Sterol regulatory element-binding protein 1

Sterol regulatory element-binding transcription factor 1 (SREBF1) also known as sterol regulatory element-binding protein 1 (SREBP-1) is a protein that in humans is encoded by the SREBF1 gene.

SREBF1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1AM9
Identifiers
Aliases	SREBF1, SREBP-1c, SREBP1, bHLHd1, SREBP1a, sterol regulatory element binding transcription factor 1
External IDs	OMIM: 184756; MGI: 107606; HomoloGene: 3079; GeneCards: SREBF1; OMA:SREBF1 - orthologs
Gene location (Human) Chr. Chromosome 17 (human) Band 17p11.2 Start 17,810,399 bp End 17,837,011 bp
Gene location (Mouse) Chr. Chromosome 11 (mouse) Band 11|11 B2 Start 60,089,915 bp End 60,113,407 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in left adrenal gland right adrenal gland left adrenal cortex right adrenal cortex right lobe of liver left uterine tube minor salivary glands tibial nerve anterior pituitary right ovary Top expressed in white adipose tissue lip neural layer of retina urinary bladder exocrine gland hepatobiliary system liver skeletal muscle tissue olfactory bulb islet of Langerhans More reference expression data BioGPS More reference expression data
Gene ontology Molecular function DNA binding sequence-specific DNA binding protein dimerization activity DNA-binding transcription factor activity sterol response element binding chromatin binding RNA polymerase II cis-regulatory region sequence-specific DNA binding transcription factor activity, RNA polymerase II core promoter proximal region sequence-specific binding protein binding protein kinase binding RNA polymerase II transcription regulatory region sequence-specific DNA binding nuclear receptor activity DNA-binding transcription factor activity, RNA polymerase II-specific DNA-binding transcription activator activity, RNA polymerase II-specific protein-containing complex binding enzyme activator activity Cellular component cytoplasm integral component of membrane cytosol Golgi apparatus nuclear envelope endoplasmic reticulum membrane membrane intracellular membrane-bounded organelle Golgi membrane nucleoplasm endoplasmic reticulum ER to Golgi transport vesicle membrane cytoplasmic vesicle nucleus protein-containing complex Biological process positive regulation of histone deacetylation insulin receptor signaling pathway positive regulation of triglyceride biosynthetic process steroid metabolic process negative regulation of insulin secretion response to fatty acid lipid biosynthetic process response to glucagon regulation of protein stability regulation of transcription, DNA-templated response to retinoic acid response to organic cyclic compound lung development lipid metabolism regulation of insulin secretion regulation of transcription by RNA polymerase II cellular response to starvation response to progesterone ageing response to peptide hormone mRNA transcription by RNA polymerase II cholesterol metabolic process negative regulation of transcription by RNA polymerase II response to glucose transcription, DNA-templated positive regulation of transcription, DNA-templated response to lipid cellular response to fatty acid regulation of autophagy of mitochondrion regulation of protein targeting to mitochondrion regulation of fatty acid metabolic process circadian rhythm cellular response to insulin stimulus response to food positive regulation of cholesterol biosynthetic process response to cAMP regulation of heart rate by chemical signal fat cell differentiation intracellular receptor signaling pathway positive regulation of transcription by RNA polymerase II regulation of cholesterol biosynthetic process transcription by RNA polymerase II positive regulation of pri-miRNA transcription by RNA polymerase II positive regulation of catalytic activity Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 6720 20787 Ensembl ENSG00000072310 ENSMUSG00000020538 UniProt P36956 Q9WTN3 RefSeq (mRNA) NM_001005291 NM_004176 NM_001321096 NM_011480 NM_001313979 NM_001358314 NM_001358315 RefSeq (protein) NP_001005291 NP_001308025 NP_004167 NP_001300908 NP_035610 NP_001345243 NP_001345244 Location (UCSC) Chr 17: 17.81 – 17.84 Mb Chr 11: 60.09 – 60.11 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

This gene is located within the Smith–Magenis syndrome region on chromosome 17. Two transcript variants encoding different isoforms have been found for this gene. The isoforms are SREBP-1a and SREBP-1c (the latter also called ADD-1). SREBP-1a is expressed in the intestine and spleen, whereas SREBP-1c is mainly expressed in liver, muscle, and fat (among other tissues).

Expression

Main article: Sterol regulatory element-binding protein

The proteins encoded by this gene are transcription factors that bind to a sequence in the promoter of different genes, called sterol regulatory element-1 (SRE1). This element is a decamer (oligomer with ten subunits) flanking the LDL receptor gene and other genes involved in, for instance, sterol biosynthesis. The protein is synthesized as a precursor that is attached to the nuclear membrane and endoplasmic reticulum. Following cleavage, the mature protein translocates to the nucleus and activates transcription by binding to the SRE1. Sterols inhibit the cleavage of the precursor, and the mature nuclear form is rapidly catabolized, thereby reducing transcription. The protein is a member of the basic helix-loop-helix-leucine zipper (bHLH-Zip) transcription factor family.

SREBP-1a regulates genes related to lipid and cholesterol production and its activity is regulated by sterol levels in the cell.

SREBP-1a and SREBP-1c are both encoded by the same gene, but are transcribed by different promoters. For animals in a fasted state, SREBP-1c expression is suppressed in the liver, but a high carbohydrate meal (by insulin release) strongly induces SREBP-1c expression.

Function

SREBP-1 plays a key role in the induction of lipogenesis by the liver. mTORC1 is activated by insulin (a hormone of nutrient abundance) leading to increased production of SREBP-1c, which facilitates storage of fatty acids (excess nutrients) as triglycerides.

Clinical relevance

SREBP-1c regulates genes required for glucose metabolism and fatty acid and lipid production and its expression is induced by insulin. Insulin-stimulated SREBP-1c increases glycolysis by activation of glucokinase enzyme, and increases lipogenesis (conversion of carbohydrates into fatty acids). Insulin stimulation of SREBP-1c is mediated by liver X receptor (LXR) and mTORC1.

High blood levels of insulin due to insulin resistance often leads to steatosis in the liver because of SREBP-1 activation. Suppression of SREBP-1c by sirtuin 1 or by other means protects against development of fatty liver.

SREBP-1 is highly activated in cancers because tumor cells require lipids for cell membranes, second messengers, and energy.

Interactions

SREBF1 has been shown to interact with:

• CREB-binding protein,
• DAX1
• LMNA, and
• TWIST2.
• BHLHE40
• BHLHE41

See also

• Sterol regulatory element-binding protein

Further reading

• Osborne TF (August 2001). "CREating a SCAP-less liver keeps SREBPs pinned in the ER membrane and prevents increased lipid synthesis in response to low cholesterol and high insulin". Genes & Development. 15 (15): 1873–1878. doi:10.1101/gad.916601. PMID 11485982.
• Kotzka J, Müller-Wieland D (April 2004). "Sterol regulatory element-binding protein (SREBP)-1: gene regulatory target for insulin resistance?". Expert Opinion on Therapeutic Targets. 8 (2): 141–149. doi:10.1517/14728222.8.2.141. PMID 15102555. S2CID 34317215.
• Szolkiewicz M, Chmielewski M, Nogalska A, Stelmanska E, Swierczynski J, Rutkowski B (January 2007). "The potential role of sterol regulatory element binding protein transcription factors in renal injury". Journal of Renal Nutrition. 17 (1): 62–65. doi:10.1053/j.jrn.2006.10.009. PMID 17198935.
• Ferré P, Foufelle F (2007). "SREBP-1c transcription factor and lipid homeostasis: clinical perspective". Hormone Research. 68 (2): 72–82. doi:10.1159/000100426 (inactive 23 December 2024). PMID 17344645.{{cite journal}}: CS1 maint: DOI inactive as of December 2024 (link)
• Hua X, Yokoyama C, Wu J, Briggs MR, Brown MS, Goldstein JL, et al. (December 1993). "SREBP-2, a second basic-helix-loop-helix-leucine zipper protein that stimulates transcription by binding to a sterol regulatory element". Proceedings of the National Academy of Sciences of the United States of America. 90 (24): 11603–11607. Bibcode:1993PNAS...9011603H. doi:10.1073/pnas.90.24.11603. PMC 48032. PMID 7903453.
• Sato R, Yang J, Wang X, Evans MJ, Ho YK, Goldstein JL, et al. (June 1994). "Assignment of the membrane attachment, DNA binding, and transcriptional activation domains of sterol regulatory element-binding protein-1 (SREBP-1)". The Journal of Biological Chemistry. 269 (25): 17267–17273. doi:10.1016/S0021-9258(17)32550-4. PMID 8006035.
• Wang X, Sato R, Brown MS, Hua X, Goldstein JL (April 1994). "SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis". Cell. 77 (1): 53–62. doi:10.1016/0092-8674(94)90234-8. PMID 8156598. S2CID 44899129.
• Wang X, Briggs MR, Hua X, Yokoyama C, Goldstein JL, Brown MS (July 1993). "Nuclear protein that binds sterol regulatory element of low density lipoprotein receptor promoter. II. Purification and characterization". The Journal of Biological Chemistry. 268 (19): 14497–14504. doi:10.1016/S0021-9258(19)85266-3. PMID 8314806.
• Hua X, Sakai J, Brown MS, Goldstein JL (April 1996). "Regulated cleavage of sterol regulatory element binding proteins requires sequences on both sides of the endoplasmic reticulum membrane". The Journal of Biological Chemistry. 271 (17): 10379–10384. doi:10.1074/jbc.271.17.10379. PMID 8626610.
• Shimomura I, Shimano H, Horton JD, Goldstein JL, Brown MS (March 1997). "Differential expression of exons 1a and 1c in mRNAs for sterol regulatory element binding protein-1 in human and mouse organs and cultured cells". The Journal of Clinical Investigation. 99 (5): 838–845. doi:10.1172/JCI119247. PMC 507890. PMID 9062340.
• Miserez AR, Cao G, Probst LC, Hobbs HH (February 1997). "Structure of the human gene encoding sterol regulatory element binding protein 2 (SREBF2)". Genomics. 40 (1): 31–40. doi:10.1006/geno.1996.4525. PMID 9070916.
• Párraga A, Bellsolell L, Ferré-D'Amaré AR, Burley SK (May 1998). "Co-crystal structure of sterol regulatory element binding protein 1a at 2.3 A resolution". Structure. 6 (5): 661–672. doi:10.1016/S0969-2126(98)00067-7. PMID 9634703.
• Ericsson J, Edwards PA (July 1998). "CBP is required for sterol-regulated and sterol regulatory element-binding protein-regulated transcription". The Journal of Biological Chemistry. 273 (28): 17865–17870. doi:10.1074/jbc.273.28.17865. PMID 9651391.
• Bennett MK, Ngo TT, Athanikar JN, Rosenfeld JM, Osborne TF (May 1999). "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". The Journal of Biological Chemistry. 274 (19): 13025–13032. doi:10.1074/jbc.274.19.13025. PMID 10224053.
• Moldes M, Boizard M, Liepvre XL, Fève B, Dugail I, Pairault J (December 1999). "Functional antagonism between inhibitor of DNA binding (Id) and adipocyte determination and differentiation factor 1/sterol regulatory element-binding protein-1c (ADD1/SREBP-1c) trans-factors for the regulation of fatty acid synthase promoter in adipocytes". The Biochemical Journal. 344 Pt 3 (Pt 3): 873–880. doi:10.1042/0264-6021:3440873. PMC 1220711. PMID 10585876.
• DeBose-Boyd RA, Brown MS, Li WP, Nohturfft A, Goldstein JL, Espenshade PJ (December 1999). "Transport-dependent proteolysis of SREBP: relocation of site-1 protease from Golgi to ER obviates the need for SREBP transport to Golgi". Cell. 99 (7): 703–712. doi:10.1016/S0092-8674(00)81668-2. PMID 10619424.
• Roth G, Kotzka J, Kremer L, Lehr S, Lohaus C, Meyer HE, et al. (October 2000). "MAP kinases Erk1/2 phosphorylate sterol regulatory element-binding protein (SREBP)-1a at serine 117 in vitro". The Journal of Biological Chemistry. 275 (43): 33302–33307. doi:10.1074/jbc.M005425200. PMID 10915800.
• Shimomura I, Matsuda M, Hammer RE, Bashmakov Y, Brown MS, Goldstein JL (July 2000). "Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice". Molecular Cell. 6 (1): 77–86. doi:10.1016/S1097-2765(00)00009-5. PMID 10949029.

External links

• SREBF1+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• FactorBook SREBP1

This article incorporates text from the United States National Library of Medicine, which is in the public domain.