Sterol regulatory element-binding protein 1

{{Short description|Protein-coding gene in the species Homo sapiens}}

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.{{cite journal | vauthors = Yokoyama C, Wang X, Briggs MR, Admon A, Wu J, Hua X, Goldstein JL, Brown MS | title = SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene | journal = Cell | volume = 75 | issue = 1 | pages = 187–197 | date = October 1993 | pmid = 8402897 | doi = 10.1016/S0092-8674(05)80095-9 | s2cid = 2784016 }}{{cite journal | vauthors = Hua X, Wu J, Goldstein JL, Brown MS, Hobbs HH | title = 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 | journal = Genomics | volume = 25 | issue = 3 | pages = 667–673 | date = February 1995 | pmid = 7759101 | doi = 10.1016/0888-7543(95)80009-B }}

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.{{cite web | title = Entrez Gene: SREBF1 sterol regulatory element binding transcription factor 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6720}} 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|date=June 2020}}

Expression

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.{{cite journal | vauthors = Eberlé D, Hegarty B, Bossard P, Ferré P, Foufelle F | title = SREBP transcription factors: master regulators of lipid homeostasis | journal = Biochimie | volume = 86 | issue = 11 | pages = 839–848 | date = November 2004 | pmid = 15589694 | doi = 10.1016/j.biochi.2004.09.018 }}

SREBP-1a and SREBP-1c are both encoded by the same gene, but are transcribed by different promoters.{{cite journal | vauthors = Xu X, So JS, Park JG, Lee AH | title = Transcriptional control of hepatic lipid metabolism by SREBP and ChREBP | journal = Seminars in Liver Disease | volume = 33 | issue = 4 | pages = 301–311 | date = November 2013 | pmid = 24222088 | pmc = 4035704 | doi = 10.1055/s-0033-1358523 }} 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.{{cite journal | vauthors = 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 | title = Sterol regulatory element-binding protein-1 as a key transcription factor for nutritional induction of lipogenic enzyme genes | journal = The Journal of Biological Chemistry | volume = 274 | issue = 50 | pages = 35832–35839 | date = December 1999 | pmid = 10585467 | pmc = 5218901 | doi = 10.21037/hbsn.2016.11.08 | doi-access = free }} 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.{{cite journal | vauthors = Li S, Brown MS, Goldstein JL | title = Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 8 | pages = 3441–3446 | date = February 2010 | pmid = 20133650 | pmc = 2840492 | doi = 10.1073/pnas.0914798107 | doi-access = free | bibcode = 2010PNAS..107.3441L }}

Clinical relevance

SREBP-1c regulates genes required for glucose metabolism and fatty acid and lipid production and its expression is induced by insulin.{{cite journal | vauthors = Ferré P, Foufelle F | title = Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c | journal = Diabetes, Obesity & Metabolism | volume = 12 Suppl 2 | issue = Suppl 2 | pages = 83–92 | date = October 2010 | pmid = 21029304 | doi = 10.1111/j.1463-1326.2010.01275.x | s2cid = 23614683 }} 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.{{cite journal | vauthors = Bakan I, Laplante M | title = Connecting mTORC1 signaling to SREBP-1 activation | journal = Current Opinion in Lipidology | volume = 23 | issue = 3 | pages = 226–234 | date = June 2012 | pmid = 22449814 | doi = 10.1097/MOL.0b013e328352dd03 | s2cid = 19390378 }}

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{{cite journal | vauthors = Ponugoti B, Kim DH, Xiao Z, Smith Z, Miao J, Zang M, Wu SY, Chiang CM, Veenstra TD, Kemper JK | title = SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism | journal = The Journal of Biological Chemistry | volume = 285 | issue = 44 | pages = 33959–33970 | date = October 2010 | pmid = 20817729 | pmc = 2962496 | doi = 10.1074/jbc.M110.122978 | doi-access = free }} or by other means{{cite journal | vauthors = Song Z, Xiaoli AM, Yang F | title = Regulation and Metabolic Significance of De Novo Lipogenesis in Adipose Tissues | journal = Nutrients | volume = 10 | issue = 10 | pages = E1383 | date = September 2018 | pmid = 30274245 | pmc = 6213738 | doi = 10.3390/nu10101383 | doi-access = free }} 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.{{cite journal | vauthors = Guo D, Bell EH, Mischel P, Chakravarti A | title = Targeting SREBP-1-driven lipid metabolism to treat cancer | journal = Current Pharmaceutical Design | volume = 20 | issue = 15 | pages = 2619–2626 | year = 2014 | pmid = 23859617 | pmc = 4148912 | doi = 10.2174/13816128113199990486 }}{{cite journal | vauthors = Ezzeddini R, Taghikhani M, Somi MH, Samadi N, Rasaee MJ | title = Clinical importance of FASN in relation to HIF-1α and SREBP-1c in gastric adenocarcinoma | journal = Life Sciences | volume = 224 | issue = | pages = 169–176 | date = May 2019 | pmid = 30914315 | doi = 10.1016/j.lfs.2019.03.056 | s2cid = 85532042 }}

Interactions

SREBF1 has been shown to interact with:

CREB-binding protein,{{cite journal | vauthors = Oliner JD, Andresen JM, Hansen SK, Zhou S, Tjian R | title = SREBP transcriptional activity is mediated through an interaction with the CREB-binding protein | journal = Genes & Development | volume = 10 | issue = 22 | pages = 2903–2911 | date = November 1996 | pmid = 8918891 | doi = 10.1101/gad.10.22.2903 | doi-access = free }}
DAX1{{cite journal | vauthors = Lopez D, Shea-Eaton W, Sanchez MD, McLean MP | title = DAX-1 represses the high-density lipoprotein receptor through interaction with positive regulators sterol regulatory element-binding protein-1a and steroidogenic factor-1 | journal = Endocrinology | volume = 142 | issue = 12 | pages = 5097–5106 | date = December 2001 | pmid = 11713202 | doi = 10.1210/endo.142.12.8523 | doi-access = free }}
LMNA,{{cite journal | vauthors = Lloyd DJ, Trembath RC, Shackleton S | title = A novel interaction between lamin A and SREBP1: implications for partial lipodystrophy and other laminopathies | journal = Human Molecular Genetics | volume = 11 | issue = 7 | pages = 769–777 | date = April 2002 | pmid = 11929849 | doi = 10.1093/hmg/11.7.769 | doi-access = free }} and
TWIST2.{{cite journal | vauthors = Lee YS, Lee HH, Park J, Yoo EJ, Glackin CA, Choi YI, Jeon SH, Seong RH, Park SD, Kim JB | title = Twist2, a novel ADD1/SREBP1c interacting protein, represses the transcriptional activity of ADD1/SREBP1c | journal = Nucleic Acids Research | volume = 31 | issue = 24 | pages = 7165–7174 | date = December 2003 | pmid = 14654692 | pmc = 291873 | doi = 10.1093/nar/gkg934 }}
BHLHE40{{cite journal | vauthors = Gorski JP, Price JL | title = Bone muscle crosstalk targets muscle regeneration pathway regulated by core circadian transcriptional repressors DEC1 and DEC2 | journal = BoneKEy Reports | volume = 5 | pages = 850 | year = 2016 | pmid = 27867498 | pmc = 5111231 | doi = 10.1038/bonekey.2016.80 }}
BHLHE41

References

External links

{{MeSH name|SREBF1+protein,+human}}
{{FactorBook|SREBP1}}

Category:Transcription factors