Biology:Sterol regulatory element-binding protein 1

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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).[citation needed]

Expression

Main page: Biology: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.[5]

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).[8] 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.[5] 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:

See also

References

  1. ↑ "SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene". Cell 75 (1): 187–97. Oct 1993. doi:10.1016/S0092-8674(05)80095-9. PMID 8402897. 
  2. ↑ "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): 667–73. Feb 1995. doi:10.1016/0888-7543(95)80009-B. PMID 7759101. 
  3. ↑ "Entrez Gene: SREBF1 sterol regulatory element binding transcription factor 1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6720. 
  4. ↑ "SREBP transcription factors: master regulators of lipid homeostasis". Biochimie 86 (11): 839–48. Nov 2004. doi:10.1016/j.biochi.2004.09.018. PMID 15589694. 
  5. ↑ 5.0 5.1 5.2 "Transcriptional control of hepatic lipid metabolism by SREBP and ChREBP". Seminars in Liver Disease 33 (4): 301–311. 2013. doi:10.1055/s-0033-1358523. PMID 24222088. 
  6. ↑ "Sterol regulatory element-binding protein-1 as a key transcription factor for nutritional induction of lipogenic enzyme gene". Journal of Biological Chemistry 274 (50): 35832–9. 1999. doi:10.21037/hbsn.2016.11.08. PMID 10585467. PMC 5218901. https://www.jbc.org/content/274/50/35832.long. 
  7. ↑ "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. 2010. doi:10.1073/pnas.0914798107. PMID 20133650. Bibcode: 2010PNAS..107.3441L. 
  8. ↑ 8.0 8.1 "Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c". Diabetes, Obesity & Metabolism 12 (Suppl 2): 83–92. Oct 2010. doi:10.1111/j.1463-1326.2010.01275.x. PMID 21029304. https://zenodo.org/record/3436727. 
  9. ↑ "Connecting mTORC1 signaling to SREBP-1 activation". Current Opinion in Lipidology 23 (3): 226–234. 2012. doi:10.1097/MOL.0b013e328352dd03. PMID 22449814. 
  10. ↑ "SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism". Journal of Biological Chemistry 285 (44): 33959–70. 2010. doi:10.1074/jbc.M110.122978. PMID 20817729. 
  11. ↑ "Regulation and Metabolic Significance of De Novo Lipogenesis in Adipose Tissues". Nutrients 10 (10): E1383. 2018. doi:10.3390/nu10101383. PMID 30274245. 
  12. ↑ "Targeting SREBP-1-driven lipid metabolism to treat cancer". Current Pharmaceutical Design 20 (15): 2619–2626. 2014. doi:10.2174/13816128113199990486. PMID 23859617. 
  13. ↑ "Clinical importance of FASN in relation to HIF-1α and SREBP-1c in gastric adenocarcinoma". Life Sciences 224: 169–176. May 2019. doi:10.1016/j.lfs.2019.03.056. PMID 30914315. https://www.sciencedirect.com/science/article/abs/pii/S0024320519302206. 
  14. ↑ "SREBP transcriptional activity is mediated through an interaction with the CREB-binding protein". Genes & Development 10 (22): 2903–11. Nov 1996. doi:10.1101/gad.10.22.2903. PMID 8918891. 
  15. ↑ "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): 5097–106. Dec 2001. doi:10.1210/endo.142.12.8523. PMID 11713202. 
  16. ↑ "A novel interaction between lamin A and SREBP1: implications for partial lipodystrophy and other laminopathies". Human Molecular Genetics 11 (7): 769–77. Apr 2002. doi:10.1093/hmg/11.7.769. PMID 11929849. 
  17. ↑ "Twist2, a novel ADD1/SREBP1c interacting protein, represses the transcriptional activity of ADD1/SREBP1c". Nucleic Acids Research 31 (24): 7165–74. Dec 2003. doi:10.1093/nar/gkg934. PMID 14654692. 
  18. ↑ 18.0 18.1 Gorski, Jeffery; Price, Jeffery (2016). "Bone muscle crosstalk targets muscle regeneration pathway regulated by core circadian transcriptional repressors DEC1 and DEC2". BoneKEy Reports 5: 850. doi:10.1038/bonekey.2016.80. PMID 27867498. PMC 5111231. http://www.portico.org/Portico/#!journalAUSimpleView/tab=HTML?cs=ISSN_20476396?ct=E-Journal%20Content?auId=ark:/27927/phx23b4bqdc. Retrieved 2017-04-13. 

Further reading

External links

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



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