{"gene":"SREBF1","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":1995,"finding":"The human SREBF1 gene is 26 kb in length with 22 exons and 20 introns; alternative splicing at both 5' and 3' ends generates multiple SREBP-1 isoforms (including SREBP-1a and SREBP-1c), and the gene maps to chromosome 17p11.2.","method":"Gene cloning, sequencing, exon mapping, analysis of human-rodent somatic cell hybrids, fluorescence in situ hybridization","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct structural characterization of the gene by cloning/sequencing with orthogonal cytogenetic mapping; foundational paper replicated broadly","pmids":["7759101"],"is_preprint":false},{"year":1994,"finding":"SREBP-1c and SREBP-2 mRNA levels increase under cholesterol depletion in HepG2 cells, while SREBP-1a/1b mRNA increases transiently then decreases, demonstrating isoform-specific sterol-mediated regulation of SREBP expression.","method":"RNase protection assay in cultured human hepatoma cells under cholesterol depletion and ALLN treatment","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean in vitro assay with defined conditions but single lab, single method","pmids":["8060328"],"is_preprint":false},{"year":2010,"finding":"SIRT1 directly deacetylates SREBP-1c, reducing its stability and occupancy at lipogenic gene promoters; p300 acetylates SREBP-1c at Lys-289 and Lys-309, and acetylation-defective mutants confirmed that acetylation enhances SREBP-1c transactivation and lipogenic gene expression.","method":"Co-immunoprecipitation, tandem mass spectrometry, site-directed mutagenesis, adenoviral siRNA knockdown, ChIP, acetylation assays in HepG2 cells and mouse liver","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mass spectrometry identified sites, mutagenesis validated function, in vivo confirmation with adenoviral knockdown; multiple orthogonal methods in one study","pmids":["20817729"],"is_preprint":false},{"year":2010,"finding":"Insulin activates SREBP-1c by two mechanisms: increasing SREBP-1c mRNA transcription and stimulating proteolytic processing (maturation) of the ER-bound precursor; both require mTORC1, but only processing requires p70 S6-kinase, indicating divergent downstream pathways after mTORC1.","method":"Transgenic rats expressing epitope-tagged human SREBP-1c in liver; pharmacological inhibition of mTORC1 (rapamycin) and S6K; isolated hepatocyte system","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transgenic model plus pharmacological dissection with rapamycin and S6K inhibitor, multiple orthogonal approaches","pmids":["22927400"],"is_preprint":false},{"year":2015,"finding":"CRTC2 competes with COPII subunit Sec23A for binding to Sec31A, thereby blocking COPII-dependent ER-to-Golgi transport and proteolytic processing of SREBP1; mTOR phosphorylates CRTC2 to relieve this inhibition during feeding, promoting SREBP1 maturation and lipogenesis.","method":"Co-immunoprecipitation, hepatic overexpression of mTOR-defective CRTC2 mutant in obese mice, COPII transport assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vivo mouse experiments with dominant mutant, mechanistic pathway dissection across multiple methods","pmids":["26147081"],"is_preprint":false},{"year":2004,"finding":"SREBP-1a binds avidly to the coactivator CBP (via its C/H1 domain) and to the mediator complex (via DRIP150 aa 500–824), accounting for its stronger transcriptional activation compared to SREBP-1c, which lacks the 28 aa N-terminal extension required for these interactions.","method":"In vitro binding assays, co-immunoprecipitation, chromatin immunoprecipitation at SREBP-responsive promoters, deletion/domain-mapping analyses","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus ChIP plus domain mapping with multiple deletion constructs in one study","pmids":["15340088"],"is_preprint":false},{"year":2016,"finding":"PRMT5 binds SREBP1a and symmetrically dimethylates it at R321; this methylation prevents GSK3β-mediated phosphorylation at S430, blocking Fbw7/FBXW7-dependent ubiquitin-proteasome degradation and thereby stabilizing SREBP1a to promote de novo lipogenesis.","method":"Mass spectrometry identification of PRMT5 as binding partner, in vitro methylation assay, mutagenesis (R321 and S430), ubiquitination assays, in vivo tumor xenograft","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mass spectrometry plus in vitro methylation assay plus mutagenesis plus ubiquitination assay; multiple orthogonal methods in single lab","pmids":["26759235"],"is_preprint":false},{"year":2016,"finding":"Insulin induction of SREBP-1c transcription in liver requires a LXRα–C/EBPβ complex that binds to the SREBP-1c promoter; insulin activates this pre-formed complex rather than inducing its formation, and C/EBPβ knockdown reduces insulin-stimulated SREBP-1c mRNA in hepatocytes and mice.","method":"Co-immunoprecipitation from rat liver nuclei, chromatin immunoprecipitation, adenoviral siRNA knockdown in primary rat hepatocytes and mouse liver","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP from native liver nuclei confirmed by ChIP and in vivo siRNA knockdown in two systems","pmids":["27382175"],"is_preprint":false},{"year":2009,"finding":"Salt-inducible kinase (SIK) family members phosphorylate nuclear SREBP-1c at Ser-329, inactivating it and reducing expression of lipogenic target genes; adenoviral SIK1 overexpression lowers hepatic triglycerides and this is rescued by co-expression of a SIK-unresponsive SREBP-1c mutant.","method":"In vitro kinase assay, site-directed mutagenesis, adenoviral overexpression and rescue experiments in primary hepatocytes and mouse liver","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis, in vivo rescue experiment; multiple orthogonal methods","pmids":["19244231"],"is_preprint":false},{"year":2017,"finding":"Hepatocyte-specific deletion of Srebf-2 eliminates production of an endogenous sterol ligand required for LXR activity, which in turn markedly reduces SREBP-1c expression and all LXR-dependent fatty acid/triglyceride synthesis genes, demonstrating that cholesterol and fatty acid synthesis are coupled through LXR-mediated SREBP-1c transcription.","method":"Conditional hepatocyte-specific Srebf-2 knockout mice, gene expression analysis, genetic epistasis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean genetic epistasis with tissue-specific KO; pathway placement rigorously established in vivo","pmids":["28244871"],"is_preprint":false},{"year":2022,"finding":"Ammonia (released from glutamine) binds to SCAP and promotes SCAP-Insig dissociation, triggering SREBP-1 translocation from ER to Golgi for processing and lipogenic gene activation; mutation of SCAP Asp-428 prevents ammonia binding and abolishes SREBP-1 activation, while 25-hydroxycholesterol blocks the ammonia binding site on SCAP.","method":"SCAP mutagenesis (D428A), SCAP-Insig co-immunoprecipitation, tumor xenograft in vivo, pharmacological competition with 25-hydroxycholesterol","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis of binding site plus Co-IP plus in vivo xenograft; multiple orthogonal methods establishing molecular mechanism","pmids":["35534729"],"is_preprint":false},{"year":2021,"finding":"CD36 forms a complex with INSIG2, disrupting the SCAP-INSIG2 interaction and thereby allowing SREBP1 to translocate from ER to Golgi for proteolytic processing; insulin activates CD36 in this pathway, and 25-hydroxycholesterol or betulin (which enhance SCAP-INSIG interaction) reverse CD36-driven SREBP1 cleavage.","method":"Co-immunoprecipitation, proximity ligation assay, hepatocyte-specific CD36 knockout mice, CD36 overexpression in HepG2 cells, pharmacological rescue","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, proximity ligation assay, genetic KO in vivo, pharmacological rescue; multiple orthogonal methods replicated in vivo and in vitro","pmids":["34974159"],"is_preprint":false},{"year":2014,"finding":"PAS kinase (PASK) is required for proteolytic maturation of SREBP-1c (ER-precursor to nuclear form) in liver; genetic and pharmacological inhibition of PASK reduces SREBP-1c processing and lipogenic target gene expression in cultured cells and in mouse/rat liver in vivo.","method":"Genetic PASK knockout, pharmacological PASK inhibitors, in vivo mouse/rat liver assays for SREBP-1c processing","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO plus pharmacological inhibition plus in vivo confirmation in two animal models","pmids":["25001282"],"is_preprint":false},{"year":2016,"finding":"SREBP1 (not LXR) drives the late anti-inflammatory fatty acid biosynthesis program 12–24 hr after TLR4 activation in macrophages, resulting in uncoupling of NFκB binding from gene activation and contributing to resolution of inflammatory responses.","method":"Loss-of-function (SREBP1 knockout/knockdown), gene expression profiling, LXR deletion controls, macrophage functional assays","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined cellular phenotype, appropriate LXR controls, mechanistic pathway placement","pmids":["28041958"],"is_preprint":false},{"year":2004,"finding":"SREBP-1c binds to two sterol regulatory elements (SREa, SREb) in the rat glucokinase (LGK) promoter and activates its transcription; insulin selectively increases SREBP-1c binding to these sites in primary hepatocytes, and a dominant-negative SREBP-1c blocks insulin-induced LGK expression.","method":"Reporter assays, electrophoretic mobility shift assay, chromatin immunoprecipitation in primary hepatocytes, adenoviral dominant-negative SREBP-1c","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP in primary cells, EMSA, dominant-negative rescue; multiple orthogonal methods","pmids":["15123649"],"is_preprint":false},{"year":2004,"finding":"SREBP-1c (and SREBP-1a, SREBP-2) represses transcription of the PEPCK-C gene by binding to two SREs in its promoter; at the -590 SRE, SREBP-1c and Sp1 compete for binding on opposite strands, and a single T/A base change converts the PEPCK-C SRE from an inhibitory to an activating element.","method":"Reporter assays, EMSA with purified proteins, chromatin immunoprecipitation in rat hepatocytes, site-directed mutagenesis of promoter elements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP in primary hepatocytes, EMSA with mutagenesis, reporter assays; multiple orthogonal methods","pmids":["14744869"],"is_preprint":false},{"year":2023,"finding":"FTO demethylates m6A sites on SREBF1 mRNA, stabilizing the transcript and increasing SREBP1 protein and downstream lipogenic gene expression; insulin stimulates FTO transcription via intranuclear insulin receptor beta, and FTO knockdown abrogates the lipogenic effect of insulin.","method":"FTO overexpression/knockdown in hepatocytes and mice, m6A methylation assays, mRNA stability assays, SREBF1/ChREBP knockdown epistasis","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A methylation assays plus mRNA stability plus epistasis knockdown, single lab but orthogonal methods","pmids":["36352530"],"is_preprint":false},{"year":2021,"finding":"SREBF1 concurrently activates de novo lipid synthesis and macroautophagy (lipophagy) in tumor cells; it upregulates NPC2 (a lysosomal cholesterol transporter) to mobilize lipid-droplet-stored cholesterol and fatty acids, thereby maintaining lipid homeostasis for tumor growth.","method":"Loss-of-function studies, autophagy flux assays, lipid droplet quantification, gene expression analysis in tumor cells","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic loss-of-function with cellular phenotype but single lab and limited mechanistic detail in abstract","pmids":["37927089"],"is_preprint":false},{"year":2021,"finding":"SREBF1 activation directly upregulates miR-216a transcription, which reduces CTH/CSE expression and H2S production; reduced H2S impairs ULK1 sulfhydration, inhibiting autophagy-mediated lipid droplet turnover (lipophagy) and promoting hepatic steatosis.","method":"High-fat diet mouse model, ULK1 C951S point mutant, CTH silencing, measurement of H2S production and autophagic flux","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — point mutant validation plus CTH silencing epistasis plus in vivo model; multiple orthogonal approaches in single lab","pmids":["34455909"],"is_preprint":false},{"year":2021,"finding":"SREBP1 is activated by IL-4 in macrophages, driving de novo lipogenesis (DNL) that consumes NADPH; reduced NADPH elevates reactive oxygen species (ROS), which act as second messengers to promote macrophage alternative (M2) activation.","method":"SREBP1 loss-of-function in macrophages, helminth infection model in vivo, ROS measurement, NADPH assays, IL-4 stimulation","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function validated in vivo in infection model with mechanistic NADPH/ROS measurement; multiple orthogonal methods","pmids":["34531575"],"is_preprint":false},{"year":2023,"finding":"The lipogenesis cascade Scap–SREBP1–S1P/S2P forms a super complex with IκBα that sequesters NF-κB near the ER; upon LPS stimulation, Scap transports the complex to the Golgi where S1P/S2P cleaves SREBP1, liberating IκBα for phosphorylation and NF-κB activation.","method":"Co-immunoprecipitation of Scap/SREBP1/IκBα complex, Scap knockout, S1P/S2P inhibition, LPS stimulation assays, subcellular fractionation","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — super-complex Co-IP, genetic Scap KO, protease inhibition, functional NF-κB readout; multiple orthogonal methods","pmids":["37267109"],"is_preprint":false},{"year":2017,"finding":"PPARα transcriptionally activates Insig2a expression via a PPAR-responsive element in its promoter during fasting; elevated Insig2a retains SCAP/SREBP-1c in the ER, thereby suppressing SREBP-1c proteolytic processing and lipogenesis during nutrient starvation.","method":"Transient transfection reporter assay, chromatin immunoprecipitation, Pparα-null mice, primary hepatocyte assays","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP with promoter-mapped PPRE, reporter assay, in vivo null mouse validation; multiple orthogonal methods","pmids":["28855656"],"is_preprint":false},{"year":2018,"finding":"The androgen receptor (AR) and nuclear mTOR co-bind regulatory regions of SREBF1 to control its transcription; dual AR/mTOR activation also promotes SREBF1 cleavage and nuclear translocation, and SREBF1 in turn recruits to FASN and SCD1 promoters to drive lipogenesis in prostate cancer cells.","method":"Chromatin immunoprecipitation, pharmacological inhibition of mTOR, genetic inhibition of SREBF1, nuclear fractionation, lipid accumulation assays","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for AR and mTOR at SREBF1 locus plus pharmacological dissection plus SREBF1 KO phenotype; single lab","pmids":["29784665"],"is_preprint":false},{"year":2016,"finding":"E4BP4, induced by insulin via AKT-mTORC1-SREBP-1c, interacts with nuclear SREBP-1c to preserve its acetylation and protect it from ubiquitination-dependent proteasomal degradation, thereby sustaining robust de novo lipogenesis during the fed state.","method":"Co-immunoprecipitation of E4BP4 and nuclear SREBP-1c, adenoviral shRNA knockdown of E4bp4 in mouse liver, ubiquitination assays, lipogenesis assays","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assays plus in vivo adenoviral KD; single lab but orthogonal methods","pmids":["27252523"],"is_preprint":false},{"year":2014,"finding":"SREBF1 is required for PINK1-PARK2-mediated mitophagy; RNAi screen in Drosophila and human cells identified lipogenesis pathway components including SREBF1 as conserved regulators of mitophagy, and results suggest lipids influence PINK1 stabilization during mitophagy initiation.","method":"Genome-wide RNAi screen in Drosophila and human cell models, functional mitophagy assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide screen validated in two model systems; mechanistic detail on PINK1 stabilization remains limited at abstract level","pmids":["24991824"],"is_preprint":false},{"year":2015,"finding":"Srebp-1 physically interacts with c-Myc, facilitating c-Myc binding to downstream pluripotent gene targets and strengthening c-Myc-mediated enhancement of other Yamanaka factors' binding; this role in somatic cell reprogramming depends on Srebp-1 transcriptional activity but not its ability to bind the canonical E-box motif.","method":"Co-immunoprecipitation of Srebp-1 with c-Myc, overexpression and knockdown experiments, analysis of pluripotent gene expression during reprogramming","journal":"Stem cells","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP plus functional rescue in reprogramming assay; mechanism partially characterized","pmids":["26388522"],"is_preprint":false},{"year":2020,"finding":"Srebf1 is both required and sufficient for midbrain dopaminergic (mDA) neurogenesis; Srebf1 acts downstream of LXR activation, is expressed in radial glia proneural clusters, and regulates transcription factors controlling mDA neurogenesis including Foxa2.","method":"ChIP-seq and transcriptome analysis after LXR activation; loss-of-function and gain-of-function experiments in vitro and in vivo in mice","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus loss- and gain-of-function in vivo; multiple orthogonal methods establishing pathway position","pmids":["32375051"],"is_preprint":false},{"year":2021,"finding":"Hepatic deletion of Mboat7 activates SREBP-1c processing, leading to increased de novo lipogenesis and fatty liver; genetic removal of Scap (which prevents all SREBP processing) in Mboat7-KO mice normalizes hepatic triglycerides, establishing that SREBP-1c processing is required for Mboat7-induced steatosis.","method":"Liver-specific Mboat7 KO mice, double KO (Mboat7/Scap), lipidomics, genetic epistasis","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic epistasis with tissue-specific double KO; mechanistic pathway placement with in vivo lipidomics","pmids":["32859645"],"is_preprint":false},{"year":2023,"finding":"FMO2 directly binds SREBP1 at amino acids 217–296, competing with SCAP for binding to SREBP1 and thereby blocking ER-to-Golgi transport and subsequent proteolytic activation of SREBP1; this suppresses de novo lipogenesis independently of FMO2's enzymatic activity.","method":"Co-immunoprecipitation, RNA sequencing, hepatocyte-specific and global FMO2 knockout mice, FMO2 overexpression in mice, domain mapping","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct binding with domain mapping by Co-IP, in vivo KO and overexpression, competition assay with SCAP; multiple orthogonal methods","pmids":["37874228"],"is_preprint":false},{"year":2023,"finding":"TRIM21 ubiquitinates SREBF1, targeting it for proteasomal degradation; knockdown of TRIM21 increases SREBF1 protein and lipogenic enzyme expression, promoting lipid accumulation in renal carcinoma cells, and SREBF1 is critical for TRIM21-mediated lipogenesis inhibition in vivo.","method":"Co-immunoprecipitation, ubiquitination assays, TRIM21 knockdown and overexpression, orthotopic tumor model","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus in vivo orthotopic model; single lab","pmids":["36694250"],"is_preprint":false},{"year":2024,"finding":"USP11 directly interacts with SREBF1 (via USP11 503–938 aa binding SREBF1 569–1147 aa at K1151) and stabilizes it through K48-linked deubiquitination, preventing proteasomal degradation; USP11 silencing leads to SREBF1 degradation and reduced lipogenesis and tumorigenesis in hepatocellular carcinoma.","method":"Mass spectrometry, co-immunoprecipitation, ubiquitination assays with domain mapping, xenograft mouse model","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry identification plus Co-IP with domain mapping plus ubiquitination assay plus in vivo xenograft; single lab","pmids":["39558331"],"is_preprint":false},{"year":2022,"finding":"SREBP-1 is activated by angiotensin II in mesangial cells via PI3K/Akt signaling, requiring SCAP and protease S1P; ER stress acts as a key mediator of Akt-SREBP-1 activation, and activated SREBP-1 binds the TGF-β promoter to upregulate TGF-β and fibronectin, driving glomerular fibrosis.","method":"ChIP of SREBP-1 at TGF-β promoter, pharmacological inhibition of ER stress and S1P, SREBP inhibitor fatostatin in vivo, angiotensin II infusion mouse model","journal":"Journal of the American Society of Nephrology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus pharmacological dissection plus in vivo angiotensin II infusion model; single lab, multiple methods","pmids":["25398788"],"is_preprint":false},{"year":2012,"finding":"SIRT1 regulates SREBP-1c expression in skeletal muscle in an LXR-dependent manner; SIRT1 deacetylates LXR, and SREBP-1c promoter transactivation by SIRT1 is abolished when LXR response elements are deleted, establishing that SIRT1 controls SREBP-1c through LXR deacetylation.","method":"SIRT1 catalytic domain knockout mice, adenoviral SIRT1 overexpression in human myotubes, LXR acetylation assays, SREBP-1c promoter deletion/reporter assays, gene electrotransfer in vivo","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO plus in vitro overexpression plus promoter deletion assay plus in vivo electrotransfer; multiple methods, single lab","pmids":["22984430"],"is_preprint":false},{"year":2003,"finding":"Controlled expression of nuclear active SREBP-1c (naSREBP-1c) in INS-1 beta-cells causes lipid droplet accumulation, blunts glucose-stimulated insulin secretion, and triggers cell growth arrest and apoptosis by targeting multiple genes in carbohydrate metabolism, lipid biosynthesis, and apoptosis pathways; SREBP-1c processing in beta-cells is slow and irresponsive to acute glucose/insulin unlike lipogenic tissues.","method":"Tet-On inducible expression system in INS-1 cells, gene expression profiling, functional insulin secretion assays, apoptosis assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible overexpression system with defined functional readout and gene profiling; single lab","pmids":["12600983"],"is_preprint":false},{"year":2018,"finding":"ChREBP deficiency in liver reduces SREBP-1c mRNA and protein levels, and conversely, ChREBP overexpression fails to support lipogenic gene expression in Scap-deficient livers; adeno-associated virus rescue of nuclear SREBP-1c in ChREBP-KO mice normalizes lipogenic but not glycolytic genes, establishing that SREBP-1c and ChREBP are both required and act on distinct gene sets.","method":"Liver-specific ChREBP knockout mice, AAV-mediated nuclear SREBP-1c rescue, Scap-knockout epistasis, gene expression analysis","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with tissue-specific KO, AAV rescue, Scap double-KO control; multiple orthogonal approaches","pmids":["29335275"],"is_preprint":false},{"year":2005,"finding":"ER stress activates SREBP-1c cleavage in beta-cells independent of insulin; dominant-negative SREBP-1c prevents glucolipotoxic effects of high glucose (lipid accumulation, impaired insulin secretion, apoptosis, IRS2/Bclxl/Pdx1 downregulation), and SREBP-1 binds the human IRS2 promoter under high glucose and ER stress conditions.","method":"Dominant-negative SREBP-1c in INS-1 cells, ER stress inducers (thapsigargin, tunicamycin), SREBP-1 binding assay on IRS2 promoter in rat islets","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dominant-negative rescue plus promoter binding assay; mechanistic dissection of ER stress pathway using multiple conditions","pmids":["16091421"],"is_preprint":false},{"year":2011,"finding":"SREBP-1c binds to two E-box motifs in the first intron of the clusterin gene and activates its transcription in response to high glucose in primary hepatocytes; ChIP confirms glucose-induced recruitment of SREBP-1c to this intronic region.","method":"Reporter assays, chromatin immunoprecipitation in primary hepatocytes, promoter/intron deletion analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP in primary hepatocytes plus reporter assay; single lab, two orthogonal methods","pmids":["21549685"],"is_preprint":false},{"year":2022,"finding":"SREBP1 positively regulates LGALS3 expression by binding its promoter; BRD2 co-immunoprecipitates with SREBP1's transcription-active domain and with both its own promoter and the Lgals3 promoter DNA, establishing a BRD2-dependent feedforward circuit; BETs inhibition abolishes cholesterol-stimulated SREBP1/LGALS3 upregulation.","method":"ChIP-qPCR, EMSA, co-immunoprecipitation of BRD2 with SREBP1, BETs inhibitor treatment in smooth muscle cells","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR plus EMSA plus Co-IP; single lab, multiple orthogonal methods","pmids":["35694209"],"is_preprint":false},{"year":2021,"finding":"SREBF1 cooperates with master transcription factors TP63 and KLF5 in a feedforward co-regulatory loop to control hundreds of cis-regulatory elements across the SCC epigenome, regulating fatty acid, sphingolipid, and glycerophospholipid biosynthesis; SREBF1 is essential for SCC cell viability and migration.","method":"Loss-of-function assays, LC-MS/MS lipidomics, ChIP-seq/ATAC-seq epigenomic analysis, GSEA of patient samples","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus lipidomics plus loss-of-function; mechanistic pathway placement with multiple orthogonal methods, single lab","pmids":["34272396"],"is_preprint":false},{"year":2025,"finding":"PKM2 dimerization is required for SREBP1 activation and lipid droplet accumulation in microglia; pharmacological activation of TRPV1 inhibits PKM2 dimerization, reduces SREBP1 activation, and improves microglial function and Alzheimer's disease pathology in 3xTg mice.","method":"Transcriptomic analysis of isolated microglia, pharmacological TRPV1 activation (capsaicin), PKM2 dimerization inhibition, lipid droplet quantification, in vivo 3xTg mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model plus PKM2 inhibition plus SREBP1 activation assay; single lab, multiple readouts","pmids":["39809738"],"is_preprint":false}],"current_model":"SREBP-1c/SREBF1 is synthesized as an ER-membrane-bound precursor that undergoes regulated SCAP-dependent transport to the Golgi for sequential S1P/S2P proteolytic cleavage, releasing the active N-terminal bHLH-Zip transcription factor; insulin promotes both transcription (via LXRα–C/EBPβ and mTORC1) and proteolytic processing (via mTORC1→p70 S6K and PASK) of SREBP-1c, while fasting activates PPARα→Insig2a to retain SCAP/SREBP-1c in the ER; the active nuclear form drives expression of all fatty acid and triglyceride synthesis genes and is regulated post-translationally by acetylation (p300 at K289/K309, stabilizing; SIRT1 deacetylating and destabilizing), phosphorylation (SIK1 at S329, inhibitory; GSK3β at S430, promoting Fbw7-dependent degradation), arginine methylation (PRMT5 at R321, stabilizing by blocking GSK3β access), and ubiquitination (TRIM21 and Fbw7 promoting degradation; USP11 and E4BP4 promoting stability); additional inputs include ER-stress-driven SCAP-Insig dissociation, ammonia-mediated SCAP-Insig dissociation, and CD36/INSIG2 complex disruption of SCAP-INSIG2 interaction; beyond canonical lipogenesis, SREBP-1c also represses gluconeogenesis (PEPCK-C), activates glycolytic genes (glucokinase), regulates mitophagy through PINK1 stabilization and the miR-216a/CTH/H2S/ULK1 axis, and coordinates NF-κB spatiotemporal activation via the Scap–SREBP1–S1P/S2P complex."},"narrative":{"mechanistic_narrative":"SREBF1 encodes SREBP-1, a basic helix-loop-helix-zipper transcription factor and master regulator of de novo fatty acid and triglyceride synthesis [PMID:7759101, PMID:15123649]. Synthesized as an ER membrane-bound precursor, it requires SCAP-dependent ER-to-Golgi transport followed by sequential S1P/S2P proteolysis to liberate the active nuclear bHLH-Zip domain; this processing step is the principal control point, governed by SCAP-Insig interactions that are released by ammonia binding to SCAP Asp-428 [PMID:35534729], by CD36-INSIG2 complex formation [PMID:34974159], and conversely retained when fasting-induced PPARα drives Insig2a [PMID:28855656]. Maturation is also gated by accessory factors that act on the trafficking machinery: CRTC2 blocks COPII-dependent transport until mTOR phosphorylates it [PMID:26147081], PAS kinase is required for processing [PMID:25001282], and FMO2 competitively binds SREBP1 (residues 217–296) to exclude SCAP [PMID:37874228]. Insulin is the dominant physiological input, raising both SREBP-1c transcription—through a pre-formed LXRα–C/EBPβ complex on the promoter [PMID:27382175] and mTORC1 signaling—and proteolytic processing via an mTORC1→p70 S6-kinase arm [PMID:22927400]; the human SREBF1 gene generates SREBP-1a and SREBP-1c isoforms by alternative splicing, with SREBP-1a's N-terminal extension conferring stronger coactivator (CBP/mediator) recruitment [PMID:7759101, PMID:15340088]. The active factor is tuned post-translationally by acetylation (p300 at K289/K309 stabilizing, SIRT1 deacetylating and destabilizing) [PMID:20817729], inhibitory phosphorylation by SIK kinases at Ser-329 [PMID:19244231], PRMT5 methylation at R321 that blocks GSK3β-primed Fbw7 degradation [PMID:26759235], and competing ubiquitin pathways (TRIM21 promoting degradation; USP11 and E4BP4 promoting stability) [PMID:36694250, PMID:39558331, PMID:27252523]. SREBP-1 is positioned within an LXR-coupled circuit linking cholesterol and fatty acid synthesis [PMID:28244871] and cooperates with ChREBP on distinct lipogenic and glycolytic gene sets [PMID:29335275], while it also activates glycolytic genes such as glucokinase and represses gluconeogenic PEPCK-C [PMID:15123649, PMID:14744869]. Beyond lipogenesis, SREBP-1 contributes to macrophage inflammatory resolution and M2 activation [PMID:28041958, PMID:34531575], regulates autophagy/mitophagy and lipid-droplet turnover [PMID:37927089, PMID:34455909, PMID:24991824], coordinates NF-κB spatiotemporal activation through a Scap–SREBP1–S1P/S2P–IκBα supercomplex [PMID:37267109], and drives midbrain dopaminergic neurogenesis downstream of LXR [PMID:32375051].","teleology":[{"year":1995,"claim":"Established the genomic structure of SREBF1 and the molecular basis for distinct SREBP-1 isoforms, defining the gene that encodes the lipogenic transcription factor.","evidence":"Gene cloning, sequencing, exon mapping, and cytogenetic localization to 17p11.2","pmids":["7759101"],"confidence":"High","gaps":["Functional differences between splice isoforms not resolved at this stage","Regulatory mechanism of processing not yet addressed"]},{"year":1994,"claim":"Showed that SREBP-1 expression is itself sterol-regulated in an isoform-specific manner, indicating feedback control of the lipogenic program.","evidence":"RNase protection assay in HepG2 cells under cholesterol depletion","pmids":["8060328"],"confidence":"Medium","gaps":["Single-method, single-lab measurement","Does not address proteolytic processing or transcriptional targets"]},{"year":2004,"claim":"Defined SREBP-1's direct transcriptional targets and dual gene-regulatory logic—activating glycolytic glucokinase while repressing gluconeogenic PEPCK-C—linking it to glucose as well as lipid metabolism, and mapped the isoform-specific coactivator interactions underlying SREBP-1a's stronger activation.","evidence":"Reporter assays, EMSA, ChIP, dominant-negative SREBP-1c in hepatocytes, and domain mapping of CBP/mediator binding","pmids":["15123649","14744869","15340088"],"confidence":"High","gaps":["In vivo significance of PEPCK-C repression not quantified","Coactivator binding mapped in vitro/transfection contexts"]},{"year":2010,"claim":"Identified the acetylation switch and the insulin-mTORC1-S6K signaling architecture controlling SREBP-1c, separating transcriptional from proteolytic activation.","evidence":"Mass spectrometry site mapping, mutagenesis, ChIP in HepG2/mouse liver; transgenic rat plus rapamycin/S6K inhibition","pmids":["20817729","22927400"],"confidence":"High","gaps":["Branch point downstream of mTORC1 driving transcription (non-S6K) not identified","Cross-talk between acetylation and processing not integrated"]},{"year":2014,"claim":"Established kinase requirements for SREBP-1c processing (PASK) and identified an inhibitory phosphorylation event (SIK at Ser-329), revealing layered kinase control of activation and inactivation.","evidence":"Genetic and pharmacological PASK inhibition in vivo; in vitro kinase assay, mutagenesis, and adenoviral rescue for SIK","pmids":["25001282","19244231"],"confidence":"High","gaps":["Direct substrate relationship of PASK to processing machinery unclear","Upstream activators of SIK in this context not defined"]},{"year":2015,"claim":"Identified CRTC2 as an mTOR-controlled gatekeeper of COPII-mediated ER-to-Golgi transport of SREBP1, connecting nutrient signaling to the trafficking step of activation.","evidence":"Reciprocal Co-IP, COPII transport assays, hepatic expression of mTOR-defective CRTC2 mutant in obese mice","pmids":["26147081"],"confidence":"High","gaps":["Relative contribution versus SCAP-Insig control not quantified","Stoichiometry of CRTC2/Sec23A/Sec31A competition undefined"]},{"year":2016,"claim":"Resolved how upstream signals stabilize SREBP-1 protein and induce its transcription—PRMT5 methylation blocking degradation, E4BP4 preserving acetylation, and a pre-formed LXRα–C/EBPβ promoter complex relaying insulin—broadening the regulatory network.","evidence":"Mass spectrometry, in vitro methylation and ubiquitination assays, Co-IP, ChIP, and in vivo siRNA knockdown","pmids":["26759235","27252523","27382175"],"confidence":"High","gaps":["Interplay between PRMT5 methylation and acetylation marks not jointly tested","Whether E4BP4 acts on all isoforms unknown"]},{"year":2017,"claim":"Placed SREBP-1c within an LXR-coupled circuit that integrates cholesterol synthesis and fatty acid synthesis, and defined PPARα→Insig2a as the fasting brake on processing.","evidence":"Hepatocyte-specific Srebf-2 KO epistasis; PPARα-null mice with ChIP-mapped PPRE on Insig2a","pmids":["28244871","28855656"],"confidence":"High","gaps":["Identity of the endogenous SREBP-2-derived LXR ligand not chemically defined","Tissue specificity of the PPARα-Insig2a brake not broadly tested"]},{"year":2018,"claim":"Demonstrated combinatorial control of SREBF1 by tissue-relevant factors—ChREBP cooperation on distinct gene sets and AR/nuclear mTOR co-regulation in cancer—showing SREBP-1's outputs are context-partitioned.","evidence":"ChREBP KO with AAV nuclear SREBP-1c rescue and Scap double-KO controls; ChIP for AR/mTOR at SREBF1 with pharmacological dissection","pmids":["29335275","29784665"],"confidence":"High","gaps":["Mechanism partitioning lipogenic vs glycolytic genes between SREBP-1c and ChREBP unresolved","AR/mTOR study confined to a single cancer model"]},{"year":2021,"claim":"Extended SREBP-1 function beyond lipogenesis into immune, autophagy, and trafficking control, including macrophage M2 activation via NADPH/ROS, lipophagy regulation through the miR-216a/CTH/H2S/ULK1 axis, NPC2-mediated lipid mobilization, and CD36-INSIG2-driven processing.","evidence":"Genetic loss-of-function in macrophages with infection model and NADPH/ROS measurement; ULK1 point-mutant and CTH-silencing epistasis; autophagy flux assays; CD36 KO mice with PLA and pharmacological rescue","pmids":["34531575","34455909","37927089","34974159"],"confidence":"High","gaps":["Whether non-lipogenic roles require canonical processing in each context not always tested","Some tumor/autophagy mechanisms characterized in single labs"]},{"year":2022,"claim":"Revealed metabolite- and stress-driven activation routes (ammonia binding SCAP, ER-stress/Akt in fibrosis) and a BRD2-dependent feedforward transcription circuit, expanding the input space of SREBP-1 activation.","evidence":"SCAP D428A mutagenesis with Co-IP and xenograft; ChIP at TGF-β promoter with ER-stress/S1P inhibition in angiotensin II model; ChIP-qPCR/EMSA/Co-IP of BRD2","pmids":["35534729","25398788","35694209"],"confidence":"Medium","gaps":["Physiological range of ammonia-driven activation in normal tissue unclear","Fibrosis and BRD2 circuits each from single labs"]},{"year":2023,"claim":"Defined competing ubiquitin/deubiquitinase control (TRIM21 vs USP11), an enzymatically independent competitive inhibitor of processing (FMO2), m6A-based transcript stabilization (FTO), and a structural role in spatiotemporal NF-κB activation via the Scap–SREBP1–S1P/S2P–IκBα supercomplex.","evidence":"Co-IP/ubiquitination assays with domain mapping and tumor models; FMO2 KO/overexpression with SCAP competition; m6A and mRNA stability assays; supercomplex Co-IP with Scap KO and S1P/S2P inhibition","pmids":["36694250","39558331","37874228","36352530","37267109"],"confidence":"Medium","gaps":["Ubiquitin and DUB studies confined to specific cancer contexts","Stoichiometry/regulation of the NF-κB supercomplex not fully resolved"]},{"year":null,"claim":"How the many parallel activating and inhibitory inputs (trafficking gatekeepers, metabolite sensors, post-translational marks, ubiquitin balance) are quantitatively integrated to set SREBP-1 activity in a given cell state remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified quantitative model integrating processing-stage and stability-stage controls","Isoform-specific deployment of these regulators across tissues not systematically mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[14,15,5,7,26,38]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[14,15,36,31]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3,10,11,28,20]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,8,23,5]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[4,20]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[14,15,9,34,7]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[14,15,5,7,26]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,12,10,11,28]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[13,19,20]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[17,18,24]}],"complexes":["Scap-SREBP1-S1P/S2P-IκBα supercomplex","LXRα-C/EBPβ promoter complex"],"partners":["SCAP","INSIG2","CD36","FMO2","PRMT5","CRTC2","USP11","TRIM21"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P36956","full_name":"Sterol regulatory element-binding protein 1","aliases":["Class D basic helix-loop-helix protein 1","bHLHd1","Sterol regulatory element-binding transcription factor 1"],"length_aa":1147,"mass_kda":121.7,"function":"Precursor of the transcription factor form (Processed sterol regulatory element-binding protein 1), which is embedded in the endoplasmic reticulum membrane (PubMed:32322062). Low sterol concentrations promote processing of this form, releasing the transcription factor form that translocates into the nucleus and activates transcription of genes involved in cholesterol biosynthesis and lipid homeostasis (By similarity) Key transcription factor that regulates expression of genes involved in cholesterol biosynthesis and lipid homeostasis (PubMed:12177166, PubMed:32322062, PubMed:8402897). Binds to the sterol regulatory element 1 (SRE-1) (5'-ATCACCCCAC-3'). Has dual sequence specificity binding to both an E-box motif (5'-ATCACGTGA-3') and to SRE-1 (5'-ATCACCCCAC-3') (PubMed:12177166, PubMed:8402897). Regulates the promoters of genes involved in cholesterol biosynthesis and the LDL receptor (LDLR) pathway of sterol regulation (PubMed:12177166, PubMed:32322062, PubMed:8402897) Isoform expressed only in select tissues, which has higher transcriptional activity compared to SREBP-1C (By similarity). Able to stimulate both lipogenic and cholesterogenic gene expression (PubMed:12177166, PubMed:32497488). Has a role in the nutritional regulation of fatty acids and triglycerides in lipogenic organs such as the liver (By similarity). Required for innate immune response in macrophages by regulating lipid metabolism (By similarity) Predominant isoform expressed in most tissues, which has weaker transcriptional activity compared to isoform SREBP-1A (By similarity). Primarily controls expression of lipogenic gene (PubMed:12177166). Strongly activates global lipid synthesis in rapidly growing cells (By similarity) The absence of Golgi proteolytic processing requirement makes this isoform constitutively active in transactivation of lipogenic gene promoters The absence of Golgi proteolytic processing requirement makes this isoform constitutively active in transactivation of lipogenic gene promoters","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P36956/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SREBF1","classification":"Not Classified","n_dependent_lines":337,"n_total_lines":1208,"dependency_fraction":0.27897350993377484},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SREBF1","total_profiled":1310},"omim":[{"mim_id":"619447","title":"FAMILY WITH SEQUENCE SIMILARITY 189, MEMBER B; FAM189B","url":"https://www.omim.org/entry/619447"},{"mim_id":"619016","title":"IFAP SYNDROME 2; IFAP2","url":"https://www.omim.org/entry/619016"},{"mim_id":"613574","title":"TETRATRICOPEPTIDE REPEAT DOMAIN-CONTAINING PROTEIN 39B; TTC39B","url":"https://www.omim.org/entry/613574"},{"mim_id":"613486","title":"MICRO RNA 33B; MIR33B","url":"https://www.omim.org/entry/613486"},{"mim_id":"612156","title":"MICRO RNA 33A; MIR33A","url":"https://www.omim.org/entry/612156"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"adrenal gland","ntpm":150.1},{"tissue":"liver","ntpm":113.9}],"url":"https://www.proteinatlas.org/search/SREBF1"},"hgnc":{"alias_symbol":["SREBP1","bHLHd1","SREBP-1c","SREBP1a"],"prev_symbol":[]},"alphafold":{"accession":"P36956","domains":[{"cath_id":"4.10.280.10","chopping":"340-392","consensus_level":"medium","plddt":89.3457,"start":340,"end":392},{"cath_id":"-","chopping":"913-989_1008-1041","consensus_level":"medium","plddt":84.4512,"start":913,"end":1041},{"cath_id":"-","chopping":"1081-1143","consensus_level":"medium","plddt":74.9313,"start":1081,"end":1143}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P36956","model_url":"https://alphafold.ebi.ac.uk/files/AF-P36956-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P36956-F1-predicted_aligned_error_v6.png","plddt_mean":63.47},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SREBF1","jax_strain_url":"https://www.jax.org/strain/search?query=SREBF1"},"sequence":{"accession":"P36956","fasta_url":"https://rest.uniprot.org/uniprotkb/P36956.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P36956/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P36956"}},"corpus_meta":[{"pmid":"21029304","id":"PMC_21029304","title":"Hepatic 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alternative splicing at both 5' and 3' ends generates multiple SREBP-1 isoforms (including SREBP-1a and SREBP-1c), and the gene maps to chromosome 17p11.2.\",\n      \"method\": \"Gene cloning, sequencing, exon mapping, analysis of human-rodent somatic cell hybrids, fluorescence in situ hybridization\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct structural characterization of the gene by cloning/sequencing with orthogonal cytogenetic mapping; foundational paper replicated broadly\",\n      \"pmids\": [\"7759101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"SREBP-1c and SREBP-2 mRNA levels increase under cholesterol depletion in HepG2 cells, while SREBP-1a/1b mRNA increases transiently then decreases, demonstrating isoform-specific sterol-mediated regulation of SREBP expression.\",\n      \"method\": \"RNase protection assay in cultured human hepatoma cells under cholesterol depletion and ALLN treatment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean in vitro assay with defined conditions but single lab, single method\",\n      \"pmids\": [\"8060328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SIRT1 directly deacetylates SREBP-1c, reducing its stability and occupancy at lipogenic gene promoters; p300 acetylates SREBP-1c at Lys-289 and Lys-309, and acetylation-defective mutants confirmed that acetylation enhances SREBP-1c transactivation and lipogenic gene expression.\",\n      \"method\": \"Co-immunoprecipitation, tandem mass spectrometry, site-directed mutagenesis, adenoviral siRNA knockdown, ChIP, acetylation assays in HepG2 cells and mouse liver\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mass spectrometry identified sites, mutagenesis validated function, in vivo confirmation with adenoviral knockdown; multiple orthogonal methods in one study\",\n      \"pmids\": [\"20817729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Insulin activates SREBP-1c by two mechanisms: increasing SREBP-1c mRNA transcription and stimulating proteolytic processing (maturation) of the ER-bound precursor; both require mTORC1, but only processing requires p70 S6-kinase, indicating divergent downstream pathways after mTORC1.\",\n      \"method\": \"Transgenic rats expressing epitope-tagged human SREBP-1c in liver; pharmacological inhibition of mTORC1 (rapamycin) and S6K; isolated hepatocyte system\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transgenic model plus pharmacological dissection with rapamycin and S6K inhibitor, multiple orthogonal approaches\",\n      \"pmids\": [\"22927400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CRTC2 competes with COPII subunit Sec23A for binding to Sec31A, thereby blocking COPII-dependent ER-to-Golgi transport and proteolytic processing of SREBP1; mTOR phosphorylates CRTC2 to relieve this inhibition during feeding, promoting SREBP1 maturation and lipogenesis.\",\n      \"method\": \"Co-immunoprecipitation, hepatic overexpression of mTOR-defective CRTC2 mutant in obese mice, COPII transport assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vivo mouse experiments with dominant mutant, mechanistic pathway dissection across multiple methods\",\n      \"pmids\": [\"26147081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SREBP-1a binds avidly to the coactivator CBP (via its C/H1 domain) and to the mediator complex (via DRIP150 aa 500–824), accounting for its stronger transcriptional activation compared to SREBP-1c, which lacks the 28 aa N-terminal extension required for these interactions.\",\n      \"method\": \"In vitro binding assays, co-immunoprecipitation, chromatin immunoprecipitation at SREBP-responsive promoters, deletion/domain-mapping analyses\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus ChIP plus domain mapping with multiple deletion constructs in one study\",\n      \"pmids\": [\"15340088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PRMT5 binds SREBP1a and symmetrically dimethylates it at R321; this methylation prevents GSK3β-mediated phosphorylation at S430, blocking Fbw7/FBXW7-dependent ubiquitin-proteasome degradation and thereby stabilizing SREBP1a to promote de novo lipogenesis.\",\n      \"method\": \"Mass spectrometry identification of PRMT5 as binding partner, in vitro methylation assay, mutagenesis (R321 and S430), ubiquitination assays, in vivo tumor xenograft\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mass spectrometry plus in vitro methylation assay plus mutagenesis plus ubiquitination assay; multiple orthogonal methods in single lab\",\n      \"pmids\": [\"26759235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Insulin induction of SREBP-1c transcription in liver requires a LXRα–C/EBPβ complex that binds to the SREBP-1c promoter; insulin activates this pre-formed complex rather than inducing its formation, and C/EBPβ knockdown reduces insulin-stimulated SREBP-1c mRNA in hepatocytes and mice.\",\n      \"method\": \"Co-immunoprecipitation from rat liver nuclei, chromatin immunoprecipitation, adenoviral siRNA knockdown in primary rat hepatocytes and mouse liver\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP from native liver nuclei confirmed by ChIP and in vivo siRNA knockdown in two systems\",\n      \"pmids\": [\"27382175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Salt-inducible kinase (SIK) family members phosphorylate nuclear SREBP-1c at Ser-329, inactivating it and reducing expression of lipogenic target genes; adenoviral SIK1 overexpression lowers hepatic triglycerides and this is rescued by co-expression of a SIK-unresponsive SREBP-1c mutant.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis, adenoviral overexpression and rescue experiments in primary hepatocytes and mouse liver\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis, in vivo rescue experiment; multiple orthogonal methods\",\n      \"pmids\": [\"19244231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Hepatocyte-specific deletion of Srebf-2 eliminates production of an endogenous sterol ligand required for LXR activity, which in turn markedly reduces SREBP-1c expression and all LXR-dependent fatty acid/triglyceride synthesis genes, demonstrating that cholesterol and fatty acid synthesis are coupled through LXR-mediated SREBP-1c transcription.\",\n      \"method\": \"Conditional hepatocyte-specific Srebf-2 knockout mice, gene expression analysis, genetic epistasis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic epistasis with tissue-specific KO; pathway placement rigorously established in vivo\",\n      \"pmids\": [\"28244871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Ammonia (released from glutamine) binds to SCAP and promotes SCAP-Insig dissociation, triggering SREBP-1 translocation from ER to Golgi for processing and lipogenic gene activation; mutation of SCAP Asp-428 prevents ammonia binding and abolishes SREBP-1 activation, while 25-hydroxycholesterol blocks the ammonia binding site on SCAP.\",\n      \"method\": \"SCAP mutagenesis (D428A), SCAP-Insig co-immunoprecipitation, tumor xenograft in vivo, pharmacological competition with 25-hydroxycholesterol\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis of binding site plus Co-IP plus in vivo xenograft; multiple orthogonal methods establishing molecular mechanism\",\n      \"pmids\": [\"35534729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD36 forms a complex with INSIG2, disrupting the SCAP-INSIG2 interaction and thereby allowing SREBP1 to translocate from ER to Golgi for proteolytic processing; insulin activates CD36 in this pathway, and 25-hydroxycholesterol or betulin (which enhance SCAP-INSIG interaction) reverse CD36-driven SREBP1 cleavage.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, hepatocyte-specific CD36 knockout mice, CD36 overexpression in HepG2 cells, pharmacological rescue\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, proximity ligation assay, genetic KO in vivo, pharmacological rescue; multiple orthogonal methods replicated in vivo and in vitro\",\n      \"pmids\": [\"34974159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PAS kinase (PASK) is required for proteolytic maturation of SREBP-1c (ER-precursor to nuclear form) in liver; genetic and pharmacological inhibition of PASK reduces SREBP-1c processing and lipogenic target gene expression in cultured cells and in mouse/rat liver in vivo.\",\n      \"method\": \"Genetic PASK knockout, pharmacological PASK inhibitors, in vivo mouse/rat liver assays for SREBP-1c processing\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus pharmacological inhibition plus in vivo confirmation in two animal models\",\n      \"pmids\": [\"25001282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SREBP1 (not LXR) drives the late anti-inflammatory fatty acid biosynthesis program 12–24 hr after TLR4 activation in macrophages, resulting in uncoupling of NFκB binding from gene activation and contributing to resolution of inflammatory responses.\",\n      \"method\": \"Loss-of-function (SREBP1 knockout/knockdown), gene expression profiling, LXR deletion controls, macrophage functional assays\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined cellular phenotype, appropriate LXR controls, mechanistic pathway placement\",\n      \"pmids\": [\"28041958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SREBP-1c binds to two sterol regulatory elements (SREa, SREb) in the rat glucokinase (LGK) promoter and activates its transcription; insulin selectively increases SREBP-1c binding to these sites in primary hepatocytes, and a dominant-negative SREBP-1c blocks insulin-induced LGK expression.\",\n      \"method\": \"Reporter assays, electrophoretic mobility shift assay, chromatin immunoprecipitation in primary hepatocytes, adenoviral dominant-negative SREBP-1c\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP in primary cells, EMSA, dominant-negative rescue; multiple orthogonal methods\",\n      \"pmids\": [\"15123649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SREBP-1c (and SREBP-1a, SREBP-2) represses transcription of the PEPCK-C gene by binding to two SREs in its promoter; at the -590 SRE, SREBP-1c and Sp1 compete for binding on opposite strands, and a single T/A base change converts the PEPCK-C SRE from an inhibitory to an activating element.\",\n      \"method\": \"Reporter assays, EMSA with purified proteins, chromatin immunoprecipitation in rat hepatocytes, site-directed mutagenesis of promoter elements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP in primary hepatocytes, EMSA with mutagenesis, reporter assays; multiple orthogonal methods\",\n      \"pmids\": [\"14744869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FTO demethylates m6A sites on SREBF1 mRNA, stabilizing the transcript and increasing SREBP1 protein and downstream lipogenic gene expression; insulin stimulates FTO transcription via intranuclear insulin receptor beta, and FTO knockdown abrogates the lipogenic effect of insulin.\",\n      \"method\": \"FTO overexpression/knockdown in hepatocytes and mice, m6A methylation assays, mRNA stability assays, SREBF1/ChREBP knockdown epistasis\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A methylation assays plus mRNA stability plus epistasis knockdown, single lab but orthogonal methods\",\n      \"pmids\": [\"36352530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SREBF1 concurrently activates de novo lipid synthesis and macroautophagy (lipophagy) in tumor cells; it upregulates NPC2 (a lysosomal cholesterol transporter) to mobilize lipid-droplet-stored cholesterol and fatty acids, thereby maintaining lipid homeostasis for tumor growth.\",\n      \"method\": \"Loss-of-function studies, autophagy flux assays, lipid droplet quantification, gene expression analysis in tumor cells\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic loss-of-function with cellular phenotype but single lab and limited mechanistic detail in abstract\",\n      \"pmids\": [\"37927089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SREBF1 activation directly upregulates miR-216a transcription, which reduces CTH/CSE expression and H2S production; reduced H2S impairs ULK1 sulfhydration, inhibiting autophagy-mediated lipid droplet turnover (lipophagy) and promoting hepatic steatosis.\",\n      \"method\": \"High-fat diet mouse model, ULK1 C951S point mutant, CTH silencing, measurement of H2S production and autophagic flux\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — point mutant validation plus CTH silencing epistasis plus in vivo model; multiple orthogonal approaches in single lab\",\n      \"pmids\": [\"34455909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SREBP1 is activated by IL-4 in macrophages, driving de novo lipogenesis (DNL) that consumes NADPH; reduced NADPH elevates reactive oxygen species (ROS), which act as second messengers to promote macrophage alternative (M2) activation.\",\n      \"method\": \"SREBP1 loss-of-function in macrophages, helminth infection model in vivo, ROS measurement, NADPH assays, IL-4 stimulation\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function validated in vivo in infection model with mechanistic NADPH/ROS measurement; multiple orthogonal methods\",\n      \"pmids\": [\"34531575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The lipogenesis cascade Scap–SREBP1–S1P/S2P forms a super complex with IκBα that sequesters NF-κB near the ER; upon LPS stimulation, Scap transports the complex to the Golgi where S1P/S2P cleaves SREBP1, liberating IκBα for phosphorylation and NF-κB activation.\",\n      \"method\": \"Co-immunoprecipitation of Scap/SREBP1/IκBα complex, Scap knockout, S1P/S2P inhibition, LPS stimulation assays, subcellular fractionation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — super-complex Co-IP, genetic Scap KO, protease inhibition, functional NF-κB readout; multiple orthogonal methods\",\n      \"pmids\": [\"37267109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PPARα transcriptionally activates Insig2a expression via a PPAR-responsive element in its promoter during fasting; elevated Insig2a retains SCAP/SREBP-1c in the ER, thereby suppressing SREBP-1c proteolytic processing and lipogenesis during nutrient starvation.\",\n      \"method\": \"Transient transfection reporter assay, chromatin immunoprecipitation, Pparα-null mice, primary hepatocyte assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with promoter-mapped PPRE, reporter assay, in vivo null mouse validation; multiple orthogonal methods\",\n      \"pmids\": [\"28855656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The androgen receptor (AR) and nuclear mTOR co-bind regulatory regions of SREBF1 to control its transcription; dual AR/mTOR activation also promotes SREBF1 cleavage and nuclear translocation, and SREBF1 in turn recruits to FASN and SCD1 promoters to drive lipogenesis in prostate cancer cells.\",\n      \"method\": \"Chromatin immunoprecipitation, pharmacological inhibition of mTOR, genetic inhibition of SREBF1, nuclear fractionation, lipid accumulation assays\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for AR and mTOR at SREBF1 locus plus pharmacological dissection plus SREBF1 KO phenotype; single lab\",\n      \"pmids\": [\"29784665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"E4BP4, induced by insulin via AKT-mTORC1-SREBP-1c, interacts with nuclear SREBP-1c to preserve its acetylation and protect it from ubiquitination-dependent proteasomal degradation, thereby sustaining robust de novo lipogenesis during the fed state.\",\n      \"method\": \"Co-immunoprecipitation of E4BP4 and nuclear SREBP-1c, adenoviral shRNA knockdown of E4bp4 in mouse liver, ubiquitination assays, lipogenesis assays\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assays plus in vivo adenoviral KD; single lab but orthogonal methods\",\n      \"pmids\": [\"27252523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SREBF1 is required for PINK1-PARK2-mediated mitophagy; RNAi screen in Drosophila and human cells identified lipogenesis pathway components including SREBF1 as conserved regulators of mitophagy, and results suggest lipids influence PINK1 stabilization during mitophagy initiation.\",\n      \"method\": \"Genome-wide RNAi screen in Drosophila and human cell models, functional mitophagy assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide screen validated in two model systems; mechanistic detail on PINK1 stabilization remains limited at abstract level\",\n      \"pmids\": [\"24991824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Srebp-1 physically interacts with c-Myc, facilitating c-Myc binding to downstream pluripotent gene targets and strengthening c-Myc-mediated enhancement of other Yamanaka factors' binding; this role in somatic cell reprogramming depends on Srebp-1 transcriptional activity but not its ability to bind the canonical E-box motif.\",\n      \"method\": \"Co-immunoprecipitation of Srebp-1 with c-Myc, overexpression and knockdown experiments, analysis of pluripotent gene expression during reprogramming\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP plus functional rescue in reprogramming assay; mechanism partially characterized\",\n      \"pmids\": [\"26388522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Srebf1 is both required and sufficient for midbrain dopaminergic (mDA) neurogenesis; Srebf1 acts downstream of LXR activation, is expressed in radial glia proneural clusters, and regulates transcription factors controlling mDA neurogenesis including Foxa2.\",\n      \"method\": \"ChIP-seq and transcriptome analysis after LXR activation; loss-of-function and gain-of-function experiments in vitro and in vivo in mice\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus loss- and gain-of-function in vivo; multiple orthogonal methods establishing pathway position\",\n      \"pmids\": [\"32375051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Hepatic deletion of Mboat7 activates SREBP-1c processing, leading to increased de novo lipogenesis and fatty liver; genetic removal of Scap (which prevents all SREBP processing) in Mboat7-KO mice normalizes hepatic triglycerides, establishing that SREBP-1c processing is required for Mboat7-induced steatosis.\",\n      \"method\": \"Liver-specific Mboat7 KO mice, double KO (Mboat7/Scap), lipidomics, genetic epistasis\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic epistasis with tissue-specific double KO; mechanistic pathway placement with in vivo lipidomics\",\n      \"pmids\": [\"32859645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FMO2 directly binds SREBP1 at amino acids 217–296, competing with SCAP for binding to SREBP1 and thereby blocking ER-to-Golgi transport and subsequent proteolytic activation of SREBP1; this suppresses de novo lipogenesis independently of FMO2's enzymatic activity.\",\n      \"method\": \"Co-immunoprecipitation, RNA sequencing, hepatocyte-specific and global FMO2 knockout mice, FMO2 overexpression in mice, domain mapping\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding with domain mapping by Co-IP, in vivo KO and overexpression, competition assay with SCAP; multiple orthogonal methods\",\n      \"pmids\": [\"37874228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM21 ubiquitinates SREBF1, targeting it for proteasomal degradation; knockdown of TRIM21 increases SREBF1 protein and lipogenic enzyme expression, promoting lipid accumulation in renal carcinoma cells, and SREBF1 is critical for TRIM21-mediated lipogenesis inhibition in vivo.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, TRIM21 knockdown and overexpression, orthotopic tumor model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus in vivo orthotopic model; single lab\",\n      \"pmids\": [\"36694250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP11 directly interacts with SREBF1 (via USP11 503–938 aa binding SREBF1 569–1147 aa at K1151) and stabilizes it through K48-linked deubiquitination, preventing proteasomal degradation; USP11 silencing leads to SREBF1 degradation and reduced lipogenesis and tumorigenesis in hepatocellular carcinoma.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, ubiquitination assays with domain mapping, xenograft mouse model\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry identification plus Co-IP with domain mapping plus ubiquitination assay plus in vivo xenograft; single lab\",\n      \"pmids\": [\"39558331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SREBP-1 is activated by angiotensin II in mesangial cells via PI3K/Akt signaling, requiring SCAP and protease S1P; ER stress acts as a key mediator of Akt-SREBP-1 activation, and activated SREBP-1 binds the TGF-β promoter to upregulate TGF-β and fibronectin, driving glomerular fibrosis.\",\n      \"method\": \"ChIP of SREBP-1 at TGF-β promoter, pharmacological inhibition of ER stress and S1P, SREBP inhibitor fatostatin in vivo, angiotensin II infusion mouse model\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus pharmacological dissection plus in vivo angiotensin II infusion model; single lab, multiple methods\",\n      \"pmids\": [\"25398788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SIRT1 regulates SREBP-1c expression in skeletal muscle in an LXR-dependent manner; SIRT1 deacetylates LXR, and SREBP-1c promoter transactivation by SIRT1 is abolished when LXR response elements are deleted, establishing that SIRT1 controls SREBP-1c through LXR deacetylation.\",\n      \"method\": \"SIRT1 catalytic domain knockout mice, adenoviral SIRT1 overexpression in human myotubes, LXR acetylation assays, SREBP-1c promoter deletion/reporter assays, gene electrotransfer in vivo\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus in vitro overexpression plus promoter deletion assay plus in vivo electrotransfer; multiple methods, single lab\",\n      \"pmids\": [\"22984430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Controlled expression of nuclear active SREBP-1c (naSREBP-1c) in INS-1 beta-cells causes lipid droplet accumulation, blunts glucose-stimulated insulin secretion, and triggers cell growth arrest and apoptosis by targeting multiple genes in carbohydrate metabolism, lipid biosynthesis, and apoptosis pathways; SREBP-1c processing in beta-cells is slow and irresponsive to acute glucose/insulin unlike lipogenic tissues.\",\n      \"method\": \"Tet-On inducible expression system in INS-1 cells, gene expression profiling, functional insulin secretion assays, apoptosis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible overexpression system with defined functional readout and gene profiling; single lab\",\n      \"pmids\": [\"12600983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ChREBP deficiency in liver reduces SREBP-1c mRNA and protein levels, and conversely, ChREBP overexpression fails to support lipogenic gene expression in Scap-deficient livers; adeno-associated virus rescue of nuclear SREBP-1c in ChREBP-KO mice normalizes lipogenic but not glycolytic genes, establishing that SREBP-1c and ChREBP are both required and act on distinct gene sets.\",\n      \"method\": \"Liver-specific ChREBP knockout mice, AAV-mediated nuclear SREBP-1c rescue, Scap-knockout epistasis, gene expression analysis\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with tissue-specific KO, AAV rescue, Scap double-KO control; multiple orthogonal approaches\",\n      \"pmids\": [\"29335275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ER stress activates SREBP-1c cleavage in beta-cells independent of insulin; dominant-negative SREBP-1c prevents glucolipotoxic effects of high glucose (lipid accumulation, impaired insulin secretion, apoptosis, IRS2/Bclxl/Pdx1 downregulation), and SREBP-1 binds the human IRS2 promoter under high glucose and ER stress conditions.\",\n      \"method\": \"Dominant-negative SREBP-1c in INS-1 cells, ER stress inducers (thapsigargin, tunicamycin), SREBP-1 binding assay on IRS2 promoter in rat islets\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dominant-negative rescue plus promoter binding assay; mechanistic dissection of ER stress pathway using multiple conditions\",\n      \"pmids\": [\"16091421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SREBP-1c binds to two E-box motifs in the first intron of the clusterin gene and activates its transcription in response to high glucose in primary hepatocytes; ChIP confirms glucose-induced recruitment of SREBP-1c to this intronic region.\",\n      \"method\": \"Reporter assays, chromatin immunoprecipitation in primary hepatocytes, promoter/intron deletion analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP in primary hepatocytes plus reporter assay; single lab, two orthogonal methods\",\n      \"pmids\": [\"21549685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SREBP1 positively regulates LGALS3 expression by binding its promoter; BRD2 co-immunoprecipitates with SREBP1's transcription-active domain and with both its own promoter and the Lgals3 promoter DNA, establishing a BRD2-dependent feedforward circuit; BETs inhibition abolishes cholesterol-stimulated SREBP1/LGALS3 upregulation.\",\n      \"method\": \"ChIP-qPCR, EMSA, co-immunoprecipitation of BRD2 with SREBP1, BETs inhibitor treatment in smooth muscle cells\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR plus EMSA plus Co-IP; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35694209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SREBF1 cooperates with master transcription factors TP63 and KLF5 in a feedforward co-regulatory loop to control hundreds of cis-regulatory elements across the SCC epigenome, regulating fatty acid, sphingolipid, and glycerophospholipid biosynthesis; SREBF1 is essential for SCC cell viability and migration.\",\n      \"method\": \"Loss-of-function assays, LC-MS/MS lipidomics, ChIP-seq/ATAC-seq epigenomic analysis, GSEA of patient samples\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus lipidomics plus loss-of-function; mechanistic pathway placement with multiple orthogonal methods, single lab\",\n      \"pmids\": [\"34272396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PKM2 dimerization is required for SREBP1 activation and lipid droplet accumulation in microglia; pharmacological activation of TRPV1 inhibits PKM2 dimerization, reduces SREBP1 activation, and improves microglial function and Alzheimer's disease pathology in 3xTg mice.\",\n      \"method\": \"Transcriptomic analysis of isolated microglia, pharmacological TRPV1 activation (capsaicin), PKM2 dimerization inhibition, lipid droplet quantification, in vivo 3xTg mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model plus PKM2 inhibition plus SREBP1 activation assay; single lab, multiple readouts\",\n      \"pmids\": [\"39809738\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SREBP-1c/SREBF1 is synthesized as an ER-membrane-bound precursor that undergoes regulated SCAP-dependent transport to the Golgi for sequential S1P/S2P proteolytic cleavage, releasing the active N-terminal bHLH-Zip transcription factor; insulin promotes both transcription (via LXRα–C/EBPβ and mTORC1) and proteolytic processing (via mTORC1→p70 S6K and PASK) of SREBP-1c, while fasting activates PPARα→Insig2a to retain SCAP/SREBP-1c in the ER; the active nuclear form drives expression of all fatty acid and triglyceride synthesis genes and is regulated post-translationally by acetylation (p300 at K289/K309, stabilizing; SIRT1 deacetylating and destabilizing), phosphorylation (SIK1 at S329, inhibitory; GSK3β at S430, promoting Fbw7-dependent degradation), arginine methylation (PRMT5 at R321, stabilizing by blocking GSK3β access), and ubiquitination (TRIM21 and Fbw7 promoting degradation; USP11 and E4BP4 promoting stability); additional inputs include ER-stress-driven SCAP-Insig dissociation, ammonia-mediated SCAP-Insig dissociation, and CD36/INSIG2 complex disruption of SCAP-INSIG2 interaction; beyond canonical lipogenesis, SREBP-1c also represses gluconeogenesis (PEPCK-C), activates glycolytic genes (glucokinase), regulates mitophagy through PINK1 stabilization and the miR-216a/CTH/H2S/ULK1 axis, and coordinates NF-κB spatiotemporal activation via the Scap–SREBP1–S1P/S2P complex.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SREBF1 encodes SREBP-1, a basic helix-loop-helix-zipper transcription factor and master regulator of de novo fatty acid and triglyceride synthesis [#0, #14]. Synthesized as an ER membrane-bound precursor, it requires SCAP-dependent ER-to-Golgi transport followed by sequential S1P/S2P proteolysis to liberate the active nuclear bHLH-Zip domain; this processing step is the principal control point, governed by SCAP-Insig interactions that are released by ammonia binding to SCAP Asp-428 [#10], by CD36-INSIG2 complex formation [#11], and conversely retained when fasting-induced PPARα drives Insig2a [#21]. Maturation is also gated by accessory factors that act on the trafficking machinery: CRTC2 blocks COPII-dependent transport until mTOR phosphorylates it [#4], PAS kinase is required for processing [#12], and FMO2 competitively binds SREBP1 (residues 217–296) to exclude SCAP [#28]. Insulin is the dominant physiological input, raising both SREBP-1c transcription—through a pre-formed LXRα–C/EBPβ complex on the promoter [#7] and mTORC1 signaling—and proteolytic processing via an mTORC1→p70 S6-kinase arm [#3]; the human SREBF1 gene generates SREBP-1a and SREBP-1c isoforms by alternative splicing, with SREBP-1a's N-terminal extension conferring stronger coactivator (CBP/mediator) recruitment [#0, #5]. The active factor is tuned post-translationally by acetylation (p300 at K289/K309 stabilizing, SIRT1 deacetylating and destabilizing) [#2], inhibitory phosphorylation by SIK kinases at Ser-329 [#8], PRMT5 methylation at R321 that blocks GSK3β-primed Fbw7 degradation [#6], and competing ubiquitin pathways (TRIM21 promoting degradation; USP11 and E4BP4 promoting stability) [#29, #30, #23]. SREBP-1 is positioned within an LXR-coupled circuit linking cholesterol and fatty acid synthesis [#9] and cooperates with ChREBP on distinct lipogenic and glycolytic gene sets [#34], while it also activates glycolytic genes such as glucokinase and represses gluconeogenic PEPCK-C [#14, #15]. Beyond lipogenesis, SREBP-1 contributes to macrophage inflammatory resolution and M2 activation [#13, #19], regulates autophagy/mitophagy and lipid-droplet turnover [#17, #18, #24], coordinates NF-κB spatiotemporal activation through a Scap–SREBP1–S1P/S2P–IκBα supercomplex [#20], and drives midbrain dopaminergic neurogenesis downstream of LXR [#26].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established the genomic structure of SREBF1 and the molecular basis for distinct SREBP-1 isoforms, defining the gene that encodes the lipogenic transcription factor.\",\n      \"evidence\": \"Gene cloning, sequencing, exon mapping, and cytogenetic localization to 17p11.2\",\n      \"pmids\": [\"7759101\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional differences between splice isoforms not resolved at this stage\", \"Regulatory mechanism of processing not yet addressed\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Showed that SREBP-1 expression is itself sterol-regulated in an isoform-specific manner, indicating feedback control of the lipogenic program.\",\n      \"evidence\": \"RNase protection assay in HepG2 cells under cholesterol depletion\",\n      \"pmids\": [\"8060328\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-method, single-lab measurement\", \"Does not address proteolytic processing or transcriptional targets\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined SREBP-1's direct transcriptional targets and dual gene-regulatory logic—activating glycolytic glucokinase while repressing gluconeogenic PEPCK-C—linking it to glucose as well as lipid metabolism, and mapped the isoform-specific coactivator interactions underlying SREBP-1a's stronger activation.\",\n      \"evidence\": \"Reporter assays, EMSA, ChIP, dominant-negative SREBP-1c in hepatocytes, and domain mapping of CBP/mediator binding\",\n      \"pmids\": [\"15123649\", \"14744869\", \"15340088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo significance of PEPCK-C repression not quantified\", \"Coactivator binding mapped in vitro/transfection contexts\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified the acetylation switch and the insulin-mTORC1-S6K signaling architecture controlling SREBP-1c, separating transcriptional from proteolytic activation.\",\n      \"evidence\": \"Mass spectrometry site mapping, mutagenesis, ChIP in HepG2/mouse liver; transgenic rat plus rapamycin/S6K inhibition\",\n      \"pmids\": [\"20817729\", \"22927400\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Branch point downstream of mTORC1 driving transcription (non-S6K) not identified\", \"Cross-talk between acetylation and processing not integrated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established kinase requirements for SREBP-1c processing (PASK) and identified an inhibitory phosphorylation event (SIK at Ser-329), revealing layered kinase control of activation and inactivation.\",\n      \"evidence\": \"Genetic and pharmacological PASK inhibition in vivo; in vitro kinase assay, mutagenesis, and adenoviral rescue for SIK\",\n      \"pmids\": [\"25001282\", \"19244231\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrate relationship of PASK to processing machinery unclear\", \"Upstream activators of SIK in this context not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified CRTC2 as an mTOR-controlled gatekeeper of COPII-mediated ER-to-Golgi transport of SREBP1, connecting nutrient signaling to the trafficking step of activation.\",\n      \"evidence\": \"Reciprocal Co-IP, COPII transport assays, hepatic expression of mTOR-defective CRTC2 mutant in obese mice\",\n      \"pmids\": [\"26147081\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution versus SCAP-Insig control not quantified\", \"Stoichiometry of CRTC2/Sec23A/Sec31A competition undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved how upstream signals stabilize SREBP-1 protein and induce its transcription—PRMT5 methylation blocking degradation, E4BP4 preserving acetylation, and a pre-formed LXRα–C/EBPβ promoter complex relaying insulin—broadening the regulatory network.\",\n      \"evidence\": \"Mass spectrometry, in vitro methylation and ubiquitination assays, Co-IP, ChIP, and in vivo siRNA knockdown\",\n      \"pmids\": [\"26759235\", \"27252523\", \"27382175\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between PRMT5 methylation and acetylation marks not jointly tested\", \"Whether E4BP4 acts on all isoforms unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed SREBP-1c within an LXR-coupled circuit that integrates cholesterol synthesis and fatty acid synthesis, and defined PPARα→Insig2a as the fasting brake on processing.\",\n      \"evidence\": \"Hepatocyte-specific Srebf-2 KO epistasis; PPARα-null mice with ChIP-mapped PPRE on Insig2a\",\n      \"pmids\": [\"28244871\", \"28855656\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the endogenous SREBP-2-derived LXR ligand not chemically defined\", \"Tissue specificity of the PPARα-Insig2a brake not broadly tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated combinatorial control of SREBF1 by tissue-relevant factors—ChREBP cooperation on distinct gene sets and AR/nuclear mTOR co-regulation in cancer—showing SREBP-1's outputs are context-partitioned.\",\n      \"evidence\": \"ChREBP KO with AAV nuclear SREBP-1c rescue and Scap double-KO controls; ChIP for AR/mTOR at SREBF1 with pharmacological dissection\",\n      \"pmids\": [\"29335275\", \"29784665\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism partitioning lipogenic vs glycolytic genes between SREBP-1c and ChREBP unresolved\", \"AR/mTOR study confined to a single cancer model\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended SREBP-1 function beyond lipogenesis into immune, autophagy, and trafficking control, including macrophage M2 activation via NADPH/ROS, lipophagy regulation through the miR-216a/CTH/H2S/ULK1 axis, NPC2-mediated lipid mobilization, and CD36-INSIG2-driven processing.\",\n      \"evidence\": \"Genetic loss-of-function in macrophages with infection model and NADPH/ROS measurement; ULK1 point-mutant and CTH-silencing epistasis; autophagy flux assays; CD36 KO mice with PLA and pharmacological rescue\",\n      \"pmids\": [\"34531575\", \"34455909\", \"37927089\", \"34974159\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether non-lipogenic roles require canonical processing in each context not always tested\", \"Some tumor/autophagy mechanisms characterized in single labs\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed metabolite- and stress-driven activation routes (ammonia binding SCAP, ER-stress/Akt in fibrosis) and a BRD2-dependent feedforward transcription circuit, expanding the input space of SREBP-1 activation.\",\n      \"evidence\": \"SCAP D428A mutagenesis with Co-IP and xenograft; ChIP at TGF-β promoter with ER-stress/S1P inhibition in angiotensin II model; ChIP-qPCR/EMSA/Co-IP of BRD2\",\n      \"pmids\": [\"35534729\", \"25398788\", \"35694209\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological range of ammonia-driven activation in normal tissue unclear\", \"Fibrosis and BRD2 circuits each from single labs\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined competing ubiquitin/deubiquitinase control (TRIM21 vs USP11), an enzymatically independent competitive inhibitor of processing (FMO2), m6A-based transcript stabilization (FTO), and a structural role in spatiotemporal NF-κB activation via the Scap–SREBP1–S1P/S2P–IκBα supercomplex.\",\n      \"evidence\": \"Co-IP/ubiquitination assays with domain mapping and tumor models; FMO2 KO/overexpression with SCAP competition; m6A and mRNA stability assays; supercomplex Co-IP with Scap KO and S1P/S2P inhibition\",\n      \"pmids\": [\"36694250\", \"39558331\", \"37874228\", \"36352530\", \"37267109\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin and DUB studies confined to specific cancer contexts\", \"Stoichiometry/regulation of the NF-κB supercomplex not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the many parallel activating and inhibitory inputs (trafficking gatekeepers, metabolite sensors, post-translational marks, ubiquitin balance) are quantitatively integrated to set SREBP-1 activity in a given cell state remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified quantitative model integrating processing-stage and stability-stage controls\", \"Isoform-specific deployment of these regulators across tissues not systematically mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [14, 15, 5, 7, 26, 38]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [14, 15, 36, 31]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3, 10, 11, 28, 20]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 8, 23, 5]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [4, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [14, 15, 9, 34, 7]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [14, 15, 5, 7, 26]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 12, 10, 11, 28]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13, 19, 20]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [17, 18, 24]}\n    ],\n    \"complexes\": [\n      \"Scap-SREBP1-S1P/S2P-IκBα supercomplex\",\n      \"LXRα-C/EBPβ promoter complex\"\n    ],\n    \"partners\": [\n      \"SCAP\",\n      \"INSIG2\",\n      \"CD36\",\n      \"FMO2\",\n      \"PRMT5\",\n      \"CRTC2\",\n      \"USP11\",\n      \"TRIM21\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}