Sterol regulatory element-binding proteins (SREBP) signaling (WP1982)

Homo sapiens

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Sterol regulatory element-binding proteins (SREBPs) are membrane-bound proteins that act as transcription factors. They regulate lipid, especially cholesterol, biosynthesis and uptake at a transcriptional level to maintain cellular lipid homeostasis. In addition, SREBP appears to be involved in a variety of other cellular processes. This pathway of SREBP focuses on the regulation of lipid metabolism by SREBP. The data on which this pathway is based, is derived from a variety of in vitro and in vivo studies using different species, including mouse, rat, hamster and human. This pathway served as the basis for a review about SREBP that was published in Genes and Nutrition: [http://www.ncbi.nlm.nih.gov/pubmed/23516131 PubMed]. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP1982 CPTAC Assay Portal].

Authors

Sabine Daemen , Chris Evelo , Dan Bolser , Martina Summer-Kutmon , Daniela Digles , Zahra Roudbari , Marianthi Kalafati , Egon Willighagen , Kristina Hanspers , Friederike Ehrhart , and Eric Weitz

Activity

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Cited In

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Organisms

Homo sapiens

Communities

Annotations

Cell Type Ontology

hepatocyte

Pathway Ontology

sterol regulatory element-binding protein signaling pathway sterol regulatory element-binding protein signaling pathway cholesterol biosynthetic pathway fatty acid biosynthetic pathway

Disease Ontology

obsolete hypercholesterolemia

Participants
Query Drugst.One

Label Type Compact URI Comment
Glucose Metabolite hmdb:HMDB0000122
PUFAs Metabolite chebi:26208 Inhibition of SREBP1 processing
Cholesterol Metabolite hmdb:HMDB0000067
UFAs Metabolite chebi:26208
Glutamine Metabolite hmdb:HMDB0000641
Oxysterols Metabolite chebi:53030
PKA GeneProduct ensembl:ENSG00000072062
SCAP GeneProduct ensembl:ENSG00000114650
CDK8 GeneProduct ensembl:ENSG00000132964
PRKAA2 GeneProduct ensembl:ENSG00000162409
CAMP GeneProduct ensembl:ENSG00000164047
PRKAG2 GeneProduct ensembl:ENSG00000106617
AKT GeneProduct ensembl:ENSG00000142208
gp78 GeneProduct ensembl:ENSG00000159461
PRKAG3 GeneProduct ensembl:ENSG00000115592
importin beta GeneProduct ensembl:ENSG00000108424
SREBP2 GeneProduct ensembl:ENSG00000198911
PI3K GeneProduct ensembl:ENSG00000121879
INSIG1 GeneProduct ensembl:ENSG00000186480
LPIN1 GeneProduct ensembl:ENSG00000134324
LXR GeneProduct ensembl:ENSG00000131408
NFY GeneProduct ensembl:ENSG00000001167
PRKAB2 GeneProduct ensembl:ENSG00000131791
TRC8 GeneProduct ensembl:ENSG00000170881
nSREBP GeneProduct ensembl:ENSG00000072310
ATF6 GeneProduct ensembl:ENSG00000118217
PRKAA1 GeneProduct ensembl:ENSG00000132356
S1P GeneProduct ensembl:ENSG00000140943
FGF21 GeneProduct ensembl:ENSG00000105550
GSK3 GeneProduct ensembl:ENSG00000105723
PRKAB1 GeneProduct ensembl:ENSG00000111725
RBP4 GeneProduct ensembl:ENSG00000138207
PRKAG1 GeneProduct ensembl:ENSG00000181929
mTORC1 GeneProduct ensembl:ENSG00000198793
HMGCR GeneProduct ensembl:ENSG00000113161
SIRT1 GeneProduct ensembl:ENSG00000096717
SCAP GeneProduct ensembl:ENSG00000114650
SCAP GeneProduct ensembl:ENSG00000114650
INSIG2 GeneProduct ensembl:ENSG00000125629
INSIG1 GeneProduct ensembl:ENSG00000186480
INSIG2 GeneProduct ensembl:ENSG00000125629
SREBP1a,-c GeneProduct ensembl:ENSG00000072310
SREBP2 GeneProduct ensembl:ENSG00000198911
SREBP1a,-c GeneProduct ensembl:ENSG00000072310
SREBP2 GeneProduct ensembl:ENSG00000198911
SREBP1a,-c GeneProduct ensembl:ENSG00000072310
SAR1A GeneProduct ensembl:ENSG00000079332
SCAP GeneProduct ensembl:ENSG00000114650
SREBP2 GeneProduct ensembl:ENSG00000198911
SREBP1a,-c GeneProduct ensembl:ENSG00000072310
SAR1B GeneProduct ensembl:ENSG00000152700
SAR1A GeneProduct ensembl:ENSG00000079332
SAR1B GeneProduct ensembl:ENSG00000152700
SEC23A GeneProduct ensembl:ENSG00000100934
SEC23B GeneProduct ensembl:ENSG00000101310
SEC24A GeneProduct ensembl:ENSG00000113615
SEC24B GeneProduct ensembl:ENSG00000138802
SEC24C GeneProduct ensembl:ENSG00000176986
SEC24D GeneProduct ensembl:ENSG00000150961
SEC13 GeneProduct ensembl:ENSG00000157020
SEC31A GeneProduct ensembl:ENSG00000138674
SEC31B GeneProduct ensembl:ENSG00000075826
SEC13 GeneProduct ensembl:ENSG00000157020
SEC23A GeneProduct ensembl:ENSG00000100934
SEC23B GeneProduct ensembl:ENSG00000101310
SEC24A GeneProduct ensembl:ENSG00000113615
SEC24B GeneProduct ensembl:ENSG00000138802
SEC24C GeneProduct ensembl:ENSG00000176986
SEC24D GeneProduct ensembl:ENSG00000150961
SAR1A GeneProduct ensembl:ENSG00000079332
SCAP GeneProduct ensembl:ENSG00000114650
SREBF2 GeneProduct ensembl:ENSG00000198911
SREBP1a,-c GeneProduct ensembl:ENSG00000072310
SAR1B GeneProduct ensembl:ENSG00000152700
SEC31A GeneProduct ensembl:ENSG00000138674
SEC31B GeneProduct ensembl:ENSG00000075826
S2P GeneProduct ensembl:ENSG00000012174
SCAP GeneProduct ensembl:ENSG00000114650
SREBP2 GeneProduct ensembl:ENSG00000198911
SREBP1a,-c GeneProduct ensembl:ENSG00000072310
nSREBP1a,-c GeneProduct ensembl:ENSG00000072310
nSREBP2 GeneProduct ensembl:ENSG00000198911
CREB GeneProduct ensembl:ENSG00000118260
SP1 GeneProduct ensembl:ENSG00000185591
NFY GeneProduct ensembl:ENSG00000001167
CREB GeneProduct ensembl:ENSG00000118260
SP1 GeneProduct ensembl:ENSG00000185591
YY1 GeneProduct ensembl:ENSG00000100811
YY1 GeneProduct ensembl:ENSG00000100811
PGC-1beta GeneProduct ensembl:ENSG00000155846
ARC105 GeneProduct ensembl:ENSG00000099917 activator recruited cofactor (ARC)-mediator activator complex
ARC105 GeneProduct ensembl:ENSG00000099917 activator recruited cofactor (ARC)-mediator activator complex
LSS GeneProduct ensembl:ENSG00000160285
HMGCS GeneProduct ensembl:ENSG00000112972
MVD GeneProduct ensembl:ENSG00000167508
IDI GeneProduct ensembl:ENSG00000067064
FDPS GeneProduct ensembl:ENSG00000160752
FDFT GeneProduct ensembl:ENSG00000079459
SQLE GeneProduct ensembl:ENSG00000104549
CYP51A1 GeneProduct ensembl:ENSG00000001630
LPL GeneProduct ensembl:ENSG00000175445
LDLR GeneProduct ensembl:ENSG00000130164
SCARB1 GeneProduct ensembl:ENSG00000073060
ACACA GeneProduct ensembl:ENSG00000278540
GPA GeneProduct ensembl:ENSG00000119927
FASN GeneProduct ensembl:ENSG00000169710
DBI GeneProduct ensembl:ENSG00000155368
ACLY GeneProduct ensembl:ENSG00000131473
MDH GeneProduct ensembl:ENSG00000014641
PPARG GeneProduct ensembl:ENSG00000132170
ACS GeneProduct ensembl:ENSG00000154930
SCD GeneProduct ensembl:ENSG00000099194
SIRT1 GeneProduct ensembl:ENSG00000096717
INSIG1 GeneProduct ensembl:ENSG00000186480
INSIG2 GeneProduct ensembl:ENSG00000125629
SREBP2 GeneProduct ensembl:ENSG00000198911
SREBP1a,-c GeneProduct ensembl:ENSG00000072310
Insulin Protein uniprot:P01308

References

  1. SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene. Yokoyama C, Wang X, Briggs MR, Admon A, Wu J, Hua X, et al. Cell. 1993 Oct 8;75(1):187–97. PubMed Europe PMC Scholia
  2. Cleavage of sterol regulatory element-binding proteins (SREBPs) at site-1 requires interaction with SREBP cleavage-activating protein. Evidence from in vivo competition studies. Sakai J, Nohturfft A, Goldstein JL, Brown MS. J Biol Chem. 1998 Mar 6;273(10):5785–93. PubMed Europe PMC Scholia
  3. Co-stimulation of promoter for low density lipoprotein receptor gene by sterol regulatory element-binding protein and Sp1 is specifically disrupted by the yin yang 1 protein. Bennett MK, Ngo TT, Athanikar JN, Rosenfeld JM, Osborne TF. J Biol Chem. 1999 May 7;274(19):13025–32. PubMed Europe PMC Scholia
  4. YY1 is a negative regulator of transcription of three sterol regulatory element-binding protein-responsive genes. Ericsson J, Usheva A, Edwards PA. J Biol Chem. 1999 May 14;274(20):14508–13. PubMed Europe PMC Scholia
  5. Nuclear import of sterol regulatory element-binding protein-2, a basic helix-loop-helix-leucine zipper (bHLH-Zip)-containing transcription factor, occurs through the direct interaction of importin beta with HLH-Zip. Nagoshi E, Imamoto N, Sato R, Yoneda Y. Mol Biol Cell. 1999 Jul;10(7):2221–33. PubMed Europe PMC Scholia
  6. A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Brown MS, Goldstein JL. Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11041–8. PubMed Europe PMC Scholia
  7. Asparagine-proline sequence within membrane-spanning segment of SREBP triggers intramembrane cleavage by site-2 protease. Ye J, Davé UP, Grishin NV, Goldstein JL, Brown MS. Proc Natl Acad Sci U S A. 2000 May 9;97(10):5123–8. PubMed Europe PMC Scholia
  8. Chemical activity of cholesterol in membranes. Radhakrishnan A, McConnell HM. Biochemistry. 2000 Jul 18;39(28):8119–24. PubMed Europe PMC Scholia
  9. SREBP cleavage-activating protein (SCAP) is required for increased lipid synthesis in liver induced by cholesterol deprivation and insulin elevation. Matsuda M, Korn BS, Hammer RE, Moon YA, Komuro R, Horton JD, et al. Genes Dev. 2001 May 15;15(10):1206–16. PubMed Europe PMC Scholia
  10. Sterol regulatory element-binding proteins (SREBPs): transcriptional regulators of lipid synthetic genes. Shimano H. Prog Lipid Res. 2001 Nov;40(6):439–52. PubMed Europe PMC Scholia
  11. ATF6 modulates SREBP2-mediated lipogenesis. Zeng L, Lu M, Mori K, Luo S, Lee AS, Zhu Y, et al. EMBO J. 2004 Feb 25;23(4):950–8. PubMed Europe PMC Scholia
  12. Overexpression of Insig-1 in the livers of transgenic mice inhibits SREBP processing and reduces insulin-stimulated lipogenesis. Engelking LJ, Kuriyama H, Hammer RE, Horton JD, Brown MS, Goldstein JL, et al. J Clin Invest. 2004 Apr;113(8):1168–75. PubMed Europe PMC Scholia
  13. Central role for liver X receptor in insulin-mediated activation of Srebp-1c transcription and stimulation of fatty acid synthesis in liver. Chen G, Liang G, Ou J, Goldstein JL, Brown MS. Proc Natl Acad Sci U S A. 2004 Aug 3;101(31):11245–50. PubMed Europe PMC Scholia
  14. Cholesterol and 25-hydroxycholesterol inhibit activation of SREBPs by different mechanisms, both involving SCAP and Insigs. Adams CM, Reitz J, De Brabander JK, Feramisco JD, Li L, Brown MS, et al. J Biol Chem. 2004 Dec 10;279(50):52772–80. PubMed Europe PMC Scholia
  15. Hyperlipidemic effects of dietary saturated fats mediated through PGC-1beta coactivation of SREBP. Lin J, Yang R, Tarr PT, Wu PH, Handschin C, Li S, et al. Cell. 2005 Jan 28;120(2):261–73. PubMed Europe PMC Scholia
  16. Insig required for sterol-mediated inhibition of Scap/SREBP binding to COPII proteins in vitro. Sun LP, Li L, Goldstein JL, Brown MS. J Biol Chem. 2005 Jul 15;280(28):26483–90. PubMed Europe PMC Scholia
  17. Sterol-regulated ubiquitination and degradation of Insig-1 creates a convergent mechanism for feedback control of cholesterol synthesis and uptake. Gong Y, Lee JN, Lee PCW, Goldstein JL, Brown MS, Ye J. Cell Metab. 2006 Jan;3(1):15–24. PubMed Europe PMC Scholia
  18. An ARC/Mediator subunit required for SREBP control of cholesterol and lipid homeostasis. Yang F, Vought BW, Satterlee JS, Walker AK, Jim Sun ZY, Watts JL, et al. Nature. 2006 Aug 10;442(7103):700–4. PubMed Europe PMC Scholia
  19. Insulin activates human sterol-regulatory-element-binding protein-1c (SREBP-1c) promoter through SRE motifs. Dif N, Euthine V, Gonnet E, Laville M, Vidal H, Lefai E. Biochem J. 2006 Nov 15;400(1):179–88. PubMed Europe PMC Scholia
  20. Sterol-regulated degradation of Insig-1 mediated by the membrane-bound ubiquitin ligase gp78. Lee JN, Song B, DeBose-Boyd RA, Ye J. J Biol Chem. 2006 Dec 22;281(51):39308–15. PubMed Europe PMC Scholia
  21. Protein kinase A suppresses sterol regulatory element-binding protein-1C expression via phosphorylation of liver X receptor in the liver. Yamamoto T, Shimano H, Inoue N, Nakagawa Y, Matsuzaka T, Takahashi A, et al. J Biol Chem. 2007 Apr 20;282(16):11687–95. PubMed Europe PMC Scholia
  22. Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: oxysterols block transport by binding to Insig. Radhakrishnan A, Ikeda Y, Kwon HJ, Brown MS, Goldstein JL. Proc Natl Acad Sci U S A. 2007 Apr 17;104(16):6511–8. PubMed Europe PMC Scholia
  23. Unsaturated fatty acids inhibit proteasomal degradation of Insig-1 at a postubiquitination step. Lee JN, Zhang X, Feramisco JD, Gong Y, Ye J. J Biol Chem. 2008 Nov 28;283(48):33772–83. PubMed Europe PMC Scholia
  24. A phosphorylation cascade controls the degradation of active SREBP1. Bengoechea-Alonso MT, Ericsson J. J Biol Chem. 2009 Feb 27;284(9):5885–95. PubMed Europe PMC Scholia
  25. Insulin enhances post-translational processing of nascent SREBP-1c by promoting its phosphorylation and association with COPII vesicles. Yellaturu CR, Deng X, Cagen LM, Wilcox HG, Mansbach CM 2nd, Siddiqi SA, et al. J Biol Chem. 2009 Mar 20;284(12):7518–32. PubMed Europe PMC Scholia
  26. The sterol-sensing endoplasmic reticulum (ER) membrane protein TRC8 hampers ER to Golgi transport of sterol regulatory element-binding protein-2 (SREBP-2)/SREBP cleavage-activated protein and reduces SREBP-2 cleavage. Irisawa M, Inoue J, Ozawa N, Mori K, Sato R. J Biol Chem. 2009 Oct 16;284(42):28995–9004. PubMed Europe PMC Scholia
  27. Insulin enhances the biogenesis of nuclear sterol regulatory element-binding protein (SREBP)-1c by posttranscriptional down-regulation of Insig-2A and its dissociation from SREBP cleavage-activating protein (SCAP).SREBP-1c complex. Yellaturu CR, Deng X, Park EA, Raghow R, Elam MB. J Biol Chem. 2009 Nov 13;284(46):31726–34. PubMed Europe PMC Scholia
  28. AMPK and SIRT1: a long-standing partnership? Ruderman NB, Xu XJ, Nelson L, Cacicedo JM, Saha AK, Lan F, et al. Am J Physiol Endocrinol Metab. 2010 Apr;298(4):E751-60. PubMed Europe PMC Scholia
  29. The Akt-SREBP nexus: cell signaling meets lipid metabolism. Krycer JR, Sharpe LJ, Luu W, Brown AJ. Trends Endocrinol Metab. 2010 May;21(5):268–76. PubMed Europe PMC Scholia
  30. Polyunsaturated fatty acids selectively suppress sterol regulatory element-binding protein-1 through proteolytic processing and autoloop regulatory circuit. Takeuchi Y, Yahagi N, Izumida Y, Nishi M, Kubota M, Teraoka Y, et al. J Biol Chem. 2010 Apr 9;285(15):11681–91. PubMed Europe PMC Scholia
  31. Sterol metabolism and SREBP activation. Sato R. Arch Biochem Biophys. 2010 Sep 15;501(2):177–81. PubMed Europe PMC Scholia
  32. Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP. Walker AK, Yang F, Jiang K, Ji JY, Watts JL, Purushotham A, et al. Genes Dev. 2010 Jul 1;24(13):1403–17. PubMed Europe PMC Scholia
  33. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Düvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL, et al. Mol Cell. 2010 Jul 30;39(2):171–83. PubMed Europe PMC Scholia
  34. SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism. Ponugoti B, Kim DH, Xiao Z, Smith Z, Miao J, Zang M, et al. J Biol Chem. 2010 Oct 29;285(44):33959–70. PubMed Europe PMC Scholia
  35. PI3K/Akt pathway mediates high glucose-induced lipogenesis and extracellular matrix accumulation in HKC cells through regulation of SREBP-1 and TGF-β1. Hao J, Liu S, Zhao S, Liu Q, Lv X, Chen H, et al. Histochem Cell Biol. 2011 Feb;135(2):173–81. PubMed Europe PMC Scholia
  36. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Li Y, Xu S, Mihaylova MM, Zheng B, Hou X, Jiang B, et al. Cell Metab. 2011 Apr 6;13(4):376–88. PubMed Europe PMC Scholia
  37. The link between fibroblast growth factor 21 and sterol regulatory element binding protein 1c during lipogenesis in hepatocytes. Zhang Y, Lei T, Huang JF, Wang SB, Zhou LL, Yang ZQ, et al. Mol Cell Endocrinol. 2011 Aug 6;342(1–2):41–7. PubMed Europe PMC Scholia
  38. Glutamine stimulates the gene expression and processing of sterol regulatory element binding proteins, thereby increasing the expression of their target genes. Inoue J, Ito Y, Shimada S, Satoh S ich, Sasaki T, Hashidume T, et al. FEBS J. 2011 Aug;278(15):2739–50. PubMed Europe PMC Scholia
  39. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Peterson TR, Sengupta SS, Harris TE, Carmack AE, Kang SA, Balderas E, et al. Cell. 2011 Aug 5;146(3):408–20. PubMed Europe PMC Scholia
  40. SREBP-1 activation by glucose mediates TGF-β upregulation in mesangial cells. Uttarwar L, Gao B, Ingram AJ, Krepinsky JC. Am J Physiol Renal Physiol. 2012 Feb 1;302(3):F329-41. PubMed Europe PMC Scholia
  41. SREBPs: metabolic integrators in physiology and metabolism. Jeon TI, Osborne TF. Trends Endocrinol Metab. 2012 Feb;23(2):65–72. PubMed Europe PMC Scholia
  42. MicroRNAs in metabolism and metabolic disorders. Rottiers V, Näär AM. Nat Rev Mol Cell Biol. 2012 Mar 22;13(4):239–50. PubMed Europe PMC Scholia
  43. Regulation of lipogenesis by cyclin-dependent kinase 8-mediated control of SREBP-1. Zhao X, Feng D, Wang Q, Abdulla A, Xie XJ, Zhou J, et al. J Clin Invest. 2012 Jul;122(7):2417–27. PubMed Europe PMC Scholia
  44. Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase. Owen JL, Zhang Y, Bae SH, Farooqi MS, Liang G, Hammer RE, et al. Proc Natl Acad Sci U S A. 2012 Oct 2;109(40):16184–9. PubMed Europe PMC Scholia
  45. Sirtuin 1 regulates SREBP-1c expression in a LXR-dependent manner in skeletal muscle. Defour A, Dessalle K, Castro Perez A, Poyot T, Castells J, Gallot YS, et al. PLoS One. 2012;7(9):e43490. PubMed Europe PMC Scholia
  46. Retinol binding protein 4 stimulates hepatic sterol regulatory element-binding protein 1 and increases lipogenesis through the peroxisome proliferator-activated receptor-γ coactivator 1β-dependent pathway. Xia M, Liu Y, Guo H, Wang D, Wang Y, Ling W. Hepatology. 2013 Aug;58(2):564–75. PubMed Europe PMC Scholia
  47. A pathway approach to investigate the function and regulation of SREBPs. Daemen S, Kutmon M, Evelo CT. Genes Nutr. 2013 May;8(3):289–300. PubMed Europe PMC Scholia