pathway in 2003; PubMed Scopus Google Scholar). The in NPC-1 expression in that N. D. N. Niemann-Pick C1 protein is expressed in and by 2002; PubMed Scopus Google Scholar) shown to result from transcription by the protein pathway of Niemann-Pick C1 gene expression by the pathway in 2003; PubMed Scopus Google Scholar), rather than The for NPC-1 in cholesterol trafficking and homeostasis with genes that intracellular cholesterol its expression the transcription of a membrane the Niemann-Pick protein was shown to regulated by intracellular cholesterol via a SREBP S. of human Niemann-Pick gene expression by of sterol regulatory element binding protein J. PubMed Scopus Google Scholar). a mouse cholesterol was by mice or by cholesterol by Niemann-Pick C1 (NPC1) expression is regulated by the of cholesterol cells in the Res. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). of NPC-1 mRNA and protein in this it was that cholesterol cells via the endosomal pathway NPC-1 expression Niemann-Pick C1 (NPC1) expression is regulated by the of cholesterol cells in the Res. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). a human demonstrated that LDL cholesterol in NPC-1 expression via SREBP D. and D. The Niemann-Pick C1 gene is by feedback inhibition of the SREBP pathway in human J. Res. Scholar). We in the porcine to this in porcine granulosa cells in cholesterol depletion the expression of NPC-1 and this is by with in the mouse Niemann-Pick C1 (NPC1) expression is regulated by the of cholesterol cells in the Res. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar) with in human that the promoter of the human, and mouse and that SREBP with SREBP of the porcine NPC-1 promoter bearing SREs. both depletion of cholesterol in the cellular medium and of SREBP the activity of the NPC-1 SRE recombinant and SREBP induction of transcriptional activity. and that NPC-1 is regulated by intracellular cholesterol in was the 5′ flanking region of the porcine of Niemann-Pick C1 gene expression by the pathway in 2003; PubMed Scopus Google Scholar), mouse The and regulation of the Niemann-Pick C1 gene in Res. 2002; PubMed Scopus Google Scholar), and human (11.Morris J.A. Zhang D. Coleman K.G. Nagle J. Pentchev P.G. Carstea E.D. The genomic organization and polymorphism analysis of the human Niemann- Pick C1 gene.Biochem. Biophys. Res. Commun. 1999; 261: 493-498Crossref PubMed Scopus (58) Google Scholar) NPC-1 gene promoter by the sequence analysis with transcription binding analysis with homology to the SRE three The NPC-1 gene promoter was into and deletion by with and for SREBP sites and E-box with the for SREBP1a, and in L. J. of gene expression by is by a sterol regulatory element and is of the of Mol. Biol. PubMed Scopus Google Scholar). the of the porcine, human, and mouse of the human and of the mouse 5′ flanking upstream from the transcription sites into the of porcine granulosa cells N. of regulatory protein and in the pig 1999; PubMed Scopus Google Scholar) and cultured for in containing and for a in The porcine granulosa cell J.D. of a porcine granulosa cell PubMed Scopus Google Scholar) was cultured in with the and mouse cells in with and human granulosa cells from of cultured in with and cells from the cultured in with cells in medium with and with of the deletion of the pig NPC-1 promoter in the to the with the a of to for The with the of of the nuclear transcriptionally of SREBP L. J. of gene expression by is by a sterol regulatory element and is of the of Mol. Biol. PubMed Scopus Google Scholar) or expression for the of with for of Niemann-Pick C1 gene expression by the pathway in 2003; PubMed Scopus Google Scholar). activity was by the and was in a the of of the with the a of in with in the of in to which was and Cell lines and medium was with depletion medium containing in of along with the concentrations of and cells with medium of the depletion medium with or of cells with medium the depletion medium or medium to which or The shift assays of Niemann-Pick C1 gene expression by the pathway in 2003; PubMed Scopus Google Scholar) with to the NPC-1 promoter region with by SREBP was with of in binding and for The binding on a in of of a demonstrated SRE SRE from the lipoprotein promoter L. J. of gene expression by is by a sterol regulatory element and is of the of Mol. Biol. PubMed Scopus Google Scholar), was a was a the SRE to that SREBP binding to the by of in electromobility shift in a was from cholesterol-depleted or and cells with analysis of was N. D. N. Niemann-Pick C1 protein is expressed in and by 2002; PubMed Scopus Google Scholar). cultured cells in and and was with of of to on a acid to and for in with a from the 5′ region of the porcine NPC-1 by to for and of the NPC-1 Chromatin immunoprecipitation (ChIP) assays the of and and immunoprecipitation for in a 1999; PubMed Scopus Google Scholar) with and cell proteins in granulosa cell by the of to a of for and in containing and by for and in of ChIP and by for on and The was in ChIP 1.2 and of of was for the of Each was by with of for to was into two and was with of and with in this the and form of histone H3 and Cruz was with with of for with and with the in and and and and and was achieved by of and The was by for by was by with the the with a fragment from the promoter region of NPC-1 was by in and a negative derived from the region of the porcine NPC-1 on and by means of the second granulosa cells and to to the SRE and of the and to was to the in the The for in both are in in NPC-1 immunoprecipitation and region region region region region region sterol-regulatory in a sterol-regulatory lines of that the expression of the NPC-1 gene in is regulated by the concentrations of intracellular in analysis from the revealed a in porcine NPC-1 mRNA in of porcine granulosa cells with of or We a for the of NPC-1 N. D. N. Niemann-Pick C1 protein is expressed in and by 2002; PubMed Scopus Google Scholar). the of cholesterol in the regulation of NPC-1 granulosa cells for in cholesterol-depleted medium with the to cholesterol depletion of intracellular cholesterol in in the of NPC-1 mRNA of cholesterol by the of or the in NPC-1 mRNA in to cholesterol depletion We to whether there was a transcriptional to this by from the porcine granulosa cultured in a medium or in cholesterol-depleted medium with the fragment of the porcine NPC-1 promoter to the cultured in the medium a in promoter activity to cells in with cholesterol the The in transcriptional activity in to in cholesterol-depleted medium was by the of or to the medium SREBP isoforms are factors that the transcription of proteins in cholesterol homeostasis (3.Horton J.D. Goldstein J.L. Brown M.S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver.J. Clin. Invest. 2002; 109: 1125-1131Crossref PubMed Scopus (3632) Google Scholar, J. J.D. Goldstein J.L. Brown M.S. to and in mice with of sterol regulatory Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). the of SREBP in NPC-1 the of the of SREBP isoforms on the transcriptional activity of a fragment of the NPC-1 promoter the upstream of the transcription initiation site. SREBP1a, SREBP1c, and SREBP2 all to in promoter activity in the pig granulosa cell the of the porcine granulosa cell with the along with with SREBP1a the reporter to SREBP1a We the of the SREBP by of SREBP1a along with the NPC-1 into two cell the human granulosa and the mouse cell The human cell which is was lines with significant in promoter for the the in cells We to whether the was to of the NPC-1 by of fragments of the human, and pig into cells and the human The that the reporter derived from the 5′-flanking of all three genes significant in transcriptional activity with SREBP1a to the in the of transcriptional that the porcine NPC-1 promoter reporter activity in to SREBP in and cell sterol-regulatory element binding The promoter was with a SREBP1a and for induction the and are means of three in a activity of three is by of the SREBP1a promoter in two cell and the human to the and are means of three in a sterol-regulatory element binding The promoter was with a SREBP1a and for induction the and are means of three to the and are means of three The of the human, and mouse NPC-1 to in analysis to the with to interact with SREBP transcription from three bearing homology with the SRE in the upstream of the in the pig promoter, three in the human 5′ flanking region of and two in the Deletion fragments to the of the porcine promoter with the to expression of SREBP by the The promoter sequence required for both the and promoter activity was bp. The or with promoter from to 1.2 and the SREBP the promoter was derived from fragments of to 1.2 of the revealed a significant in promoter activity between fragments bp and −636 bp that the in this region in the regulation of this gene. The three and to to to to recombinant human that all three along with the E-box with the transcription a the containing two of the three SRE sites and demonstrated that SREBP binding to the recombinant and mutation with NPC-1 shift the binding of recombinant SREBP to the three in the region of SREBP by deletion The for binding was confirmed in the lipoprotein SREBP was with the SRE binding region in the or of The the of the on the of the mutation of SRE and E-box sites on the of the porcine NPC-1 promoter-luciferase to SREBP1a in of the required mutation of all three sites and the We with of the SRE the or all three sites and the E-box into cells with of the mutations the transcriptional activity. Mutation of the the whereas mutation of the Mutation of the and and sites or the E-box both the in promoter activity. to of activity in the of SREBP was achieved by mutation of all three SRE sites along with the E-box ChIP assays to the between cholesterol of cells and SREBP in NPC-1 transcription and to the of the promoter to cells in the cholesterol-depleted and bound to SREBP of nuclear was by derived from the region that the three SRE sites on the NPC-1 The increased association of the promoter with SREBP in cells of cholesterol of a sequence of from the region of the NPC-1 gene that the was to the promoter It was shown that SREBP activation of two sterol-sensitive the LDL and a in histone H3 Osborne T.F. regulation of gene expression by the sterol regulatory element binding increased of factors and of histone H3 in PubMed Scopus Google Scholar). the of a regulation of NPC-1 of porcine granulosa cells cultured in or medium with to H3 acetylated on and of the region of the NPC-1 promoter revealed a in the association of the promoter with acetylated H3 in cells We porcine cells in under of or cholesterol to the of the SRE sites and the E-box in the porcine NPC-1 ChIP analysis SREBP for immunoprecipitation and of of the promoter demonstrated that both the containing the E-box and the SRE sites by the SREBP whereas the or to sites was to of the of the E-box and the of SRE in cells in cholesterol-depleted medium to the in cells in that this the association of the transcription with both of of a mouse bearing spontaneous mutation of the NPC-1 gene have demonstrated its in the trafficking of cholesterol in S. intracellular cholesterol transport gene and 2004; PubMed Scopus Google Scholar). The of the protein in the of cholesterol in late endosomal and the of the of cholesterol and its into (8.Ory D.S. The Niemann-Pick disease genes: regulators of cellular cholesterol homeostasis.Trends Cardiovasc. Med. 2004; 14: 66-72Crossref PubMed Scopus (66) Google Scholar). of of the elements of cholesterol its and are by cholesterol via the SREBP transcriptional mechanism L. protein in a of SREBP in cholesterol Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar, J.L. Intracellular cholesterol Biol. 2004; 24: PubMed Scopus Google Scholar). It is to that NPC-1 is regulated by the of the of the human NPC-1 promoter (11.Morris J.A. Zhang D. Coleman K.G. Nagle J. Pentchev P.G. Carstea E.D. The genomic organization and polymorphism analysis of the human Niemann- Pick C1 gene.Biochem. Biophys. Res. Commun. 1999; 261: 493-498Crossref PubMed Scopus (58) Google Scholar, S. Pentchev P.G. of expression and key promoter and the of a Cell Res. PubMed Scopus Google Scholar) suggested that the gene is constitutively in a of cholesterol in in in which mice a it was that NPC-1 expression is of cholesterol and Niemann-Pick C1 (NPC1) expression is regulated by the of cholesterol cells in the Res. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). The of that intracellular cholesterol and the transcriptional pathway in the expression of NPC-1 in along with the SREBP regulation of NPC-1 expression in human D. and D. The Niemann-Pick C1 gene is by feedback inhibition of the SREBP pathway in human J. Res. Scholar), with the expression analysis of of the NPC-1 gene L. sequence a of and Res. 2003; PubMed Scopus Google Scholar) the for SREBP of the 5′-flanking region of the NPC-1 gene between three of revealed SRE and E-box sequences, both of to the of SRE in the pig promoter between and upstream of the initiation was in the analysis recombinant SREBP and ChIP assays demonstrated that the of the porcine promoter that the E-box and the three regulatory SRE sites by SREBP that elements are in the NPC-1 The 5′-flanking human gene that has shown to regulated by the of contains two SRE sites S. of human Niemann-Pick gene expression by of sterol regulatory element binding protein J. PubMed Scopus Google Scholar). have shown to in the porcine promoter a gene to regulated by cholesterol via SREBP N. J.D. of and SREBP-1a in transcriptional activation of the LDL gene by and in cultured porcine J. 2004; PubMed Scopus Google Scholar). Cotransfection of a all three isoforms of SREBP of SREBP regulation of the porcine NPC-1 gene. Each increased the activation of NPC-1 sequence by in the porcine granulosa cell the of the promoter to to analysis of and human demonstrated activity in two cell lines in to with the transcriptionally active form of form of SREBP significant in transcriptional activity of the pig NPC-1 in diverse cell The in SREBP with analysis of the human NPC-1 promoter that transcriptional activity is S. Pentchev P.G. of expression and key promoter and the of a Cell Res. PubMed Scopus Google Scholar). It has shown that the nuclear form of SREBP has a in cells and that its attenuated by both Brown M.S. Goldstein J.L. a membrane-bound transcription by sterol-regulated Full Text PDF PubMed Scopus Google Scholar) and of in is regulated by and Biophys. Res. Commun. 2005; PubMed Scopus Google Scholar). is of the of the transcriptionally active form of SREBP Brown M.S. Goldstein J.L. a membrane-bound transcription by sterol-regulated Full Text PDF PubMed Scopus Google Scholar). that with the to by the of the for a of this transcription in NPC-1 SRE elements SREBP induction of promoter activity in sterol-sensitive lipoprotein L. J. of gene expression by is by a sterol regulatory element and is of the of Mol. Biol. PubMed Scopus Google Scholar) and the LDL N. J.D. of and SREBP-1a in transcriptional activation of the LDL gene by and in cultured porcine J. 2004; PubMed Scopus Google Scholar). to the SRE sites of the NPC-1 promoter, activity of or two of It is that the SRE was the sequence that is between the human and pig and that the binding to recombinant SREBP in the of the three SRE sites and the E-box SREBP induction of NPC-1 transcriptional activity. It has that SREBP with E-box Brown M.S. Goldstein J.L. protein that sterol regulatory element of low density lipoprotein of the protein and of its Biol. Chem. Full Text PDF PubMed Google Scholar), and there is for a of SRE and E-box in the L. J. of gene expression by is by a sterol regulatory element and is of the of Mol. Biol. PubMed Scopus Google Scholar) and negative L. protein in a of SREBP in cholesterol Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar) regulation of and SREBP-modulated We conclude that a of SRE and E-box regulates NPC-1 gene for the sterol regulation of the NPC-1 gene from cholesterol of granulosa cells in cholesterol-depleted medium in a significant in NPC-1 whereas sterol in and in the expression of this gene. result was in of the of the NPC-1 5′-flanking region to the in that cholesterol depletion in a in promoter attenuated by the of the ChIP demonstrated increased association of SREBP with the NPC-1 promoter, with the E-box and SRE in granulosa cells cultured in cholesterol-depleted to medium. NPC-1 in the with a of sterol-regulated Osborne T.F. regulation of gene expression by the sterol regulatory element binding increased of factors and of histone H3 in PubMed Scopus Google Scholar), the LDL M.S. Goldstein J.L. Sterol regulatory element binding proteins (SREBPs): controllers of lipid synthesis and cellular uptake.Nutr. Rev. 1998; 56 (discussion 54–75).: 1-3PubMed Google Scholar), and lipoprotein L. J. of gene expression by is by a sterol regulatory element and is of the of Mol. Biol. PubMed Scopus Google Scholar). The that cholesterol the pathway NPC-1 expression N. D. N. Niemann-Pick C1 protein is expressed in and by 2002; PubMed Scopus Google Scholar) was on a different the mouse to of the J.D. Goldstein J.L. Brown M.S. Cholesterol nuclear of sterol regulatory element binding proteins in PubMed Scopus Google Scholar) and mouse J.D. of sterol regulatory element binding proteins in of and 1998; PubMed Scopus Google Scholar) this the of the nuclear form of the are to The that cells that cholesterol for whereas studies Niemann-Pick C1 (NPC1) expression is regulated by the of cholesterol cells in the Res. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar) on the the We and transcriptional activation of NPC-1 by the nuclear form of SREBP in and The to the nuclear form of SREBP was in the human cell that NPC-1 regulated in a We that NPC-1 is rather that constitutively regulated The and regulation of the Niemann-Pick C1 gene in Res. 2002; PubMed Scopus Google Scholar, N. and D. The of sterol regulatory proteins in the transactivation of promoter the Scholar). is for regulation of transcription of cholesterol trafficking the LDL that is and to SREBP J.A. mechanisms, of sterol regulatory element binding low density lipoprotein gene Res. Full Text Full Text PDF PubMed Google Scholar). the mechanism of cell SREBPs are believed to activators of and on to expression of The interactions are with the transcription mutation of of the three sites flanking the SRE in the porcine LDL promoter the to N. J.D. of and SREBP-1a in transcriptional activation of the LDL gene by and in cultured porcine J. 2004; PubMed Scopus Google Scholar). of the pig revealed two sites on the upstream of and a element bp to the sites the for with and of the to the of of and LDL transcription in the cholesterol depletion demonstrated that SREBP activation was by increased association of both with acetylated histone H3 Osborne T.F. regulation of gene expression by the sterol regulatory element binding increased of factors and of histone H3 in PubMed Scopus Google Scholar). the the association of the NPC-1 promoter with acetylated H3 was in cells of the of regulation of the NPC-1 gene. the regulation of NPC-1 a of in a of cell We conclude that this gene is constitutively it is by cholesterol via the intracellular cholesterol feedback pathway by means of was by to from the of was the of a from the and of The and for

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