Affinage

SREBF1

Sterol regulatory element-binding protein 1 · UniProt P36956

Length
1147 aa
Mass
121.7 kDa
Annotated
2026-04-28
100 papers in source corpus 43 papers cited in narrative 43 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SREBF1 encodes a master transcriptional regulator of lipid metabolism that is synthesized as an ER-anchored precursor and activated by regulated intramembrane proteolysis: the SCAP–SREBP1 complex translocates from ER to Golgi for S1P/S2P cleavage, a step promoted by insulin via mTORC1/p70 S6K signaling and CRTC2 phosphorylation relieving COPII blockade, by ammonia-induced SCAP–INSIG dissociation, and by CD36-mediated INSIG2 sequestration, while being opposed by sterol-dependent INSIG retention (reinforced by PPARα-induced Insig2a) and by FMO2 competition with SCAP for SREBP1 binding (PMID:22927400, PMID:26147081, PMID:35534729, PMID:34974159, PMID:28855656, PMID:37874228). Nuclear SREBP1 stability and transcriptional potency are tuned by SIRT1-mediated deacetylation at K289/K309 (destabilizing), SIRT6 repression through multiple axes, PRMT5-mediated R321 dimethylation blocking Fbw7 degradation, SIK phosphorylation at S329 (inhibitory), Cdk1/Plk1-mediated mitotic stabilization, and TRIM21-dependent ubiquitination (PMID:20817729, PMID:24012758, PMID:26759235, PMID:19244231, PMID:27579997, PMID:36694250). Beyond canonical lipogenic target genes, nuclear SREBP1 directly activates glucokinase and granuphilin promoters linking it to hepatic glucose sensing and pancreatic β-cell insulin secretion, drives anti-inflammatory fatty acid biosynthesis during macrophage inflammatory resolution and IL-4-induced alternative activation, participates in NF-κB activation via an ER-localized IκBα super-complex, regulates macroautophagy, and is required for midbrain dopaminergic neurogenesis downstream of LXR (PMID:15123649, PMID:16890542, PMID:28041958, PMID:34531575, PMID:37267109, PMID:32375051).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2003 Medium

    Establishing that intracellular lipid redistribution (sphingolipid accumulation trapping cholesterol) can trigger SREBP-1 cleavage showed that ER cholesterol sensing, not just exogenous sterols, governs SREBP1 processing.

    Evidence Sphingolipid analog studies with cholesterol esterification and LDL receptor assays in human fibroblasts

    PMID:12657626

    Open questions at the time
    • Single lab; indirect cholesterol redistribution model
    • Direct binding of cholesterol to SCAP not tested here
  2. 2004 High

    Demonstrating that SREBP-1c directly binds SRE elements in the glucokinase promoter extended SREBP1's role beyond lipogenesis to hepatic glucose metabolism, establishing it as a mediator of insulin-induced glucokinase expression.

    Evidence ChIP in primary hepatocytes, dominant-negative SREBP-1c, promoter mutagenesis, EMSA

    PMID:15123649

    Open questions at the time
    • Whether SREBP-1c is the sole mediator or acts cooperatively with other insulin-responsive factors at LGK
  3. 2006 High

    Identifying granuphilin as a direct SREBP-1c target in β-cells revealed a non-lipogenic function: SREBP-1c overactivation impairs insulin vesicle exocytosis, linking lipotoxic SREBP1 activation to β-cell dysfunction.

    Evidence Adenoviral overexpression/knockdown and islet knockout with insulin secretion readout

    PMID:16890542

    Open questions at the time
    • Mechanism by which SREBP-1c is activated in diabetic islets not fully delineated
    • Relevance to human β-cell pathology not directly tested
  4. 2009 High

    Identifying SIK as a kinase that phosphorylates nuclear SREBP-1c at S329 to inactivate it provided the first direct inhibitory phosphorylation event on the mature transcription factor.

    Evidence In vitro kinase assay, adenoviral SIK1 overexpression, SREBP-1c S329 mutant rescue in primary hepatocytes

    PMID:19244231

    Open questions at the time
    • Upstream signals controlling SIK activity toward SREBP-1c in vivo
    • Whether S329 phosphorylation promotes degradation or just transcriptional inactivation
  5. 2010 High

    Two contemporaneous advances clarified post-translational control of SREBP1: ER stress was shown to activate SREBP-1c processing independently of insulin (explaining paradoxical lipogenesis in insulin resistance), and SIRT1-mediated deacetylation at K289/K309 was shown to destabilize nuclear SREBP-1c, identifying p300 acetylation as a stabilizing modification.

    Evidence Obese rodent models with ER stress inhibition; tandem mass spectrometry, site-directed mutagenesis, ChIP in mouse liver/HepG2

    PMID:20817729 PMID:21029304

    Open questions at the time
    • Identity of the protease mediating ER-stress-induced SREBP1 cleavage (canonical S1P/S2P vs. alternative)
    • Whether K289/K309 acetylation is dynamically regulated by feeding/fasting cycles in vivo
  6. 2012 High

    Dissecting insulin signaling downstream of mTORC1 revealed that p70 S6K is required for SREBP-1c proteolytic processing but not for its transcriptional induction, demonstrating bifurcation of the mTORC1 pathway at two levels of SREBP1 regulation.

    Evidence Transgenic rat hepatocytes with epitope-tagged SREBP-1c, p70 S6K inhibitors, rapamycin

    PMID:22927400

    Open questions at the time
    • Direct substrate of p70 S6K in the processing pathway not identified
    • Whether other mTORC1 effectors contribute to the processing arm
  7. 2013 High

    SIRT6 was identified as a multi-level repressor of SREBP1 — suppressing transcription, inhibiting cleavage, and activating AMPK — establishing SIRT6 as a central metabolic brake on the SREBP1 lipogenic program.

    Evidence SIRT6-overexpressing mice, AMPK activity assays, SREBP cleavage assays

    PMID:24012758

    Open questions at the time
    • Whether SIRT6 deacetylates SREBP1 directly at this stage was unclear (later addressed)
    • Relative contribution of each of the three SIRT6-mediated mechanisms in physiological contexts
  8. 2014 High

    PAS kinase (PASK) was shown to be required for SREBP-1c proteolytic maturation in liver, and SREBF1 was identified in a genome-wide screen as a participant in PINK1-PARK2-mediated mitophagy, broadening SREBP1's roles to include organelle quality control.

    Evidence PASK KO/pharmacological inhibition in rodent liver; genome-wide RNAi screen in Drosophila and human cells for mitophagy

    PMID:24991824 PMID:25001282

    Open questions at the time
    • PASK's direct substrate in the processing machinery unknown
    • Mechanism by which SREBF1/lipogenesis influences PINK1 stabilization during mitophagy unresolved
  9. 2015 High

    The CRTC2-COPII mechanism was uncovered: CRTC2 blocks SREBP1 ER-to-Golgi transport by competing with Sec23A for Sec31A binding, and mTOR-mediated CRTC2 phosphorylation relieves this block during feeding, providing a direct link between mTOR and the vesicular trafficking step of SREBP1 activation.

    Evidence Co-IP, hepatic overexpression of mTOR-defective CRTC2 mutant in obese mice, genetic rescue

    PMID:26147081

    Open questions at the time
    • Whether CRTC2 regulation is specific to SREBP1 cargo or affects general COPII trafficking
    • Stoichiometry of CRTC2 vs. Sec23A competition in physiological conditions
  10. 2016 High

    Multiple discoveries in 2016 deepened understanding of nuclear SREBP1 regulation and transcriptional control: PRMT5 methylation at R321 blocks Fbw7 degradation; Cdk1/Plk1 stabilize SREBP1 during mitosis by phosphorylating the Fbw7-docking region; LXRα–C/EBPβ cooperatively drive insulin-induced SREBF1 transcription; and SREBP1 was shown to mediate inflammatory resolution in macrophages via anti-inflammatory fatty acid biosynthesis.

    Evidence Mass spectrometry, mutagenesis, kinase assays, Co-IP, ChIP from rat liver nuclei, in vivo C/EBPβ knockdown, macrophage loss-of-function with lipidomics

    PMID:26759235 PMID:27382175 PMID:27579997 PMID:28041958

    Open questions at the time
    • Whether PRMT5-R321 methylation occurs on SREBP-1c isoform or is SREBP-1a-specific
    • Whether Cdk1/Plk1 stabilization has metabolic consequences beyond cell division
    • The identity of anti-inflammatory lipid species produced by SREBP1 in macrophages
  11. 2017 Medium

    PPARα was shown to upregulate Insig2a during fasting by binding a PPRE in its promoter, thereby retaining SREBP-1c in the ER; separately, oleate (product of SCD1) was identified as a positive regulator of SREBP-1 expression and nuclear accumulation, creating a feedforward loop.

    Evidence ChIP for PPARα at Insig2a promoter, PPARα-null mice; SCD1 KO and oleate-producing transgenic mice

    PMID:28851735 PMID:28855656

    Open questions at the time
    • Whether Insig2a-mediated retention is quantitatively dominant over other fasting suppression mechanisms
    • Mechanism by which oleate promotes SREBP-1 expression (transcriptional vs. post-transcriptional)
  12. 2020 Medium

    SREBF1 was shown to be necessary and sufficient for midbrain dopaminergic neurogenesis downstream of LXR, acting through proneural factor Foxa2, revealing a developmental role outside metabolism.

    Evidence ChIP-seq, transcriptomics, loss-of-function and gain-of-function in mouse midbrain

    PMID:32375051

    Open questions at the time
    • Whether the lipogenic or transcription-factor function of SREBP1 mediates neurogenesis
    • Relevance to human neurodevelopment not established
  13. 2021 High

    Multiple 2021 studies expanded the regulatory network: CD36 disrupts SCAP–INSIG2 interaction to promote SREBP1 processing; SIRT6 directly deacetylates SREBP1c and LXRα; IL-4 activates SREBP1 in macrophages to consume NADPH and generate ROS for alternative activation; TRIM21 ubiquitinates SREBP1 for proteasomal degradation; and SREBP1 upregulates macroautophagy/NPC2 for lipid mobilization in tumors.

    Evidence Co-IP/PLA with CD36 KO mice; SIRT6 liver-specific KO; macrophage SREBP1 KO with NADPH/ROS measurement in helminth infection; TRIM21 ubiquitination assay; SREBP1 gain/loss-of-function with autophagy flux assays

    PMID:34425214 PMID:34531575 PMID:34974159 PMID:36694250 PMID:37927089

    Open questions at the time
    • Whether CD36-INSIG2 interaction is regulated by specific lipid ligands
    • TRIM21-mediated degradation not tested in non-cancer contexts
    • Whether autophagy regulation is a direct or indirect SREBP1 target gene effect
  14. 2022 High

    Ammonia was identified as a metabolic signal that binds SCAP to dissociate SCAP–INSIG and promote SREBP-1 Golgi translocation; the SCAP D428A mutation and 25-hydroxycholesterol competition defined the binding site, linking glutamine catabolism to lipogenesis.

    Evidence Site-directed mutagenesis, 25-HC competition, cell-based and in vivo tumor models

    PMID:35534729

    Open questions at the time
    • Structural basis of ammonia binding to SCAP
    • Whether ammonia-SCAP axis operates in normal hepatocytes or is tumor-specific
  15. 2023 High

    Three 2023 discoveries refined SREBP1 pathway architecture: the SCAP–SREBP1–S1P/S2P complex was shown to harbor IκBα as a super-complex component whose liberation upon Golgi cleavage activates NF-κB; FMO2 was identified as a competitor of SCAP for SREBP1 binding that blocks ER-to-Golgi transport; and FTO-mediated m6A demethylation was found to stabilize SREBF1 mRNA downstream of insulin-activated nuclear insulin receptor β.

    Evidence Co-IP/loss-of-function/S1P-S2P inhibition for IκBα super-complex; FMO2 domain mapping and hepatocyte-specific KO; m6A sequencing and mRNA stability assays

    PMID:36352530 PMID:37267109 PMID:37874228

    Open questions at the time
    • Stoichiometry and structural organization of the SCAP–SREBP1–IκBα super-complex
    • Whether FMO2 inhibition of SREBP1 transport is regulated by its enzymatic activity
    • Whether FTO-SREBF1 mRNA axis is relevant outside hepatocytes

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of ammonia and sterol sensing by SCAP, the relative contribution of each post-translational modification in physiological vs. pathological contexts, whether SREBP1's developmental and immune roles require its canonical lipogenic targets or reflect distinct transcriptional programs, and the mechanistic link between SREBF1/lipogenesis and PINK1-PARK2 mitophagy.
  • No high-resolution structure of SCAP–SREBP1–INSIG ternary complex
  • Integrated quantitative model of competing PTMs on nuclear SREBP1 lacking
  • Lipogenic vs. non-lipogenic transcriptional programs of SREBP1 not systematically distinguished

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 15 GO:0003677 DNA binding 4
Localization
GO:0005634 nucleus 8 GO:0005783 endoplasmic reticulum 7 GO:0005794 Golgi apparatus 5
Pathway
R-HSA-1430728 Metabolism 18 R-HSA-74160 Gene expression (Transcription) 7 R-HSA-392499 Metabolism of proteins 5 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 3 R-HSA-9609507 Protein localization 3 R-HSA-9612973 Autophagy 2 R-HSA-1266738 Developmental Biology 1
Partners
CRTC2FBXW7INSIG1INSIG2PRMT5SCAPSIRT1SIRT6
Complex memberships
SCAP-SREBP1-INSIGSCAP-SREBP1-IκBα super-complex

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 SREBP-1c undergoes proteolytic maturation initiated at the endoplasmic reticulum, and ER stress activates this cleavage independently of insulin, explaining paradoxical lipogenesis activation in insulin-resistant liver. In vivo studies in obese rodents with ER stress inhibition; biochemical fractionation and proteolytic processing assays Diabetes, obesity & metabolism High 21029304
2010 SIRT1 deacetylates SREBP-1c at Lys-289 and Lys-309 (acetylated by p300), decreasing its stability and occupancy at lipogenic gene promoters; acetylation-defective mutants confirm this mechanism. Tandem mass spectrometry, site-directed mutagenesis, adenoviral siRNA knockdown, chromatin immunoprecipitation, Co-IP in mouse liver and HepG2 cells The Journal of biological chemistry High 20817729
2015 CRTC2 competes with Sec23A (COPII subunit) for binding to Sec31A (another COPII subunit), blocking SREBP1 ER-to-Golgi transport; mTOR phosphorylates CRTC2 to attenuate this inhibition during feeding, enabling SREBP1 proteolytic processing. Co-IP, hepatic overexpression of mTOR-defective CRTC2 mutant in obese mice, genetic rescue experiments Nature High 26147081
2012 Insulin-stimulated SREBP-1c proteolytic processing requires mTORC1 and p70 S6-kinase, whereas insulin induction of SREBP-1c mRNA requires mTORC1 but not p70 S6-kinase, demonstrating divergent downstream pathways. Transgenic rat hepatocytes expressing epitope-tagged SREBP-1c, p70 S6-kinase inhibitors, rapamycin treatment Proceedings of the National Academy of Sciences of the United States of America High 22927400
2016 LXRα and C/EBPβ form a complex that binds the SREBP-1c promoter at LXR-binding sites required for insulin induction; knockdown of C/EBPβ reduces insulin-induced SREBP-1c mRNA in rat hepatocytes and mouse liver. Co-immunoprecipitation from rat liver nuclei, chromatin immunoprecipitation, in vivo C/EBPβ knockdown Proceedings of the National Academy of Sciences of the United States of America High 27382175
2016 PRMT5 symmetrically dimethylates SREBP1a at R321, promoting its transcriptional activity and preventing GSK3β-mediated phosphorylation at S430, thereby blocking Fbw7-dependent ubiquitin-proteasome degradation. Mass spectrometry identification of PRMT5 as binding partner, mutagenesis of R321, in vitro kinase assay, Co-IP, in vivo xenograft Cancer research High 26759235
2022 Ammonia released from glutamine promotes SCAP-Insig dissociation and SREBP-1 translocation to the Golgi for processing; 25-hydroxycholesterol blocks ammonia's binding site on SCAP, and SCAP D428A mutation abolishes SREBP-1 activation. Site-directed mutagenesis (SCAP D428A), 25-hydroxycholesterol competition assay, cell-based and in vivo tumor growth studies Nature metabolism High 35534729
2021 CD36 forms a complex with INSIG2 that disrupts SCAP-INSIG2 interaction, enabling SREBP1 translocation from ER to Golgi for processing; betulin or 25-hydroxycholesterol, which enhance SCAP-INSIG interaction, reverses this effect. Co-immunoprecipitation, proximity ligation assay, hepatocyte-specific CD36 knockout mice, RNA sequencing Molecular metabolism High 34974159
2013 SIRT6 represses SREBP1 by: (1) suppressing SREBP1/2 transcription, (2) inhibiting SREBP1/2 cleavage into active forms, and (3) activating AMPK to increase AMP/ATP ratio and promote AMPK-mediated phosphorylation and inhibition of SREBP1. SIRT6 overexpressing mice (MOSES), AMPK activity assays, SREBP cleavage assays, genetic and biochemical studies Cell reports High 24012758
2016 During mitosis, Cdk1 phosphorylates nuclear SREBP1 creating a docking site for Plk1; Plk1 then phosphorylates residues in the C-terminal domain blocking Fbw7 interaction and attenuating Fbw7-dependent SREBP1 degradation, stabilizing SREBP1 during cell division. Mutagenesis, kinase assays, co-immunoprecipitation, mitotic cell synchronization experiments Cell cycle (Georgetown, Tex.) High 27579997
2009 Salt-inducible kinase (SIK) phosphorylates nuclear SREBP-1c at Ser329, inactivating it; in vitro kinase assay and SREBP-1c Ser329 mutant rescue experiments confirm SIK-mediated repression of hepatic lipogenic gene expression. In vitro kinase assay, adenoviral overexpression of SIK1, SREBP-1c mutant co-infection rescue, RT-PCR in primary hepatocytes The Journal of biological chemistry High 19244231
2014 PAS kinase (PASK) is required for proteolytic maturation of SREBP-1c in cultured cells and in mouse/rat liver; pharmacological PASK inhibition decreases hepatic lipogenic SREBP-1c target gene expression and improves lipid and glucose metabolism. Genetic PASK knockout, pharmacological inhibitor, adenoviral overexpression in rodent liver, lipid profiling Cell reports High 25001282
2016 SREBP1 contributes to the resolution phase of TLR4-induced inflammation in macrophages 12–24 hr post-activation by driving anti-inflammatory fatty acid biosynthesis, which uncouples NFκB binding from gene activation; this is LXR-independent. SREBP1 loss-of-function in macrophages, ChIP for NFκB, lipidomic analysis, gene expression profiling Cell metabolism High 28041958
2023 The Scap-SREBP1-S1P/S2P lipogenesis cascade forms a super complex with IκBα near the ER; upon LPS stimulation, Scap transports the complex to the Golgi where SREBP1 cleavage by S1P/S2P liberates IκBα for IKK-mediated phosphorylation and NF-κB activation. Co-immunoprecipitation, Scap/SREBP1 loss-of-function, S1P/S2P inhibition, NF-κB reporter assays Cell reports High 37267109
2004 SREBP-1c directly binds to two functional SRE elements (SREa and SREb) in the rat liver glucokinase (LGK) promoter to mediate insulin-induced LGK transcription; adenoviral expression of dominant-negative SREBP-1c blocks insulin-induced LGK expression. Chromatin immunoprecipitation in primary hepatocytes, adenoviral dominant-negative SREBP-1c, promoter mutagenesis, EMSA The Journal of biological chemistry High 15123649
2006 SREBP-1c transcriptionally activates the granuphilin gene (a component of insulin vesicle docking machinery) in beta cells; knockdown or knockout of either granuphilin or SREBP-1c restores potassium-stimulated insulin secretion in diabetic islets. Adenoviral overexpression and knockdown, islet knockout, promoter binding assays Cell metabolism High 16890542
2021 SREBP1 is activated by interleukin-4 in macrophages to drive de novo lipogenesis, which consumes NADPH, reducing antioxidant capacity, raising ROS levels that serve as second messengers promoting alternative macrophage activation; SREBP1 is required for this process in vivo in helminth infection. SREBP1 loss-of-function in macrophages, NADPH/ROS measurements, in vivo helminth infection model Nature metabolism High 34531575
2015 p54(nrb)/NONO binds the nuclear form of SREBP-1a via its conserved Y267 residue, increasing nuclear SREBP-1a protein stability and stimulating SREBP-1-mediated lipogenic gene transcription and lipid production in breast cancer cells. Co-immunoprecipitation, Y267 mutagenesis, knockdown studies, in vivo tumor growth Oncogene Medium 26148231
2013 JNK2 regulates SREBP-1c expression in human adipocytes in response to insulin; JNK2 coimmunoprecipitates with SREBP-1, and JNK2 knockdown suppresses insulin-induced nuclear accumulation of active SREBP-1 and downstream lipogenic enzyme expression. Microarray, siRNA knockdown of JNK2, Co-immunoprecipitation, nuclear fractionation, fatty acid synthesis assay Journal of lipid research Medium 23515281
2019 Nuclear active SREBP1 (nSREBP1) binds the PERK promoter and upregulates its expression, amplifying ER stress, cell cycle arrest, apoptosis, and autophagy through the PERK signaling pathway. Promoter binding assay (luciferase reporter), overexpression of SREBP1/nSREBP1, PERK pathway analysis The FEBS journal Medium 31736227
2021 SIRT6 directly interacts with LXRα, ChREBP, and SREBP1c in hepatocytes, and suppresses SREBP1c transcriptional activity through direct deacetylation; SIRT6 liver-specific knockout mice develop more severe fatty liver disease. Co-immunoprecipitation, deacetylation assays, Sirt6 liver-specific knockout mice on Western diet Biochimica et biophysica acta. Molecular basis of disease Medium 34425214
2017 PPARα upregulates Insig2a expression in fasting mouse liver by binding a PPAR-responsive element (-126 to -114 bp) in the Insig2a promoter; elevated Insig2a retains SREBP-1c in the ER and inhibits its processing during nutrient starvation. Transient transfection promoter assay, chromatin immunoprecipitation, Pparα-null mice Scientific reports Medium 28855656
2023 FMO2 directly interacts with SREBP1 at amino acids 217-296, competing with SCAP for SREBP1 binding and inhibiting SREBP1 translocation from ER to Golgi, thereby suppressing de novo lipogenesis. Co-immunoprecipitation, domain mapping, hepatocyte-specific FMO2 KO mice, RNA sequencing Hepatology (Baltimore, Md.) Medium 37874228
2014 SREBP-1 is activated by angiotensin II in rat mesangial cells through TSHR→cAMP/PKA→PPARα pathway, requiring SCAP and S1P protease; ER stress mediates Akt-SREBP-1 activation, and activated SREBP-1 directly binds the TGF-β promoter to upregulate TGF-β and fibronectin. ChIP showing SREBP-1 binding to TGF-β promoter, pharmacological inhibitors of ER stress/SREBP-1, in vivo angiotensin II infusion with fatostatin treatment Journal of the American Society of Nephrology : JASN Medium 25398788
2015 Srebp-1 interacts with c-Myc in somatic cell reprogramming; Srebp-1 facilitates c-Myc binding to downstream pluripotency targets and strengthens Yamanaka factor binding, promoting pluripotent gene expression; this function requires SREBP-1's transactivation domain but not its E-box binding capacity. Co-immunoprecipitation, ChIP for c-Myc targets, domain mutant analysis, overexpression/knockdown during reprogramming Stem cells (Dayton, Ohio) Medium 26388522
2014 SREBF1 plays a role in PINK1-PARK2-mediated mitophagy; components of the lipogenesis pathway including SREBF1 influence PINK1 stabilization during mitophagy initiation, conserved from Drosophila to human cells. Genome-wide RNAi screen in Drosophila and human cell models, mitophagy assays Autophagy Medium 24991824
2020 Srebf1 is required and sufficient for midbrain dopaminergic (mDA) neurogenesis; it acts downstream of LXR activation and regulates proneural transcription factors including Foxa2; Srebf1 is expressed in radial glia during mDA neurogenesis. LXR activation ChIP-seq and transcriptomics, loss-of-function and gain-of-function in vitro and in vivo (mouse midbrain) Cell reports Medium 32375051
2023 TRIM21 ubiquitinates SREBF1 and promotes its proteasomal degradation, suppressing lipogenic enzyme expression; Co-IP confirmed TRIM21-SREBF1 interaction; TRIM21 overexpression decreases lipid content via SREBF1 ubiquitination. Co-immunoprecipitation, ubiquitination assay, TRIM21 overexpression/knockdown, in vivo orthotopic model Journal of experimental & clinical cancer research : CR Medium 36694250
2009 SREBP-1 and SREBP-2 directly bind the proximal promoter region of the CASP7 gene and positively regulate caspase 7 mRNA and protein expression, as shown by ChIP and SREBP knockdown. Chromatin immunoprecipitation, SREBP-1/2 siRNA knockdown, promoter analysis The Biochemical journal Medium 19323650
2017 Oleate specifically restores SREBP-1 expression and increases nuclear SREBP-1 accumulation in SCD1-deficient hepatocytes, demonstrating that oleate (a SCD1 product) acts as a positive regulator of SREBP-1 signaling activity. SCD1 knockout mice, transgenic mice producing oleate (GLS5) in liver, HepG2 cell oleate treatment, nuclear fractionation American journal of physiology. Endocrinology and metabolism Medium 28851735
2021 SREBF1/SREBP-1 upregulates macroautophagy and NPC2 (lysosomal cholesterol transporter) expression in tumor cells, enabling hydrolysis of lipid droplets and mobilization of stored cholesterol/fatty acids to maintain lipid homeostasis for tumor growth. SREBP-1 gain/loss-of-function, autophagy flux assays, NPC2 promoter binding, tumor growth models Autophagy Medium 37927089
2011 SREBP-1c regulates hepatic clusterin expression through two E-box motifs in the first intronic region (resembling a ChoRE) that are activated by SREBP-1c but not ChREBP; glucose induces SREBP-1c recruitment to these E-box motifs. Chromatin immunoprecipitation in primary hepatocytes, promoter/intronic reporter assays, E-box mutagenesis Biochemical and biophysical research communications Medium 21549685
2023 BHLHE40 regulates SREBF1 transcription both as a classic transcription factor binding the SREBF1 promoter and by linking SREBF1 enhancer and promoter regions (chromatin looping); BHLHE40-SREBF1-SCD axis protects pancreatic cancer cells from ferroptosis. ChIP-seq, RNA-seq, Hi-C/chromosome conformation capture, ChIP-PCR, SREBF1 gain/loss-of-function Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 38064101
2021 Hepatic deletion of Mboat7 activates SREBP-1c processing; removal of Scap (SREBP cleavage-activating protein) in Mboat7 LSKO mice normalizes hepatic triglycerides, confirming that increased SREBP-1c processing is required for Mboat7 deletion-induced steatosis. Liver-specific Mboat7 KO mice, Scap/Mboat7 double KO, lipidomics, de novo lipogenesis measurement Journal of lipid research Medium 32859645
2019 TSH, acting through TSHR, triggers hepatic SREBP-1c activity via the cAMP/PKA/PPARα pathway associated with decreased AMPK activity; Tshr-/-Srebp-1c-/- double knockout mice show no difference in liver triglyceride content compared to Tshr+/+Srebp-1c-/- mice, confirming SREBP-1c is essential for TSH-induced lipid accumulation. Tshr-/- mice, Tshr-/-Srebp-1c-/- double knockout, pharmacological activators/inhibitors (forskolin, H89, AICAR), hepatocyte in vitro experiments Journal of hepatology Medium 25016220
2007 HCV core protein increases SREBP1 gene expression and enhances SREBP1 transcriptional activity in hepatocytes, leading to upregulation of lipogenic enzyme genes; this was demonstrated in transiently transfected and stably expressing hepatocyte cell lines. HCV core protein transfection in multiple hepatocyte cell lines, transcriptional activity assays Biochemical and biophysical research communications Low 17331464
2005 Chronic high glucose treatment in INS-1 beta cells leads to ER stress marker induction and enhanced SREBP-1 binding to the human IRS2 promoter; dominant-negative SREBP-1c prevents glucolipotoxic effects including lipid accumulation and impaired insulin secretion. Dominant-negative SREBP-1c expression (Tet-On inducible), SREBP-1 binding assay on IRS2 promoter, ER stress marker analysis Journal of cell science Medium 16091421
2021 SETD8 (stabilized by USP17-mediated deubiquitination) transcriptionally activates SREBP1 by monomethylating H4K20 at the SREBP1 locus, elevating lipid biosynthesis in clear cell renal cell carcinoma. siRNA/inhibitor knockdown, ChIP for H4K20me1 at SREBP1 locus, Co-IP of USP17-SETD8, ubiquitination assay Cancer letters Medium 34942305
2021 BRG1 (chromatin remodeling protein) is recruited to the TLR4 promoter and activates TLR4 transcription; ectopic TLR4 then restores SREBP1a expression in BRG1-null hepatocytes; a BRG1-TLR4-SREBP1a axis mediates LPS-induced liver injury. Liver conditional BRG1 KO mice, adenoviral TLR4/SREBP1a rescue, promoter ChIP for BRG1 at TLR4 promoter Frontiers in cell and developmental biology Medium 33816466
2023 FTO demethylates m6A sites on SREBF1 mRNA, stabilizing it; FTO knockdown abrogates insulin's lipogenic effect, and insulin stimulates FTO transcription via intranuclear insulin receptor beta, placing FTO upstream of SREBF1 in hepatic lipogenesis. m6A sequencing, FTO overexpression/knockdown, SREBF1 mRNA stability assays, insulin receptor beta nuclear localization studies Journal of molecular cell biology Medium 36352530
2015 Vitamin B12 deficiency reduces the AdoMet/AdoHcy methylation potential, causing hypomethylation of the SREBF1 promoter and increased SREBF1 expression and cholesterol biosynthesis in human adipocytes. Bisulfite pyrosequencing of SREBF1 promoter, genome-wide methylation analysis, methylation inhibitor (5-aza-2'-deoxycytidine), in vitro adipocyte B12-deficiency model Clinical epigenetics Medium 25763114
2003 Overaccumulation of sphingolipids in endocytic compartments acts as a molecular trap for cholesterol, reducing cholesterol at the ER and inducing SREBP-1 cleavage and LDL receptor upregulation in human fibroblasts. SL analog studies (hydrolyzable vs. non-hydrolyzable), cholesterol esterification assays, LDL receptor upregulation measurements The Journal of biological chemistry Medium 12657626
2021 In zebrafish, SREBF1 knockout alters lipid mediator profiles (particularly 11,12-EET levels), bone mineral density, and gene expression pathways including fatty acid elongation and arachidonic acid metabolism, confirming SREBF1 as a bone-muscle pleiotropic gene. Zebrafish SREBF1 knockout, targeted lipidomics (LC-MS/MS of 48 lipid mediators), RNA-sequencing, bone mineral density measurement Endocrinology Medium 33068391

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c. Diabetes, obesity & metabolism 550 21029304
2010 SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism. The Journal of biological chemistry 442 20817729
2007 SREBP-1c transcription factor and lipid homeostasis: clinical perspective. Hormone research 300 17344645
2008 SREBP-1c, regulated by the insulin and AMPK signaling pathways, plays a role in nonalcoholic fatty liver disease. International journal of molecular medicine 293 18360697
2016 SREBP1 Contributes to Resolution of Pro-inflammatory TLR4 Signaling by Reprogramming Fatty Acid Metabolism. Cell metabolism 283 28041958
2015 The CREB coactivator CRTC2 controls hepatic lipid metabolism by regulating SREBP1. Nature 258 26147081
2005 ER stress and SREBP-1 activation are implicated in beta-cell glucolipotoxicity. Journal of cell science 226 16091421
2012 Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase. Proceedings of the National Academy of Sciences of the United States of America 225 22927400
2019 Berberine attenuates nonalcoholic hepatic steatosis through the AMPK-SREBP-1c-SCD1 pathway. Free radical biology & medicine 208 31226399
2012 Connecting mTORC1 signaling to SREBP-1 activation. Current opinion in lipidology 208 22449814
2020 ACSL4 reprograms fatty acid metabolism in hepatocellular carcinoma via c-Myc/SREBP1 pathway. Cancer letters 185 33340617
2021 CD36 promotes de novo lipogenesis in hepatocytes through INSIG2-dependent SREBP1 processing. Molecular metabolism 163 34974159
2013 Multiple regulatory layers of SREBP1/2 by SIRT6. Cell reports 132 24012758
2014 Thyrotropin increases hepatic triglyceride content through upregulation of SREBP-1c activity. Journal of hepatology 123 25016220
2007 HCV core protein induces hepatic lipid accumulation by activating SREBP1 and PPARgamma. Biochemical and biophysical research communications 120 17331464
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2016 Arginine Methylation of SREBP1a via PRMT5 Promotes De Novo Lipogenesis and Tumor Growth. Cancer research 111 26759235
2022 Ammonia stimulates SCAP/Insig dissociation and SREBP-1 activation to promote lipogenesis and tumour growth. Nature metabolism 110 35534729
2018 Oxidative Stress Inhibits Healthy Adipose Expansion Through Suppression of SREBF1-Mediated Lipogenic Pathway. Diabetes 103 29618580
2004 SREBP-1c mediates the insulin-dependent hepatic glucokinase expression. The Journal of biological chemistry 84 15123649
2003 The transcription factor SREBP-1c is instrumental in the development of beta-cell dysfunction. The Journal of biological chemistry 84 12600983
2003 Sphingolipid storage induces accumulation of intracellular cholesterol by stimulating SREBP-1 cleavage. The Journal of biological chemistry 80 12657626
2024 Rutin ameliorated lipid metabolism dysfunction of diabetic NAFLD via AMPK/SREBP1 pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 79 38394735
2023 Regulation and targeting of SREBP-1 in hepatocellular carcinoma. Cancer metastasis reviews 77 38036934
2021 SREBP1-induced fatty acid synthesis depletes macrophages antioxidant defences to promote their alternative activation. Nature metabolism 75 34531575
2015 Vitamin B12 insufficiency induces cholesterol biosynthesis by limiting s-adenosylmethionine and modulating the methylation of SREBF1 and LDLR genes. Clinical epigenetics 73 25763114
2015 p54(nrb)/NONO regulates lipid metabolism and breast cancer growth through SREBP-1A. Oncogene 70 26148231
2002 Up-regulation of SREBP-1c and lipogenic genes in skeletal muscles after exercise training. Biochemical and biophysical research communications 68 12163031
2016 Insulin induction of SREBP-1c in rodent liver requires LXRα-C/EBPβ complex. Proceedings of the National Academy of Sciences of the United States of America 66 27382175
2019 Salicylic acid treats acne vulgaris by suppressing AMPK/SREBP1 pathway in sebocytes. Experimental dermatology 63 30972839
2007 Involvement of glomerular SREBP-1c in diabetic nephropathy. Biochemical and biophysical research communications 59 17961514
2006 Granuphilin is activated by SREBP-1c and involved in impaired insulin secretion in diabetic mice. Cell metabolism 58 16890542
2023 Aberrant elevation of FTO levels promotes liver steatosis by decreasing the m6A methylation and increasing the stability of SREBF1 and ChREBP mRNAs. Journal of molecular cell biology 56 36352530
2017 Oleate activates SREBP-1 signaling activity in SCD1-deficient hepatocytes. American journal of physiology. Endocrinology and metabolism 56 28851735
2016 AMPK and SREBP-1c mediate the anti-adipogenic effect of β-hydroxyisovalerylshikonin. International journal of molecular medicine 56 26865314
2009 Salt-inducible kinase regulates hepatic lipogenesis by controlling SREBP-1c phosphorylation. The Journal of biological chemistry 56 19244231
2015 Srebp-1 Interacts with c-Myc to Enhance Somatic Cell Reprogramming. Stem cells (Dayton, Ohio) 54 26388522
2008 Polymorphisms in SREBF1 and SREBF2, two antipsychotic-activated transcription factors controlling cellular lipogenesis, are associated with schizophrenia in German and Scandinavian samples. Molecular psychiatry 54 18936756
2023 SREBF1/SREBP-1 concurrently regulates lipid synthesis and lipophagy to maintain lipid homeostasis and tumor growth. Autophagy 52 37927089
2014 SIRT1 promotes endometrial tumor growth by targeting SREBP1 and lipogenesis. Oncology reports 50 25270091
2021 Fatostatin reverses progesterone resistance by inhibiting the SREBP1-NF-κB pathway in endometrial carcinoma. Cell death & disease 49 34039951
2021 Hepatic deletion of Mboat7 (LPIAT1) causes activation of SREBP-1c and fatty liver. Journal of lipid research 48 32859645
2022 The NQO1/p53/SREBP1 axis promotes hepatocellular carcinoma progression and metastasis by regulating Snail stability. Oncogene 47 36253445
2019 PGC1β Regulates Breast Tumor Growth and Metastasis by SREBP1-Mediated HKDC1 Expression. Frontiers in oncology 47 31058090
2018 JAZF1 ameliorates age and diet-associated hepatic steatosis through SREBP-1c -dependent mechanism. Cell death & disease 47 30154417
2016 The phosphorylation-dependent regulation of nuclear SREBP1 during mitosis links lipid metabolism and cell growth. Cell cycle (Georgetown, Tex.) 44 27579997
2011 Haplotype combination of SREBP-1c gene sequence variants is associated with growth traits in cattle. Genome 43 21639705
2008 Investigation of the role of SREBP-1c in the pathogenesis of HCV-related steatosis. Journal of hepatology 42 18752865
2019 The active nuclear form of SREBP1 amplifies ER stress and autophagy via regulation of PERK. The FEBS journal 41 31736227
2014 SREBP-1 Mediates Angiotensin II-Induced TGF-β1 Upregulation and Glomerular Fibrosis. Journal of the American Society of Nephrology : JASN 41 25398788
2003 Lipogenesis in fetal rat lung: importance of C/EBPalpha, SREBP-1c, and stearoyl-CoA desaturase. American journal of respiratory cell and molecular biology 41 12896875
2021 SIRT6 controls hepatic lipogenesis by suppressing LXR, ChREBP, and SREBP1. Biochimica et biophysica acta. Molecular basis of disease 39 34425214
2023 TRIM21 attenuates renal carcinoma lipogenesis and malignancy by regulating SREBF1 protein stability. Journal of experimental & clinical cancer research : CR 38 36694250
2019 Emodin Induced SREBP1-Dependent and SREBP1-Independent Apoptosis in Hepatocellular Carcinoma Cells. Frontiers in pharmacology 38 31297058
2019 Glycerol kinase 5 confers gefitinib resistance through SREBP1/SCD1 signaling pathway. Journal of experimental & clinical cancer research : CR 37 30791926
2013 A novel JNK2/SREBP-1c pathway involved in insulin-induced fatty acid synthesis in human adipocytes. Journal of lipid research 35 23515281
2021 An AKT/PRMT5/SREBP1 axis in lung adenocarcinoma regulates de novo lipogenesis and tumor growth. Cancer science 34 34033176
2019 Clinical importance of FASN in relation to HIF-1α and SREBP-1c in gastric adenocarcinoma. Life sciences 34 30914315
2017 Kukoamine A attenuates insulin resistance and fatty liver through downregulation of Srebp-1c. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 34 28254666
2017 PPARα-dependent Insig2a overexpression inhibits SREBP-1c processing during fasting. Scientific reports 34 28855656
2014 PAS kinase drives lipogenesis through SREBP-1 maturation. Cell reports 34 25001282
2009 Human caspase 7 is positively controlled by SREBP-1 and SREBP-2. The Biochemical journal 34 19323650
2022 Resveratrol Inhibits Proliferation and Induces Autophagy by Blocking SREBP1 Expression in Oral Cancer Cells. Molecules (Basel, Switzerland) 33 36500345
2022 Exosomal miR-122 promotes adipogenesis and aggravates obesity through the VDR/SREBF1 axis. Obesity (Silver Spring, Md.) 32 35170865
2022 Apolipoprotein A4 Restricts Diet-Induced Hepatic Steatosis via SREBF1-Mediated Lipogenesis and Enhances IRS-PI3K-Akt Signaling. Molecular nutrition & food research 32 35909347
2019 Critical evaluation of the DNA-methylation markers ABCG1 and SREBF1 for Type 2 diabetes stratification. Epigenomics 32 31169416
2014 SREBF1 links lipogenesis to mitophagy and sporadic Parkinson disease. Autophagy 31 24991824
2023 The roles and mechanisms of SREBP1 in cancer development and drug response. Genes & diseases 30 38560498
2021 SREBP1 promotes invasive phenotypes by upregulating CYR61/CTGF via the Hippo-YAP pathway. Endocrine-related cancer 30 34821220
2019 Interplay of PKD3 with SREBP1 Promotes Cell Growth via Upregulating Lipogenesis in Prostate Cancer Cells. Journal of Cancer 30 31772672
2021 miR-23a/b-3p promotes hepatic lipid accumulation by regulating Srebp-1c and Fas. Journal of molecular endocrinology 29 34723832
2011 Overexpression of Insig-1 protects β cell against glucolipotoxicity via SREBP-1c. Journal of biomedical science 29 21843373
2023 BHLHE40 Inhibits Ferroptosis in Pancreatic Cancer Cells via Upregulating SREBF1. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 28 38064101
2023 The Scap-SREBP1-S1P/S2P lipogenesis signal orchestrates the homeostasis and spatiotemporal activation of NF-κB. Cell reports 27 37267109
2012 Sirtuin 1 regulates SREBP-1c expression in a LXR-dependent manner in skeletal muscle. PloS one 24 22984430
2024 EXO1/P53/SREBP1 axis-regulated lipid metabolism promotes prostate cancer progression. Journal of translational medicine 23 38279172
2023 PRP19 Enhances Esophageal Squamous Cell Carcinoma Progression by Reprogramming SREBF1-Dependent Fatty Acid Metabolism. Cancer research 22 36723974
2021 Deletion of SREBF1, a Functional Bone-Muscle Pleiotropic Gene, Alters Bone Density and Lipid Signaling in Zebrafish. Endocrinology 22 33068391
2021 SETD8 stabilized by USP17 epigenetically activates SREBP1 pathway to drive lipogenesis and oncogenesis of ccRCC. Cancer letters 22 34942305
2021 BRG1 Links TLR4 Trans-Activation to LPS-Induced SREBP1a Expression and Liver Injury. Frontiers in cell and developmental biology 21 33816466
2016 Camphene, a Plant Derived Monoterpene, Exerts Its Hypolipidemic Action by Affecting SREBP-1 and MTP Expression. PloS one 21 26784701
2007 Identification of mutated Srebf1 as a QTL influencing risk for hepatic steatosis in the spontaneously hypertensive rat. Hypertension (Dallas, Tex. : 1979) 21 18071061
2019 LncRNA PU.1 AS regulates arsenic-induced lipid metabolism through EZH2/Sirt6/SREBP-1c pathway. Journal of environmental sciences (China) 20 31471020
2009 Induction of SREBP-1c mRNA by differentiation and LXR ligand in human keratinocytes. The Journal of investigative dermatology 20 19242521
2024 CLDN6 inhibits breast cancer growth and metastasis through SREBP1-mediated RAS palmitoylation. Cellular & molecular biology letters 19 39169280
2020 Srebf1 Controls Midbrain Dopaminergic Neurogenesis. Cell reports 19 32375051
2011 SREBP-1c regulates glucose-stimulated hepatic clusterin expression. Biochemical and biophysical research communications 19 21549685
2008 L-cysteine down-regulates SREBP-1c-regulated lipogenic enzymes expression via glutathione in HepG2 cells. Annals of nutrition & metabolism 19 18544973
2024 Darolutamide-mediated phospholipid remodeling induces ferroptosis through the SREBP1-FASN axis in prostate cancer. International journal of biological sciences 18 39309439
2021 Therapeutic Targeting of Nonalcoholic Fatty Liver Disease by Downregulating SREBP-1C Expression via AMPK-KLF10 Axis. Frontiers in molecular biosciences 18 34869587
2025 SREBF1-based metabolic reprogramming in prostate cancer promotes tumor ferroptosis resistance. Cell death discovery 17 39988626
2024 Loss of SREBP-1c ameliorates iron-induced liver fibrosis by decreasing lipocalin-2. Experimental & molecular medicine 17 38622198
2023 FMO2 ameliorates nonalcoholic fatty liver disease by suppressing ER-to-Golgi transport of SREBP1. Hepatology (Baltimore, Md.) 17 37874228
2005 A novel SREBP-1 splice variant: tissue abundance and transactivation potency. Biochimica et biophysica acta 17 16153721
2025 The TRPV1-PKM2-SREBP1 axis maintains microglial lipid homeostasis in Alzheimer's disease. Cell death & disease 16 39809738
2021 Dihydroartemisinin ameliorates retinal vascular dysfunction in diabetes mellitus via the FASN/Kmal-mTOR/SREBP1 feedback loop. Pharmacological research 16 34619345
2007 Clenbuterol inhibits SREBP-1c expression by activating CREB1. Journal of biochemistry and molecular biology 16 17669268
2021 Ilexgenin A restrains CRTC2 in the cytoplasm to prevent SREBP1 maturation via AMP kinase activation in the liver. British journal of pharmacology 15 33434948
2019 Critical Role of SREBP-1c Large-VLDL Pathway in Environment-Induced Hypertriglyceridemia of Apo AV Deficiency. Arteriosclerosis, thrombosis, and vascular biology 15 30700132
2019 CYP1A2 contributes to alcohol-induced abnormal lipid metabolism through the PTEN/AKT/SREBP-1c pathway. Biochemical and biophysical research communications 15 30979496