Sterol regulatory element-binding protein 1 explained

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.^{[1] [2]}

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.^[3] 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

See 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.^[4]

SREBP-1a and SREBP-1c are both encoded by the same gene, but are transcribed by different promoters.^[5] 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.^[6] 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.^[7]

Clinical relevance

SREBP-1c regulates genes required for glucose metabolism and fatty acid and lipid production and its expression is induced by insulin.^[8] 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.^[9]

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^[10] or by other means^[11] 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.^{[12] [13]}

Interactions

SREBF1 has been shown to interact with:

• CREB-binding protein,^[14]
• DAX1^[15]
• LMNA,^[16] and
• TWIST2.^[17]
• BHLHE40^[18]
• BHLHE41

See also

• Sterol regulatory element-binding protein

Further reading

• Osborne TF . 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 . August 2001 . 11485982 . 10.1101/gad.916601 . free .
• Kotzka J, Müller-Wieland D . Sterol regulatory element-binding protein (SREBP)-1: gene regulatory target for insulin resistance? . Expert Opinion on Therapeutic Targets . 8 . 2 . 141–149 . April 2004 . 15102555 . 10.1517/14728222.8.2.141 . 34317215 .
• Szolkiewicz M, Chmielewski M, Nogalska A, Stelmanska E, Swierczynski J, Rutkowski B . The potential role of sterol regulatory element binding protein transcription factors in renal injury . Journal of Renal Nutrition . 17 . 1 . 62–65 . January 2007 . 17198935 . 10.1053/j.jrn.2006.10.009 .
• Ferré P, Foufelle F . SREBP-1c transcription factor and lipid homeostasis: clinical perspective . Hormone Research . 68 . 2 . 72–82 . 2007 . 17344645 . 10.1159/000100426 . 2024-07-25 . free .
• Hua X, Yokoyama C, Wu J, Briggs MR, Brown MS, Goldstein JL, Wang X . 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 . December 1993 . 7903453 . 48032 . 10.1073/pnas.90.24.11603 . free . 1993PNAS...9011603H .
• Sato R, Yang J, Wang X, Evans MJ, Ho YK, Goldstein JL, Brown MS . 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 . June 1994 . 8006035 . 10.1016/S0021-9258(17)32550-4 . free .
• Wang X, Sato R, Brown MS, Hua X, Goldstein JL . SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis . Cell . 77 . 1 . 53–62 . April 1994 . 8156598 . 10.1016/0092-8674(94)90234-8 . 44899129 .
• Wang X, Briggs MR, Hua X, Yokoyama C, Goldstein JL, Brown MS . 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 . July 1993 . 8314806 . 10.1016/S0021-9258(19)85266-3 . free .
• Hua X, Sakai J, Brown MS, Goldstein JL . 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 . April 1996 . 8626610 . 10.1074/jbc.271.17.10379 . free .
• Shimomura I, Shimano H, Horton JD, Goldstein JL, Brown MS . 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 . March 1997 . 9062340 . 507890 . 10.1172/JCI119247 .
• Miserez AR, Cao G, Probst LC, Hobbs HH . Structure of the human gene encoding sterol regulatory element binding protein 2 (SREBF2) . Genomics . 40 . 1 . 31–40 . February 1997 . 9070916 . 10.1006/geno.1996.4525 .
• Párraga A, Bellsolell L, Ferré-D'Amaré AR, Burley SK . Co-crystal structure of sterol regulatory element binding protein 1a at 2.3 A resolution . Structure . 6 . 5 . 661–672 . May 1998 . 9634703 . 10.1016/S0969-2126(98)00067-7 . free .
• Ericsson J, Edwards PA . CBP is required for sterol-regulated and sterol regulatory element-binding protein-regulated transcription . The Journal of Biological Chemistry . 273 . 28 . 17865–17870 . July 1998 . 9651391 . 10.1074/jbc.273.28.17865 . free .
• Bennett MK, Ngo TT, Athanikar JN, Rosenfeld JM, Osborne TF . 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 . May 1999 . 10224053 . 10.1074/jbc.274.19.13025 . free .
• Moldes M, Boizard M, Liepvre XL, Fève B, Dugail I, Pairault J . 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 . December 1999 . 10585876 . 1220711 . 10.1042/0264-6021:3440873 .
• DeBose-Boyd RA, Brown MS, Li WP, Nohturfft A, Goldstein JL, Espenshade PJ . 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 . December 1999 . 10619424 . 10.1016/S0092-8674(00)81668-2 . free .
• Roth G, Kotzka J, Kremer L, Lehr S, Lohaus C, Meyer HE, Krone W, Müller-Wieland D . 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 . October 2000 . 10915800 . 10.1074/jbc.M005425200 . free .
• Shimomura I, Matsuda M, Hammer RE, Bashmakov Y, Brown MS, Goldstein JL . 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 . July 2000 . 10949029 . 10.1016/S1097-2765(00)00009-5 . free .

Notes and References

1. Yokoyama C, Wang X, Briggs MR, Admon A, Wu J, Hua X, Goldstein JL, Brown MS . SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene . Cell . 75 . 1 . 187–197 . October 1993 . 8402897 . 10.1016/S0092-8674(05)80095-9 . 2784016 .
2. Hua X, Wu J, Goldstein JL, Brown MS, Hobbs HH . Structure of the human gene encoding sterol regulatory element binding protein-1 (SREBF1) and localization of SREBF1 and SREBF2 to chromosomes 17p11.2 and 22q13 . Genomics . 25 . 3 . 667–673 . February 1995 . 7759101 . 10.1016/0888-7543(95)80009-B .
3. Web site: Entrez Gene: SREBF1 sterol regulatory element binding transcription factor 1.
4. Eberlé D, Hegarty B, Bossard P, Ferré P, Foufelle F . SREBP transcription factors: master regulators of lipid homeostasis . Biochimie . 86 . 11 . 839–848 . November 2004 . 15589694 . 10.1016/j.biochi.2004.09.018 .
5. Xu X, So JS, Park JG, Lee AH . Transcriptional control of hepatic lipid metabolism by SREBP and ChREBP . Seminars in Liver Disease . 33 . 4 . 301–311 . November 2013 . 24222088 . 4035704 . 10.1055/s-0033-1358523 .
6. Shimano H, Yahagi N, Amemiya-Kudo M, Hasty AH, Osuga J, Tamura Y, Shionoiri F, Iizuka Y, Ohashi K, Harada K, Gotoda T, Ishibashi S, Yamada N . Sterol regulatory element-binding protein-1 as a key transcription factor for nutritional induction of lipogenic enzyme genes . The Journal of Biological Chemistry . 274 . 50 . 35832–35839 . December 1999 . 10585467 . 5218901 . 10.21037/hbsn.2016.11.08 . free .
7. Li S, Brown MS, Goldstein JL . Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis . Proceedings of the National Academy of Sciences of the United States of America . 107 . 8 . 3441–3446 . February 2010 . 20133650 . 2840492 . 10.1073/pnas.0914798107 . free . 2010PNAS..107.3441L .
8. Ferré P, Foufelle F . Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c . Diabetes, Obesity & Metabolism . 12 Suppl 2 . Suppl 2 . 83–92 . October 2010 . 21029304 . 10.1111/j.1463-1326.2010.01275.x . 23614683 .
9. Bakan I, Laplante M . Connecting mTORC1 signaling to SREBP-1 activation . Current Opinion in Lipidology . 23 . 3 . 226–234 . June 2012 . 22449814 . 10.1097/MOL.0b013e328352dd03 . 19390378 .
10. Ponugoti B, Kim DH, Xiao Z, Smith Z, Miao J, Zang M, Wu SY, Chiang CM, Veenstra TD, Kemper JK . SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism . The Journal of Biological Chemistry . 285 . 44 . 33959–33970 . October 2010 . 20817729 . 2962496 . 10.1074/jbc.M110.122978 . free .
11. Song Z, Xiaoli AM, Yang F . Regulation and Metabolic Significance of De Novo Lipogenesis in Adipose Tissues . Nutrients . 10 . 10 . E1383 . September 2018 . 30274245 . 6213738 . 10.3390/nu10101383 . free .
12. Guo D, Bell EH, Mischel P, Chakravarti A . Targeting SREBP-1-driven lipid metabolism to treat cancer . Current Pharmaceutical Design . 20 . 15 . 2619–2626 . 2014 . 23859617 . 4148912 . 10.2174/13816128113199990486 .
13. Ezzeddini R, Taghikhani M, Somi MH, Samadi N, Rasaee MJ . Clinical importance of FASN in relation to HIF-1α and SREBP-1c in gastric adenocarcinoma . Life Sciences . 224 . 169–176 . May 2019 . 30914315 . 10.1016/j.lfs.2019.03.056 . 85532042 .
14. Oliner JD, Andresen JM, Hansen SK, Zhou S, Tjian R . SREBP transcriptional activity is mediated through an interaction with the CREB-binding protein . Genes & Development . 10 . 22 . 2903–2911 . November 1996 . 8918891 . 10.1101/gad.10.22.2903 . free .
15. Lopez D, Shea-Eaton W, Sanchez MD, McLean MP . DAX-1 represses the high-density lipoprotein receptor through interaction with positive regulators sterol regulatory element-binding protein-1a and steroidogenic factor-1 . Endocrinology . 142 . 12 . 5097–5106 . December 2001 . 11713202 . 10.1210/endo.142.12.8523 . free .
16. Lloyd DJ, Trembath RC, Shackleton S . A novel interaction between lamin A and SREBP1: implications for partial lipodystrophy and other laminopathies . Human Molecular Genetics . 11 . 7 . 769–777 . April 2002 . 11929849 . 10.1093/hmg/11.7.769 . free .
17. Lee YS, Lee HH, Park J, Yoo EJ, Glackin CA, Choi YI, Jeon SH, Seong RH, Park SD, Kim JB . Twist2, a novel ADD1/SREBP1c interacting protein, represses the transcriptional activity of ADD1/SREBP1c . Nucleic Acids Research . 31 . 24 . 7165–7174 . December 2003 . 14654692 . 291873 . 10.1093/nar/gkg934 .
18. Gorski JP, Price JL . Bone muscle crosstalk targets muscle regeneration pathway regulated by core circadian transcriptional repressors DEC1 and DEC2 . BoneKEy Reports . 5 . 850 . 2016 . 27867498 . 5111231 . 10.1038/bonekey.2016.80 .