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FLASH GENE
Symbol SREBF1 contributors: mct - updated : 02-09-2020
HGNC name sterol regulatory element binding transcription factor 1
HGNC id 11289
DNA
TYPE functioning gene
STRUCTURE 25.66 kb     19 Exon(s)
10 Kb 5' upstream gene genomic sequence study
regulatory sequence Promoter
cytosine-phosphate-guanine/HTF
Binding site
text structure
  • upstream of the translation start site, a functional role for the 3 GC-boxes containing overlapping sites for the Sp1 and EGR-1 transcription factors
  • a PPRE element in the proximal promoter, and direct interaction of the PPAR receptor with this SREBF1 promoter
    • MAPPING cloned Y linked   status confirmed
    Map see SMCR (phenotype)
    regionally located within the Smith-Magenis critical region
    RNA
    TRANSCRIPTS type messenger
    text three alternatively spliced isoforms, SREBF1a , SREBF1c, SREBF1b
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    20 splicing 5012 - 1177 hepatoma cell lines 2008 18267114
  • exon 1a and 2
  • inhibited the PEPCK promoter activity that was induced by HNF-4alpha
  • functional role of the three GC-boxes containing overlapping EGR-1/SP1 binding sites for promoter regulation
  • phosphorylation site in Ser-434, which regulates the FBXW7-dependent degradation of SREBP (Bengoechea-Alonso 2009)
    • 19 - 4754 - 1123 liver, adrenal gland, ovary, glomerular, predominantly expressed in liver and adipose tissues 2008 18267114
  • exon 1c and 2, SREBP1 C
  • complexing with ADD1
  • inhibited the PEPCK promoter activity that was induced by HNF-4alpha
  • enhanced oxidative stress through NADPH oxidase, and contributed to formation of diabetic nephropathy without marked lipid accumulation in glomeruli
  • activation could contribute to emergence and/or progression of diabetic nephropathy
  • upregulatiing SLC2A4 transcription in adipose tissue
  • phosphorylation site in Ser-410, which regulates the FBXW7-dependent degradation of SREBP (Bengoechea-Alonso 2009)
    • 19 splicing 4922 - 1147 - 2008 18267114
    - - 1430 - 470 - 2008 18267114
  • contains a translational stop codon-encoding exon sequence between exons 7 and 8
  • lack transmembrane and C-terminal regulatory sequences necessary for localization of SREBP-1 to the endoplasmic reticulum
    • - - 1364 - 446 - 2008 18267114
  • contains a translational stop codon-encoding exon sequence between exons 7 and 8
  • lack transmembrane and C-terminal regulatory sequences necessary for localization of SREBP-1 to the endoplasmic reticulum
    		•
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveliver   highly Homo sapiens
    Endocrineadrenal gland   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialsecretoryglandularendocrine 
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Digestivehepatocyte Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period fetal, pregnancy
    Text placenta, lung, liver
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • NH2 terminal transcription domain including a lamin A/C binding site
  • a basic helix-loop-helix, leucine zipper
  • a middle hydrophobic region with two transmembrane segments (2TM)
  • a C terminal regulatory domain
    • HOMOLOGY
    interspecies homolog to murine Srebf1
    Homologene
    FAMILY
    Sterol regulatory element-binding proteins family
    CATEGORY regulatory , transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus,nucleoplasm
    intracellular,nucleus,chromatin/chromosome
    intracellular,nuclear envelope
    text
  • released from ER to Golgi when sterol levels are low
  • in ER membrane, immature SREBF complex is retained by another ER membrane resident protein called INSIG1
    • basic FUNCTION
  • controlling cholesterol homeostasis
  • having a novel role as negative regulator of gluconeogenic genes through a cross-talk with HNF4A interference with PPARGC1B recruitment
  • playing a central role in energy homeostasis by promoting glycolysis, lipogenesis, and adipogenesis
  • involvd in suppression of VEGF expression through the indirect interaction with the proximal tandem Sp1 sites in vascular smooth muscle cells
  • preferentially activate transcription of lipogenic genes including fatty acid synthase (FAS) and glycerol-3-phosphate acyltransferase (GPAT)
  • plays a role in suppression of hepatic bile acid biosynthesis in response to insulin under feeding conditions by inhibiting transcription of CYP7A1
  • bHLH transcription factor that controls lipogenesis and is induced during overnutrition to facilitate the conversion of glucose to fatty acids and triglycerides for the storage of the excess energy (Shimano 2007)
  • regulator of lipogenesis by activating number of enzyme genes, such as FASN or ACACA, that are involved in this pathway at the transcriptional level
  • mediating SIK1-dependent regulation of hepatic lipogenesis
  • key lipogenic activator, and its expression is dynamically regulated in response to nutritional and hormonal cues
  • SREBF1 and MLXIPL are major transcriptional regulators that induce key lipogenic enzymes to promote lipogenesis in the liver
  • SREBF1 acts as a positive regulator of SFRP2 transcription in chondrogenic cells
  • SREBPF1 is part of a cluster of proneural transcription factors in radial glia and as a regulator of transcription factors controlling midbrain dopaminergic (mDA) neurogenesis, such as FOXA2
  • SREBF1 is a central player in mDA neurogenesis
  • SREBPF1 signaling plays likely an essential role in epidermal differentiation, skin barrier formation, hair growth, and eye function
    • CELLULAR PROCESS nucleotide, transcription
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling hormonal
  • activation of the SREBF1/SYTL4 pathway is a potential mechanism for impaired insulin secretion in diabetes, contributing to beta cell lipotoxicity
    • a component
  • complexing with SCAP and SREBF2
    • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • cleaved by MBTPS1 in the ER luminal loop between the two membrane spanning regions, initiating the two-step proteolytic process by which the N terminal of SREBF is translocated to nucleus after a secund cleavage by MBTPS2
  • LMNA (retention of SREBF by LMNA, causing down-regulation of PPARG expression and reducing the rate of preadipocytes differentiation)
  • target of SIRT1 (SIRT1 interaction with SREBPF1 was increased during fasting and decreased upon feeding)
  • PPARA is a novel regulatory factor in SREBF1 regulation which plays a relevant role in the interplay between lipids and insulin metabolic regulation
  • variation of LMNA level and spatial organization, in particular due to disease-linked mutations, influences the sequestration of SREBF1 at the nuclear envelope and thus contributes to the regulation of SREBF1 function
  • hypoxic cell death is promoted by the reduced expression of FASN through SREBF1 down-regulation
  • FGFR3 signaling promotes the cleavage and activation of the master transcriptional regulator of lipogenesis, SREBF1, that in turn regulates the expression of SCD
  • DDIT3 is necessary for suppression of genes encoding the transcriptional master regulators of lipid metabolism: CEBPA, PPARA, and SREBF1
  • multimeric ER proteins ERLIN1 and ERLIN2 are additional SREBF1, SREBF2 regulators
  • RNF20-induced SREBF1 ubiquitination down-regulates hepatic lipogenic activity upon PRKAA activation
  • SREBF1, SREBF2 actively prevents premature recycling of SCAP-SREBF until initiation of SREBF cleavage
  • RXRG as well as RXRA increased SREBF1 promoter activity in hepatocytes
  • SREBPF1 regulated transcriptional activation of the SFRP2 gene in chondrogenic cells
  • CD274 induces epithelial-to-mesenchymal transition via activating SREBF1 in renal cell carcinoma
  • ELOVL5 is an SREBF1 target gene and an important component of the negative feedback loop of de novo lipogenesis
  • high fat diet (HFD) or fatty acids modulate transcriptional, translational, and post-translational regulation of MIOX expression/activity and underscore MIOX being a novel target of the transcription factor SREBF1
  • ATF4 could maintain SREBF1 protein stability by directly activating the expression of USP7 which deubiquitinates SREBF1 and increases its protein content in cell
  • KRT80 expression is driven by de novo enhancer activation by sterol regulatory element-binding protein 1 (SREBF1)
  • ESRRG mediates alcohol-induced hepatic lipogenesis by upregulating SREBF1 expression, which can be blunted by the inverse agonist for ESRRG
  • MBTPS2 and SREBF1 and SREBF2 were known to be important players in the same pathway
    • cell & other
    REGULATION
    activated by NR1H2 and NR1H3 (resulting in activation of the gene for fatty acid synthase)
    liver X receptor-netinoid X receptor
    HMG-CoA reductase inhibitors (statins)
    repressed by FOXO1 (FOXO1-mediated suppression of SREBF1 promoter activity could be partially alleviated by insulin)
    Other regulated by phosphorylation during the cell cycle
    degradation controlled by cross-talk between multiple phosphorylated residues in its C-terminal domain, and the phosphorylation of Ser-434 could function as a molecular switch to control these processes (Bengoechea-Alonso 2009)
    regulation of the stability of active SREBP1 by FKBW7
    regulation of SREBPF1 expression by MTOR signaling in hepatocytes
    regulated by MTOR (its activity is regulated by MTOR which contributes to Akt-dependent cell growth) (
    ASSOCIATED DISORDERS
    corresponding disease(s) IFAP2
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional       gain of function
    significantly activated spinal cord tissue of both familial or sporadic ALS individuals, and this activation requires degradation of ER membrane resident protein INSIG1
    Susceptibility
  • to obesity and type 2 diabetes
  • in early-onset ALS or female patients
    • Variant & Polymorphism other
  • polymorphisms are associated with obesity and type 2 diabetes
  • rs11868035 is likely to be associated with ALS in early-onset or female patients
    • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    digestivelivercirrhosis
    modulation of SREBF1 activity by SIK proteins would provide an attractive means for the regulation of nonalcoholic fatty liver
    diabetemetabolic syndrom 
    reducing acetylation of SREBPF1 by targeting SIRT1 may be useful for treating metabolic disorders, including fatty liver, obesity, and type II diabetes
    neurologyneurodegenerative 
    suppressing SREBP1 activation may have a therapeutic value in Amyotrophic lateral sclerosis
    ANIMAL & CELL MODELS
  • Srebf1 acetylation levels were highly elevated in diet-induced obese mice