{"gene":"CIDEC","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2008,"finding":"FSP27/CIDEC localizes to lipid droplets in white adipocytes; ablation in mice causes multilocular lipid droplets, increased lipolysis, and decreased triacylglycerol storage. Expression of FSP27 in COS cells promoted large lipid droplet formation, demonstrating a direct role in unilocular lipid droplet formation and triglyceride storage.","method":"FSP27 knockout mice, siRNA depletion in cultured adipocytes, ectopic expression in COS cells, lipid droplet morphology and lipolysis assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic (KO mice) and cell-based gain/loss-of-function experiments with defined morphological and biochemical phenotypes, replicated across multiple model systems","pmids":["18654663"],"is_preprint":false},{"year":2008,"finding":"Fsp27/CIDEC is a direct transcriptional target of PPARγ in liver; forced expression in hepatocytes increases triglyceride levels and lipid droplet formation, while shRNA knockdown reduces hepatic triglyceride accumulation.","method":"Adenoviral overexpression and shRNA knockdown in hepatocytes in vitro and in vivo; functional PPRE identified in Fsp27 promoter; ChIP and reporter assays","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (gain-of-function, loss-of-function, promoter analysis) in both in vitro and in vivo settings","pmids":["18396136"],"is_preprint":false},{"year":2008,"finding":"Fsp27 deficiency in mice causes upregulation of BAT-specific genes (FoxC2, PPARα, PGC1α), increased mitochondrial activity and size in WAT, and a 'browning' of white adipose tissue phenotype, indicating Fsp27 acts as a regulator of WAT identity and mitochondrial activity.","method":"Fsp27−/− and Fsp27/lep double-knockout mice; MEF differentiation in vitro; mitochondrial protein and gene expression analysis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple phenotypic readouts replicated across multiple mouse models","pmids":["18682832"],"is_preprint":false},{"year":2008,"finding":"PPARγ2 transcriptionally activates Cidec by binding to a PPRE at the −219/−207 region of the Cidec promoter during adipogenesis.","method":"ChIP assay, reporter (luciferase) assay, gel shift assay, site-directed mutagenesis of PPRE","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal methods (ChIP, reporter assay, gel shift, mutagenesis) in a single lab","pmids":["18845124"],"is_preprint":false},{"year":2008,"finding":"FSP27 expression in adipocytes is regulated by TNF-α (downregulation) and insulin (upregulation via phosphatidylinositol 3-kinase signals). Ectopic FSP27 expression in 293T cells and preadipocytes induces apoptotic hallmarks.","method":"Northern blot, pharmacological inhibition (LY-294002), ectopic expression in 293T cells, detection of apoptosis markers","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological inhibition + expression analysis; single lab, multiple methods but indirect pathway inference","pmids":["18198355"],"is_preprint":false},{"year":1992,"finding":"The FSP27 promoter confers adipocyte-specific expression; a palindromic sequence (TTCGAAA) is necessary for this specificity and is bound by C/EBP and C/EBP-like proteins from preadipocyte and adipocyte nuclear extracts.","method":"Reporter gene transfection, DNase I footprinting, gel shift assay with nuclear extracts","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — DNase I footprinting + gel shift + reporter assay with nuclear extracts in multiple adipogenic cell lines","pmids":["1339452"],"is_preprint":false},{"year":2003,"finding":"Human CIDE-3 (CIDEC) induces apoptosis when transfected into 293T cells, as shown by nuclear DNA fragmentation assay. Both full-length CIDE-3 and the alternatively spliced CIDE-3α isoform (lacking exon 3) retain apoptosis-inducing activity and similar subcellular localization in cytosolic corpuscles.","method":"DNA fragmentation assay, GFP fusion localization, RT-PCR for isoforms","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — DNA fragmentation assay with ectopic expression; multiple isoforms tested; single lab","pmids":["12429024"],"is_preprint":false},{"year":2009,"finding":"A homozygous nonsense CIDEC mutation (E186X) that disrupts the CIDE-C domain causes mislocalization of the mutant protein and failure to increase lipid droplet size in transfected cells, resulting in partial lipodystrophy with multiloculated adipocyte lipid droplets in the patient.","method":"Transfection of mutant and wild-type CIDEC in cells, lipid droplet size assay, patient genetic analysis","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional domain mutagenesis validated by cell-based assay and corroborated by human genetic evidence","pmids":["20049731"],"is_preprint":false},{"year":2009,"finding":"FSP27 CIDE-C domain (amino acids 174–192) is required for lipid droplet localization. FSP27-induced apoptosis involves caspase-9 and mitochondrial cytochrome c release and also requires this 19-amino-acid region. FSP27 CIDE-C domain interacts with CIDEA, and co-expression of CIDEA reduces FSP27 protein levels.","method":"eGFP-FSP27 deletion constructs, lipid droplet localization assays in HeLa cells, caspase inhibitor experiments, cytochrome c release assay, co-immunoprecipitation","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 2 / Moderate — domain mapping with multiple deletion constructs, co-IP for interaction, functional apoptosis assays; single lab with multiple orthogonal methods","pmids":["19843876"],"is_preprint":false},{"year":2011,"finding":"Fsp27 is focally enriched at lipid droplet–lipid droplet contact sites (LDCS). FRAP analysis demonstrates lipid exchange between contacting LDs in Fsp27-expressing but not Fsp27-deficient adipocytes. Live-cell imaging reveals directional net lipid transfer from smaller to larger LDs at LDCSs mediated by Fsp27, consistent with internal pressure differences between LD pairs.","method":"FRAP, live-cell imaging, Fsp27-deficient adipocytes, fluorescence microscopy of LDCS","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — FRAP and live imaging with genetic controls (KO cells); mechanistic model validated by biophysical analysis; single paper with multiple orthogonal methods","pmids":["22144693"],"is_preprint":false},{"year":2011,"finding":"FSP27 promotes lipid droplet clustering followed by fusion. Domain mapping shows amino acids 173–220 are necessary and sufficient for LD targeting and initial clustering; amino acids 120–140 are essential but not sufficient for LD enlargement; amino acids 120–210 are necessary and sufficient for both clustering and fusion. Triglyceride accumulation is associated with LD enlargement but not clustering alone.","method":"GFP-fusion deletion mutant constructs, fluorescence microscopy in adipocytes","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — systematic deletion mutagenesis with multiple constructs and defined functional readouts; single lab","pmids":["22194867"],"is_preprint":false},{"year":2013,"finding":"Perilipin1 (Plin1) interacts with the CIDE-N domain of Fsp27 and markedly increases Fsp27-mediated lipid exchange, lipid transfer, and lipid droplet growth. The CIDE-N domain of Fsp27 forms homodimers required for lipid exchange and transfer; disruption of CIDE-N homodimerization abolishes these activities. Plin1 can rescue the activity of CIDE-N homodimerization-defective Fsp27 mutants.","method":"Co-immunoprecipitation, FRAP, live-cell imaging, site-directed mutagenesis of CIDE-N homodimerization interface, RNAi depletion of Plin1 and Fsp27","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, FRAP, live imaging, and mutagenesis in a single study; single lab with multiple orthogonal methods","pmids":["23481402"],"is_preprint":false},{"year":2013,"finding":"FSP27 (CIDEC) co-localizes and interacts with PLIN1 in human primary adipocytes. The C-terminal domain of FSP27 (aa 120–220) mediates interaction with PLIN1. Co-expression of FSP27 and PLIN1 increases average lipid droplet size and promotes unilocular lipid droplet formation.","method":"Co-immunoprecipitation, co-localization by immunofluorescence, triglyceride content assay, glycerol release assay, ectopic expression in human adipocytes","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP and co-localization in primary human adipocytes, domain mapping, functional lipid droplet readout; single lab","pmids":["23399566"],"is_preprint":false},{"year":2013,"finding":"Crystal structure of the CIDE-N domain of FSP27 solved at 2.0 Å reveals a homodimeric interface similar to the CAD/ICAD heterodimer; structural homologs include the PB1 domain of BEM1P, ubiquitin-like domain of BAG6, and ubiquitin.","method":"X-ray crystallography at 2.0 Å resolution","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — high-resolution crystal structure with mechanistic interpretation; single lab","pmids":["24025675"],"is_preprint":false},{"year":2014,"finding":"FSP27 (aa 120–220) interacts with ATGL in human adipocytes to inhibit its lipolytic function and promote triglyceride storage. FSP27 depletion increases lipolysis and impairs insulin signaling (decreased AKT phosphorylation); reducing lipolysis by ATGL depletion or FSP27 overexpression protects against free fatty acid-induced insulin resistance.","method":"Co-immunoprecipitation, siRNA knockdown of FSP27 and ATGL, ATGL KO mouse-derived fibroblasts, lipolysis assays, AKT phosphorylation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP plus orthogonal genetic (siRNA, KO cells) and biochemical (lipolysis, phospho-AKT) assays; single lab with multiple methods","pmids":["24627478"],"is_preprint":false},{"year":2014,"finding":"AMPK activation (by AICAR or phenformin) induces ubiquitination and proteasomal degradation of FSP27 in adipocytes, leading to multilocularization of lipid droplets. HSC70 is identified as a binding partner of FSP27 that stabilizes it; HSC70 knockdown reduces FSP27 half-life.","method":"Co-immunoprecipitation, mass spectrometry, siRNA knockdown, cycloheximide chase assay, AICAR/phenformin treatment, ubiquitination assay","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction confirmed by Co-IP, CHX chase, and multiple pharmacological and genetic perturbations; single lab","pmids":["25315694"],"is_preprint":false},{"year":2015,"finding":"CREBH (liver-enriched transcription factor) directly activates the Fsp27β promoter (but not the Fsp27α/PPARγ-driven promoter) in hepatocytes. Fsp27β localizes to lipid droplet surfaces and suppresses lipolysis; its enforced expression promotes lipid droplet enlargement and hepatic TG accumulation.","method":"Promoter reporter assays, constitutively active CREBH overexpression, CREBH KO fasted mice, lipid droplet imaging, lipolysis assays","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — reporter assays plus genetic KO model plus gain-of-function with functional readouts; multiple methods in single paper","pmids":["25125366"],"is_preprint":false},{"year":2015,"finding":"CIDEC/FSP27 is a direct transcriptional target of PPARα in mouse and human hepatocytes. Adenoviral silencing of hepatic Fsp27 abolishes fasting-induced liver steatosis. PPARα agonist (fenofibrate) and Fsp27 ASO synergize to reduce hepatic TG accumulation.","method":"ChIP, promoter reporter assay, adenoviral shRNA in vivo, ASO treatment, fasting model","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, reporter assay, and in vivo genetic silencing with functional metabolic readouts","pmids":["25418138"],"is_preprint":false},{"year":2015,"finding":"Cidec promotes adipocyte differentiation by interacting with AMPKα1 and promoting its degradation via the ubiquitin–proteasome pathway, thereby reducing AMPKα levels.","method":"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence co-localization, RNAi knockdown, proteasome inhibitor experiments","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP and co-localization, functional degradation assay; single lab","pmids":["26367078"],"is_preprint":false},{"year":2016,"finding":"TNF-α downregulates CIDEC expression in human adipocytes through MEK/ERK-mediated phosphorylation of PPARγ at Ser273 and its subsequent nuclear export; inhibiting MEK/ERK prevents TNF-α-mediated CIDEC downregulation.","method":"MEK/ERK inhibitors, constitutively active MEK1 mutant, immunofluorescence, subcellular fractionation, reporter assay","journal":"Obesity (Silver Spring, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibitors, constitutively active mutant, and reporter assay in human adipocytes; single lab","pmids":["27062372"],"is_preprint":false},{"year":2017,"finding":"HDAC6 deacetylates CIDEC at lysine 56 (K56); the acetyltransferase PCAF acetylates CIDEC at K56 on the endoplasmic reticulum. Acetylation of CIDEC stabilizes it and promotes lipid droplet fusion, while HDAC6-mediated deacetylation leads to CIDEC destabilization. Fatty acids prevent CIDEC deacetylation by promoting dissociation of CIDEC from HDAC6 and increasing association with PCAF.","method":"Adipocyte-specific Hdac6 KO mice, Co-IP, mass spectrometry, site-directed mutagenesis at K56, lipid droplet fusion assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vivo KO model plus biochemical identification of acetylation site (K56) by mutagenesis, Co-IP, and functional assay; multiple orthogonal methods in single high-quality study","pmids":["28287402"],"is_preprint":false},{"year":2018,"finding":"Growth hormone (GH) reduces FSP27 expression by activating MEK/ERK, which phosphorylates PPARγ at Ser273 and causes its translocation from nucleus to cytosol, thereby reducing PPARγ transcriptional activity at the FSP27 promoter. FSP27 overexpression inhibits PPARγ Ser273 phosphorylation and promotes its nuclear retention, suppressing GH-induced lipolysis.","method":"MEK/ERK inhibitors, GH antagonist treatment, immunofluorescence, PPARγ Ser273 phosphorylation assay, FSP27 overexpression in human adipocytes","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological and genetic tools in human adipocytes; single lab","pmids":["30325658"],"is_preprint":false},{"year":2018,"finding":"GH modulates FSP27 expression through both MEK/ERK- and STAT5-dependent intracellular signaling, which interact to regulate PPARγ activity on the FSP27 promoter. FSP27 overexpression fully suppresses GH-induced lipolysis and insulin resistance.","method":"Pathway-specific inhibitors, transgenic GH overexpression mice, FSP27 overexpression, lipolysis assays","journal":"The Journal of endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and transgenic approaches with functional readouts; single lab","pmids":["30400015"],"is_preprint":false},{"year":2018,"finding":"FTO promotes SREBP1c nuclear translocation and maturation, which in turn transcriptionally activates CIDEC via its promoter. CIDEC knockdown reduces SREBP1c-induced lipogenesis in HepG2 cells.","method":"FTO overexpression/knockdown, SREBP1c overexpression/knockdown, luciferase reporter assay for CIDEC promoter, lipogenesis assays","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay plus genetic gain/loss-of-function; single lab","pmids":["29486327"],"is_preprint":false},{"year":2018,"finding":"The polybasic RKKR motif in the linker region between CIDE-N and CIDE-C domains of CIDEC interacts with acidic phospholipids via electrostatic attraction. Deletion of the linker or mutation of RKKR increases formation of supersized LDs; this enhanced LD fusion requires intact CIDE-N domain interaction.","method":"Targeted protein deletions and mutations, GFP expression, fluorescence microscopy, lipid droplet size quantification","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — systematic deletion/mutation analysis with defined mechanistic readout; single lab with multiple constructs","pmids":["30361435"],"is_preprint":false},{"year":2021,"finding":"Cidec undergoes phase separation through homomeric interactions of its multivalent N-terminus, forming gel-like condensates at LD-LD contact sites (LDCS). These condensates generate lipid-permeable fusion plates geometrically constrained by donor LDs, containing stochastic sub-compartments that represent lipid passageways during LD fusion.","method":"In vitro phase separation assay, live-cell imaging, super-resolution microscopy, FRAP, genetic deletion constructs","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of phase separation plus live imaging and FRAP in vivo; single paper with multiple orthogonal methods","pmids":["34508658"],"is_preprint":false},{"year":2022,"finding":"CIDEC regulates ATGL enzymatic activity via interaction with ATGL's activator CGI-58, reducing free fatty acid release and lipotoxicity. Adipose-specific CIDEC transgenic mice (but not E186X mutant) are protected from HFD-induced glucose intolerance and show reduced serum triglycerides.","method":"Transgenic mouse model, transcriptomics, lipidomics, recombinant CIDEC treatment of human adipose tissue, Co-IP","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transgenic model plus Co-IP, lipidomics, and ex vivo human tissue experiments; multiple orthogonal methods","pmids":["35963433"],"is_preprint":false},{"year":2023,"finding":"Electron cryo-tomography reveals that Cidec facilitates lipid transfer through closely apposed LD monolayers at LD-LD interfaces. Transfer is slowed by increasing the distance between monolayers and follows exponential kinetics, consistent with pressure-driven transfer through 'leaky' monolayers.","method":"Electron cryo-tomography, quantitative live fluorescence microscopy of lipid transfer kinetics","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structural data combined with quantitative live imaging kinetics; single paper with two orthogonal methods","pmids":["36800289"],"is_preprint":false},{"year":2023,"finding":"Paxillin family proteins Hic-5 and LPXN bind CIDEC, reduce its ubiquitination, and inhibit its proteasomal degradation, thereby increasing CIDEC protein levels and promoting lipid droplet enlargement and lipid storage in adipocytes.","method":"HTRF-based high-throughput screening, Co-IP, siRNA knockdown, proteasome inhibitor experiments, lipid droplet imaging","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirmed interaction plus functional ubiquitination and proteasome assays; single lab","pmids":["38159847"],"is_preprint":false},{"year":2016,"finding":"FSP27 negatively regulates acidic residues (D215, E218, E219, E220) in the polar carboxy-terminal region (aa 202–239) of FSP27 are essential for LD enlargement; the amino-terminal domain (aa 1–130) is dispensable but accelerates LD growth. The C-terminal domain (aa 131–239) is required for LD expansion.","method":"Deletion and charge-reversal mutagenesis of FSP27 domains, LD morphology assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic deletion and mutagenesis; single lab with defined functional readout","pmids":["26921608"],"is_preprint":false},{"year":2011,"finding":"Loss of MKP-1 inhibits PPARγ function by increasing MAPK-dependent phosphorylation at inhibitory serine 112, thereby repressing Fsp27 expression and reducing PPARγ-induced lipid droplet formation in hepatocytes.","method":"MKP-1 KO mice (db/db background), microarray, PPARγ phosphorylation assay, hepatocyte lipid droplet formation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO model plus phosphorylation and cell-based lipid droplet readouts; single lab","pmids":["21521693"],"is_preprint":false},{"year":2010,"finding":"Insulin increases CIDEC mRNA and protein in human adipocytes, leading to enlargement of lipid droplets; depletion of CIDEC (but not CIDEA) by siRNA abolishes insulin-induced lipid droplet enlargement and significantly increases glycerol release (lipolysis).","method":"siRNA knockdown of CIDEC and CIDEA, lipid droplet size measurement, glycerol release assay, insulin treatment","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — isoform-selective siRNA with multiple functional readouts in human adipocytes; single lab","pmids":["20154362"],"is_preprint":false},{"year":2011,"finding":"Insulin upregulates CIDEC expression via PI3K/JNK2 (not JNK1, MEK, or p38) signaling in human adipocytes. siRNA-mediated depletion of JNK2, but not JNK1, inhibits insulin-induced CIDEC upregulation and lipid droplet enlargement.","method":"PI3K, Akt, JNK, MEK, p38 inhibitors; selective JNK1/2 siRNA knockdown; lipid droplet imaging","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-selective siRNA and pharmacological inhibitors with functional readout; single lab","pmids":["21636835"],"is_preprint":false},{"year":2010,"finding":"CIDE-3 (CIDEC) interacts with LITAF (lipopolysaccharide-induced tumor necrosis factor) in hepatic cells, as identified by yeast two-hybrid screening; overexpression of CIDE-3 induces apoptosis in HCC cells.","method":"Yeast two-hybrid, ectopic overexpression, flow cytometry apoptosis assay","journal":"Medical oncology (Northwood, London, England)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid interaction without confirmatory Co-IP; single lab, single method for interaction","pmids":["20957525"],"is_preprint":false},{"year":2014,"finding":"CIDEC translocates from the ER to lipid droplets upon fatty acid stimulation. The N-domain (aa 1–173) is involved in LD localization; the C-domain (aa 174–238) is necessary for LD fusion; the 106–173 aa region serves as an ER-binding domain.","method":"Ectopic expression of CIDEC domain mutants in HepG2 cells, fluorescence microscopy, fatty acid stimulation","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic domain deletion with co-localization imaging; single lab","pmids":["25255829"],"is_preprint":false},{"year":2022,"finding":"CIDEC interacts with 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) in intestinal cells to accelerate phosphatidic acid synthesis and promote TG accumulation. Small intestine-specific CIDEC knockout mice on HFD have lower body fat, liver TG, and higher fecal TG than wild-type.","method":"Small intestine-specific Cre/LoxP CIDEC KO mice, Co-IP with AGPAT, lipid/metabolic phenotyping","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO with metabolic phenotyping plus Co-IP for mechanistic interaction; single lab","pmids":["36263170"],"is_preprint":false},{"year":2023,"finding":"Endothelial CIDEC interacts with VEGFA-VEGFR2 signaling to reduce VEGFA and VEGFR2 degradation, thereby increasing VEGFR2 activation and improving angiogenesis and insulin signaling in endothelial cells.","method":"Endothelial-specific CIDEC transgenic mice, endothelial VEGFR2 activation assays, HFD metabolic phenotyping, vascular relaxation assays","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic model with functional vascular readouts and mechanistic VEGF pathway analysis; single lab","pmids":["36256836"],"is_preprint":false},{"year":2015,"finding":"FSP27/CIDEC promotes alcoholic steatohepatitis: chronic-plus-binge ethanol feeding upregulates Fsp27 via PPARγ (for Fsp27α) and CREBH (for Fsp27β); hepatocyte-specific Fsp27 KO or adenoviral Fsp27 shRNA markedly reduces ASH. FSP27 overexpression and ethanol synergistically increase mitochondrial reactive oxygen species and hepatocyte damage.","method":"Hepatocyte-specific Fsp27 KO mice (Fsp27Hep−/−), adenoviral shRNA, PPARγ inhibitor (GW9662), mitochondrial ROS assay, ethanol feeding model","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO, adenoviral knockdown, and pharmacological inhibition with mechanistic ROS readouts; multiple orthogonal methods","pmids":["26099526"],"is_preprint":false},{"year":2024,"finding":"FSP27 deficiency in adipocytes reduces CCL2 expression and secretion through a JNK-dependent pathway, thereby reducing macrophage migration and PVAT inflammation in obesity-associated abdominal aortic aneurysm. Cidec overexpression rescues CCL2 secretion after Fsp27 knockdown.","method":"Global and adipose-specific FSP27 KO mice, 3T3-L1 adipocyte knockdown/overexpression, CCL2 ELISA, macrophage migration assay, JNK inhibition","journal":"Life metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two genetic KO models plus cell-based rescue experiments with specific pathway inhibition; single lab","pmids":["39872985"],"is_preprint":false},{"year":2025,"finding":"CIDEC depletion after peak LD accumulation in regenerating liver promotes TG mobilization via fatty acid oxidation (FAO), supporting liver regeneration. CIDEC overexpression or DGAT2 overexpression exacerbates TG retention and impairs regeneration. FAO inhibition abolishes the pro-regenerative effect of CIDEC depletion.","method":"CIDEC KO and overexpression in mice, DGAT2 overexpression, FAO inhibitor (etomoxir), lipidomics, transcriptomics, partial hepatectomy model","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic perturbations (KO, OE) plus pharmacological FAO inhibition with lipidomics and functional liver regeneration readout; single paper with multiple orthogonal methods","pmids":["41255220"],"is_preprint":false}],"current_model":"CIDEC/FSP27 is a lipid droplet (LD)-associated protein that promotes LD fusion and unilocular LD formation by enriching at LD-LD contact sites where its N-terminal phase separation generates lipid-permeable fusion plates; it forms CIDE-N homodimers to drive directional, pressure-dependent lipid transfer from smaller to larger LDs, is activated by perilipin1 interaction, inhibited by an internal RKKR–acidic phospholipid interaction and by HDAC6-mediated deacetylation at K56, regulated transcriptionally by PPARγ2/PPARα/CREBH depending on tissue context, targeted for proteasomal degradation by AMPK via HSC70, and interacts with ATGL/CGI-58 to suppress lipolysis and maintain insulin sensitivity in adipocytes."},"narrative":{"mechanistic_narrative":"CIDEC (FSP27) is a lipid droplet (LD)-associated protein that drives the formation of unilocular, enlarged LDs and promotes triglyceride storage in adipocytes and hepatocytes; its loss in mice produces multilocular LDs, elevated lipolysis, reduced TG storage, and a 'browning' of white adipose tissue with increased mitochondrial activity [PMID:18654663, PMID:18682832]. Mechanistically, CIDEC enriches at LD–LD contact sites and mediates directional, pressure-driven net lipid transfer from smaller to larger LDs, leading to clustering and fusion [PMID:22144693, PMID:22194867]. This activity depends on homodimerization of its CIDE-N domain—whose crystal structure reveals a CAD/ICAD-like dimeric interface—and on phase separation of its multivalent N-terminus, which forms gel-like condensates that create lipid-permeable 'fusion plates' between closely apposed LD monolayers [PMID:23481402, PMID:24025675, PMID:34508658, PMID:36800289]. The fusogenic activity is amplified by interaction with perilipin1 (PLIN1) through the CIDE-N domain and is autoinhibited by a polybasic RKKR linker motif that binds acidic phospholipids [PMID:23481402, PMID:30361435]. CIDEC suppresses lipolysis by binding the lipase ATGL and its activator CGI-58, thereby limiting free fatty acid release, protecting against lipotoxicity and free-fatty-acid-induced insulin resistance, and maintaining insulin sensitivity [PMID:24627478, PMID:35963433]. CIDEC expression is transcriptionally controlled in a tissue-specific manner by PPARγ during adipogenesis and in liver, by CREBH (Fsp27β) and PPARα in hepatocytes, and is down-regulated by TNF-α/growth hormone via MEK/ERK-driven PPARγ Ser273 phosphorylation [PMID:18845124, PMID:18396136, PMID:25125366, PMID:25418138, PMID:27062372, PMID:30325658]. CIDEC protein stability is set by post-translational mechanisms: AMPK activation triggers ubiquitin-proteasome degradation (with HSC70 as a stabilizing chaperone), HDAC6-mediated deacetylation at K56 destabilizes it while PCAF acetylation stabilizes it, and paxillin-family proteins Hic-5/LPXN reduce its ubiquitination [PMID:25315694, PMID:28287402, PMID:38159847]. A homozygous nonsense CIDEC mutation (E186X) disrupting the CIDE-C domain causes protein mislocalization, failure of LD enlargement, and partial lipodystrophy with multiloculated adipocyte LDs in humans [PMID:20049731].","teleology":[{"year":1992,"claim":"Before any functional role was known, the question was what restricts FSP27 expression to fat cells; identifying the adipocyte-specific promoter element established it as a differentiation-linked gene.","evidence":"Reporter transfection, DNase I footprinting, and gel shift with adipocyte nuclear extracts identifying a C/EBP-bound palindromic element","pmids":["1339452"],"confidence":"High","gaps":["Did not connect promoter activity to a protein function","C/EBP regulation not linked to later PPARγ axis"]},{"year":2003,"claim":"An early functional annotation tested whether the human ortholog (CIDE-3) acted in cell death, framing CIDEC initially as a pro-apoptotic factor rather than a lipid regulator.","evidence":"DNA fragmentation assay and GFP localization after ectopic expression in 293T cells, including a splice isoform","pmids":["12429024"],"confidence":"Medium","gaps":["Apoptosis seen only on overexpression in non-adipose cells","No endogenous role demonstrated","Relationship to lipid storage not addressed"]},{"year":2008,"claim":"The defining question—what does CIDEC do physiologically—was answered by showing it is required for unilocular LD formation and TG storage, with knockout causing multilocular droplets and increased lipolysis.","evidence":"FSP27 knockout mice, adipocyte siRNA, ectopic expression in COS cells with LD morphology and lipolysis assays","pmids":["18654663"],"confidence":"High","gaps":["Molecular mechanism of LD enlargement unknown","Direct binding partners not yet identified"]},{"year":2008,"claim":"Parallel work established CIDEC's transcriptional control and tissue reach, showing it is a direct PPARγ target driving hepatic TG accumulation and a regulator of WAT identity whose loss browns adipose tissue.","evidence":"PPRE identification, ChIP/reporter assays, adenoviral gain/loss-of-function in hepatocytes, and KO mouse mitochondrial/gene-expression analyses","pmids":["18396136","18682832","18845124"],"confidence":"High","gaps":["How TG storage feeds back on mitochondrial/browning genes unresolved","Tissue-specific promoter usage not yet distinguished"]},{"year":2009,"claim":"Domain dissection and human genetics localized function to the CIDE-C domain, establishing it as essential for LD targeting and enlargement and causally linking CIDEC loss to human lipodystrophy.","evidence":"Deletion constructs/LD localization in HeLa, co-IP with CIDEA, and an E186X nonsense mutation in a partial lipodystrophy patient","pmids":["19843876","20049731"],"confidence":"High","gaps":["Mechanism by which CIDE-C anchors to LD not defined","Apoptosis vs. lipid functions of the domain not separated"]},{"year":2011,"claim":"The central mechanistic advance defined CIDEC as a lipid-transfer/fusion machine: it enriches at LD–LD contact sites and mediates directional, pressure-driven net lipid transfer from small to large LDs, with domains mapped for clustering versus fusion.","evidence":"FRAP and live-cell imaging in KO vs. expressing adipocytes, plus systematic GFP-deletion domain mapping","pmids":["22144693","22194867"],"confidence":"High","gaps":["Structural basis of the transfer conduit not yet resolved","How directionality is set beyond pressure inference unclear"]},{"year":2013,"claim":"The molecular requirements for lipid transfer were defined: CIDE-N homodimerization (with a crystal structure) drives transfer, and PLIN1 binding to CIDE-N markedly potentiates it.","evidence":"Reciprocal co-IP, FRAP, mutagenesis of the dimer interface, rescue by PLIN1, and a 2.0 Å CIDE-N crystal structure","pmids":["23481402","23399566","24025675"],"confidence":"High","gaps":["How dimerization couples to monolayer permeabilization unknown","Stoichiometry at contact sites not defined"]},{"year":2014,"claim":"CIDEC's anti-lipolytic mechanism was identified—direct interaction with ATGL inhibits lipolysis and protects against free-fatty-acid-induced insulin resistance—connecting LD storage to metabolic health.","evidence":"Co-IP, FSP27/ATGL siRNA, ATGL-KO fibroblasts, lipolysis assays, and phospho-AKT readouts","pmids":["24627478"],"confidence":"High","gaps":["Whether inhibition is steric or allosteric unclear","CGI-58 involvement not yet addressed"]},{"year":2014,"claim":"Protein stability was shown to be actively regulated: AMPK activation drives ubiquitin-proteasome degradation of CIDEC while HSC70 stabilizes it, providing a route to dynamically control LD architecture.","evidence":"Co-IP/MS, cycloheximide chase, siRNA, and ubiquitination assays under AICAR/phenformin","pmids":["25315694"],"confidence":"High","gaps":["E3 ligase not identified","Link between degradation and metabolic state incomplete"]},{"year":2015,"claim":"Tissue-specific transcriptional logic was extended in liver, where CREBH drives the Fsp27β promoter and PPARα drives fasting-induced hepatic CIDEC, defining context-dependent isoform control of steatosis.","evidence":"Promoter reporter assays, CREBH-KO and PPARα ChIP/reporter, in vivo adenoviral/ASO silencing in fasting models","pmids":["25125366","25418138"],"confidence":"High","gaps":["How α vs. β isoforms differ functionally beyond promoter usage unclear","Cross-talk between hepatic and adipose programs unaddressed"]},{"year":2017,"claim":"Acetylation was added as a stability switch: PCAF acetylation at K56 stabilizes CIDEC and promotes LD fusion, while HDAC6 deacetylation destabilizes it, with fatty acids biasing toward acetylation.","evidence":"Adipocyte Hdac6-KO mice, co-IP/MS, K56 mutagenesis, and LD fusion assays","pmids":["28287402"],"confidence":"High","gaps":["How K56 acetylation alters fusion mechanistically unclear","Interplay with AMPK/ubiquitin pathway not integrated"]},{"year":2018,"claim":"The fusion machinery was shown to be autoinhibited: a polybasic RKKR linker binds acidic phospholipids to limit fusion, defining a built-in brake on supersized LD formation.","evidence":"Deletion/charge mutation of the RKKR linker with LD-size quantification","pmids":["30361435"],"confidence":"High","gaps":["How phospholipid binding is relieved physiologically unclear","Relationship to PLIN1 activation not resolved"]},{"year":2021,"claim":"The physical mechanism of fusion-plate formation was revealed: CIDEC undergoes phase separation via its multivalent N-terminus to form gel-like condensates that create lipid-permeable passageways between LDs.","evidence":"In vitro phase-separation reconstitution, super-resolution and live imaging, FRAP, and deletion constructs","pmids":["34508658"],"confidence":"High","gaps":["Composition of the permeable sub-compartments incompletely defined","Regulation of condensate state by PTMs unaddressed"]},{"year":2023,"claim":"High-resolution structural and kinetic analysis confirmed pressure-driven lipid transfer through closely apposed, 'leaky' monolayers, with transfer rate set by inter-monolayer distance.","evidence":"Electron cryo-tomography of LD–LD interfaces with quantitative live transfer kinetics","pmids":["36800289"],"confidence":"High","gaps":["Atomic structure of the pore/passage not resolved","How CIDEC sculpts monolayer apposition unclear"]},{"year":2023,"claim":"Stability regulation was broadened by identifying paxillin-family proteins Hic-5 and LPXN as binders that reduce CIDEC ubiquitination, promoting LD enlargement.","evidence":"HTRF screen, co-IP, siRNA, proteasome inhibition, and LD imaging","pmids":["38159847"],"confidence":"Medium","gaps":["Single-lab interaction without reciprocal in vivo validation","Mechanism of ubiquitination protection unclear"]},{"year":2022,"claim":"The anti-lipolytic mechanism was refined and tied to metabolic protection: CIDEC engages ATGL's activator CGI-58 to limit free fatty acid release, and transgenic CIDEC (not E186X) protects against diet-induced glucose intolerance.","evidence":"Adipose-specific CIDEC transgenic mice, co-IP, lipidomics, and recombinant CIDEC on human adipose tissue","pmids":["35963433"],"confidence":"High","gaps":["Whether CGI-58 sequestration is the sole anti-lipolytic route unclear","Quantitative contribution vs. direct ATGL binding not separated"]},{"year":2025,"claim":"Beyond storage, CIDEC was placed in dynamic lipid mobilization: its depletion after peak LD accumulation promotes TG mobilization via fatty acid oxidation to support liver regeneration.","evidence":"CIDEC KO/overexpression mice, DGAT2 overexpression, etomoxir FAO inhibition, lipidomics in a partial hepatectomy model","pmids":["41255220"],"confidence":"High","gaps":["How CIDEC down-regulation is timed during regeneration unclear","Direct link between LD architecture and FAO substrate availability not resolved"]},{"year":null,"claim":"How the multiple stability/PTM inputs (AMPK-ubiquitin, K56 acetylation, paxillin binding), the RKKR autoinhibition, and PLIN1 activation are integrated to set CIDEC condensate state and fusion output at a given metabolic state remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model coupling PTM state to phase-separation/fusion activity","E3 ligase for AMPK-driven degradation unidentified","Atomic structure of the lipid-transfer conduit lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[9,24,25,27]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[9,27]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[14,26]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[11,13]}],"localization":[{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[0,9,10,16,34]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[20,34]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,14,26,39]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[9,10,25]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,3,16,17]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[15,20,28]}],"complexes":[],"partners":["PLIN1","ATGL","CGI-58","HSC70","HDAC6","CIDEA","LPXN","AGPAT"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96AQ7","full_name":"Lipid transferase CIDEC","aliases":["Cell death activator CIDE-3","Cell death-inducing DFFA-like effector protein C","Fat-specific protein FSP27 homolog"],"length_aa":238,"mass_kda":26.8,"function":"Lipid transferase specifically expressed in white adipose tissue, which promotes unilocular lipid droplet formation by mediating lipid droplet fusion (PubMed:18334488, PubMed:19843876, PubMed:20049731, PubMed:23399566, PubMed:30361435). Lipid droplet fusion promotes their enlargement, restricting lipolysis and favoring lipid storage (PubMed:18334488, PubMed:19843876, PubMed:20049731, PubMed:23399566). Localizes on the lipid droplet surface, at focal contact sites between lipid droplets, and mediates atypical lipid droplet fusion by undergoing liquid-liquid phase separation (LLPS) and promoting directional net neutral lipid transfer from the smaller to larger lipid droplets (PubMed:18334488, PubMed:19843876, PubMed:20049731, PubMed:23399566). The transfer direction may be driven by the internal pressure difference between the contacting lipid droplet pair (PubMed:18334488, PubMed:19843876, PubMed:20049731, PubMed:23399566). Its role in neutral lipid transfer and lipid droplet enlargement is activated by the interaction with PLIN1 (PubMed:23399566). May also act as a CEBPB coactivator in the white adipose tissue to control the expression of a subset of CEBPB downstream target genes, including SOCS1, SOCS3, TGFB1, TGFBR1, ID2 and XDH (By similarity). When overexpressed in preadipocytes, induces apoptosis or increases cell susceptibility to apoptosis induced by serum deprivation or TGFB treatment (PubMed:12429024)","subcellular_location":"Lipid droplet; Endoplasmic reticulum; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q96AQ7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CIDEC","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CIDEC","total_profiled":1310},"omim":[{"mim_id":"615238","title":"LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 5; FPLD5","url":"https://www.omim.org/entry/615238"},{"mim_id":"612120","title":"CELL DEATH-INDUCING DFFA-LIKE EFFECTOR C; CIDEC","url":"https://www.omim.org/entry/612120"},{"mim_id":"604441","title":"CELL DEATH-INDUCING DFFA-LIKE EFFECTOR B; CIDEB","url":"https://www.omim.org/entry/604441"},{"mim_id":"604440","title":"CELL DEATH-INDUCING DFFA-LIKE EFFECTOR A; CIDEA","url":"https://www.omim.org/entry/604440"},{"mim_id":"151660","title":"LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 2; FPLD2","url":"https://www.omim.org/entry/151660"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adipose tissue","ntpm":704.3},{"tissue":"breast","ntpm":500.3}],"url":"https://www.proteinatlas.org/search/CIDEC"},"hgnc":{"alias_symbol":["CIDE-3","FLJ20871","Fsp27"],"prev_symbol":[]},"alphafold":{"accession":"Q96AQ7","domains":[{"cath_id":"3.10.20.10","chopping":"41-117","consensus_level":"medium","plddt":88.5517,"start":41,"end":117},{"cath_id":"-","chopping":"140-177","consensus_level":"high","plddt":81.3066,"start":140,"end":177},{"cath_id":"1.20.5","chopping":"183-214","consensus_level":"medium","plddt":90.8341,"start":183,"end":214}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96AQ7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96AQ7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96AQ7-F1-predicted_aligned_error_v6.png","plddt_mean":73.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CIDEC","jax_strain_url":"https://www.jax.org/strain/search?query=CIDEC"},"sequence":{"accession":"Q96AQ7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96AQ7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96AQ7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96AQ7"}},"corpus_meta":[{"pmid":"18654663","id":"PMC_18654663","title":"FSP27 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Expression of FSP27 in COS cells promoted large lipid droplet formation, demonstrating a direct role in unilocular lipid droplet formation and triglyceride storage.\",\n      \"method\": \"FSP27 knockout mice, siRNA depletion in cultured adipocytes, ectopic expression in COS cells, lipid droplet morphology and lipolysis assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic (KO mice) and cell-based gain/loss-of-function experiments with defined morphological and biochemical phenotypes, replicated across multiple model systems\",\n      \"pmids\": [\"18654663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Fsp27/CIDEC is a direct transcriptional target of PPARγ in liver; forced expression in hepatocytes increases triglyceride levels and lipid droplet formation, while shRNA knockdown reduces hepatic triglyceride accumulation.\",\n      \"method\": \"Adenoviral overexpression and shRNA knockdown in hepatocytes in vitro and in vivo; functional PPRE identified in Fsp27 promoter; ChIP and reporter assays\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (gain-of-function, loss-of-function, promoter analysis) in both in vitro and in vivo settings\",\n      \"pmids\": [\"18396136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Fsp27 deficiency in mice causes upregulation of BAT-specific genes (FoxC2, PPARα, PGC1α), increased mitochondrial activity and size in WAT, and a 'browning' of white adipose tissue phenotype, indicating Fsp27 acts as a regulator of WAT identity and mitochondrial activity.\",\n      \"method\": \"Fsp27−/− and Fsp27/lep double-knockout mice; MEF differentiation in vitro; mitochondrial protein and gene expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple phenotypic readouts replicated across multiple mouse models\",\n      \"pmids\": [\"18682832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PPARγ2 transcriptionally activates Cidec by binding to a PPRE at the −219/−207 region of the Cidec promoter during adipogenesis.\",\n      \"method\": \"ChIP assay, reporter (luciferase) assay, gel shift assay, site-directed mutagenesis of PPRE\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal methods (ChIP, reporter assay, gel shift, mutagenesis) in a single lab\",\n      \"pmids\": [\"18845124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"FSP27 expression in adipocytes is regulated by TNF-α (downregulation) and insulin (upregulation via phosphatidylinositol 3-kinase signals). Ectopic FSP27 expression in 293T cells and preadipocytes induces apoptotic hallmarks.\",\n      \"method\": \"Northern blot, pharmacological inhibition (LY-294002), ectopic expression in 293T cells, detection of apoptosis markers\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological inhibition + expression analysis; single lab, multiple methods but indirect pathway inference\",\n      \"pmids\": [\"18198355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The FSP27 promoter confers adipocyte-specific expression; a palindromic sequence (TTCGAAA) is necessary for this specificity and is bound by C/EBP and C/EBP-like proteins from preadipocyte and adipocyte nuclear extracts.\",\n      \"method\": \"Reporter gene transfection, DNase I footprinting, gel shift assay with nuclear extracts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — DNase I footprinting + gel shift + reporter assay with nuclear extracts in multiple adipogenic cell lines\",\n      \"pmids\": [\"1339452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Human CIDE-3 (CIDEC) induces apoptosis when transfected into 293T cells, as shown by nuclear DNA fragmentation assay. Both full-length CIDE-3 and the alternatively spliced CIDE-3α isoform (lacking exon 3) retain apoptosis-inducing activity and similar subcellular localization in cytosolic corpuscles.\",\n      \"method\": \"DNA fragmentation assay, GFP fusion localization, RT-PCR for isoforms\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — DNA fragmentation assay with ectopic expression; multiple isoforms tested; single lab\",\n      \"pmids\": [\"12429024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A homozygous nonsense CIDEC mutation (E186X) that disrupts the CIDE-C domain causes mislocalization of the mutant protein and failure to increase lipid droplet size in transfected cells, resulting in partial lipodystrophy with multiloculated adipocyte lipid droplets in the patient.\",\n      \"method\": \"Transfection of mutant and wild-type CIDEC in cells, lipid droplet size assay, patient genetic analysis\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional domain mutagenesis validated by cell-based assay and corroborated by human genetic evidence\",\n      \"pmids\": [\"20049731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FSP27 CIDE-C domain (amino acids 174–192) is required for lipid droplet localization. FSP27-induced apoptosis involves caspase-9 and mitochondrial cytochrome c release and also requires this 19-amino-acid region. FSP27 CIDE-C domain interacts with CIDEA, and co-expression of CIDEA reduces FSP27 protein levels.\",\n      \"method\": \"eGFP-FSP27 deletion constructs, lipid droplet localization assays in HeLa cells, caspase inhibitor experiments, cytochrome c release assay, co-immunoprecipitation\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping with multiple deletion constructs, co-IP for interaction, functional apoptosis assays; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19843876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Fsp27 is focally enriched at lipid droplet–lipid droplet contact sites (LDCS). FRAP analysis demonstrates lipid exchange between contacting LDs in Fsp27-expressing but not Fsp27-deficient adipocytes. Live-cell imaging reveals directional net lipid transfer from smaller to larger LDs at LDCSs mediated by Fsp27, consistent with internal pressure differences between LD pairs.\",\n      \"method\": \"FRAP, live-cell imaging, Fsp27-deficient adipocytes, fluorescence microscopy of LDCS\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — FRAP and live imaging with genetic controls (KO cells); mechanistic model validated by biophysical analysis; single paper with multiple orthogonal methods\",\n      \"pmids\": [\"22144693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"FSP27 promotes lipid droplet clustering followed by fusion. Domain mapping shows amino acids 173–220 are necessary and sufficient for LD targeting and initial clustering; amino acids 120–140 are essential but not sufficient for LD enlargement; amino acids 120–210 are necessary and sufficient for both clustering and fusion. Triglyceride accumulation is associated with LD enlargement but not clustering alone.\",\n      \"method\": \"GFP-fusion deletion mutant constructs, fluorescence microscopy in adipocytes\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic deletion mutagenesis with multiple constructs and defined functional readouts; single lab\",\n      \"pmids\": [\"22194867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Perilipin1 (Plin1) interacts with the CIDE-N domain of Fsp27 and markedly increases Fsp27-mediated lipid exchange, lipid transfer, and lipid droplet growth. The CIDE-N domain of Fsp27 forms homodimers required for lipid exchange and transfer; disruption of CIDE-N homodimerization abolishes these activities. Plin1 can rescue the activity of CIDE-N homodimerization-defective Fsp27 mutants.\",\n      \"method\": \"Co-immunoprecipitation, FRAP, live-cell imaging, site-directed mutagenesis of CIDE-N homodimerization interface, RNAi depletion of Plin1 and Fsp27\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, FRAP, live imaging, and mutagenesis in a single study; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23481402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FSP27 (CIDEC) co-localizes and interacts with PLIN1 in human primary adipocytes. The C-terminal domain of FSP27 (aa 120–220) mediates interaction with PLIN1. Co-expression of FSP27 and PLIN1 increases average lipid droplet size and promotes unilocular lipid droplet formation.\",\n      \"method\": \"Co-immunoprecipitation, co-localization by immunofluorescence, triglyceride content assay, glycerol release assay, ectopic expression in human adipocytes\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and co-localization in primary human adipocytes, domain mapping, functional lipid droplet readout; single lab\",\n      \"pmids\": [\"23399566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure of the CIDE-N domain of FSP27 solved at 2.0 Å reveals a homodimeric interface similar to the CAD/ICAD heterodimer; structural homologs include the PB1 domain of BEM1P, ubiquitin-like domain of BAG6, and ubiquitin.\",\n      \"method\": \"X-ray crystallography at 2.0 Å resolution\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — high-resolution crystal structure with mechanistic interpretation; single lab\",\n      \"pmids\": [\"24025675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FSP27 (aa 120–220) interacts with ATGL in human adipocytes to inhibit its lipolytic function and promote triglyceride storage. FSP27 depletion increases lipolysis and impairs insulin signaling (decreased AKT phosphorylation); reducing lipolysis by ATGL depletion or FSP27 overexpression protects against free fatty acid-induced insulin resistance.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of FSP27 and ATGL, ATGL KO mouse-derived fibroblasts, lipolysis assays, AKT phosphorylation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP plus orthogonal genetic (siRNA, KO cells) and biochemical (lipolysis, phospho-AKT) assays; single lab with multiple methods\",\n      \"pmids\": [\"24627478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"AMPK activation (by AICAR or phenformin) induces ubiquitination and proteasomal degradation of FSP27 in adipocytes, leading to multilocularization of lipid droplets. HSC70 is identified as a binding partner of FSP27 that stabilizes it; HSC70 knockdown reduces FSP27 half-life.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, siRNA knockdown, cycloheximide chase assay, AICAR/phenformin treatment, ubiquitination assay\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction confirmed by Co-IP, CHX chase, and multiple pharmacological and genetic perturbations; single lab\",\n      \"pmids\": [\"25315694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CREBH (liver-enriched transcription factor) directly activates the Fsp27β promoter (but not the Fsp27α/PPARγ-driven promoter) in hepatocytes. Fsp27β localizes to lipid droplet surfaces and suppresses lipolysis; its enforced expression promotes lipid droplet enlargement and hepatic TG accumulation.\",\n      \"method\": \"Promoter reporter assays, constitutively active CREBH overexpression, CREBH KO fasted mice, lipid droplet imaging, lipolysis assays\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reporter assays plus genetic KO model plus gain-of-function with functional readouts; multiple methods in single paper\",\n      \"pmids\": [\"25125366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CIDEC/FSP27 is a direct transcriptional target of PPARα in mouse and human hepatocytes. Adenoviral silencing of hepatic Fsp27 abolishes fasting-induced liver steatosis. PPARα agonist (fenofibrate) and Fsp27 ASO synergize to reduce hepatic TG accumulation.\",\n      \"method\": \"ChIP, promoter reporter assay, adenoviral shRNA in vivo, ASO treatment, fasting model\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, reporter assay, and in vivo genetic silencing with functional metabolic readouts\",\n      \"pmids\": [\"25418138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Cidec promotes adipocyte differentiation by interacting with AMPKα1 and promoting its degradation via the ubiquitin–proteasome pathway, thereby reducing AMPKα levels.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence co-localization, RNAi knockdown, proteasome inhibitor experiments\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP and co-localization, functional degradation assay; single lab\",\n      \"pmids\": [\"26367078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TNF-α downregulates CIDEC expression in human adipocytes through MEK/ERK-mediated phosphorylation of PPARγ at Ser273 and its subsequent nuclear export; inhibiting MEK/ERK prevents TNF-α-mediated CIDEC downregulation.\",\n      \"method\": \"MEK/ERK inhibitors, constitutively active MEK1 mutant, immunofluorescence, subcellular fractionation, reporter assay\",\n      \"journal\": \"Obesity (Silver Spring, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibitors, constitutively active mutant, and reporter assay in human adipocytes; single lab\",\n      \"pmids\": [\"27062372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HDAC6 deacetylates CIDEC at lysine 56 (K56); the acetyltransferase PCAF acetylates CIDEC at K56 on the endoplasmic reticulum. Acetylation of CIDEC stabilizes it and promotes lipid droplet fusion, while HDAC6-mediated deacetylation leads to CIDEC destabilization. Fatty acids prevent CIDEC deacetylation by promoting dissociation of CIDEC from HDAC6 and increasing association with PCAF.\",\n      \"method\": \"Adipocyte-specific Hdac6 KO mice, Co-IP, mass spectrometry, site-directed mutagenesis at K56, lipid droplet fusion assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vivo KO model plus biochemical identification of acetylation site (K56) by mutagenesis, Co-IP, and functional assay; multiple orthogonal methods in single high-quality study\",\n      \"pmids\": [\"28287402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Growth hormone (GH) reduces FSP27 expression by activating MEK/ERK, which phosphorylates PPARγ at Ser273 and causes its translocation from nucleus to cytosol, thereby reducing PPARγ transcriptional activity at the FSP27 promoter. FSP27 overexpression inhibits PPARγ Ser273 phosphorylation and promotes its nuclear retention, suppressing GH-induced lipolysis.\",\n      \"method\": \"MEK/ERK inhibitors, GH antagonist treatment, immunofluorescence, PPARγ Ser273 phosphorylation assay, FSP27 overexpression in human adipocytes\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological and genetic tools in human adipocytes; single lab\",\n      \"pmids\": [\"30325658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GH modulates FSP27 expression through both MEK/ERK- and STAT5-dependent intracellular signaling, which interact to regulate PPARγ activity on the FSP27 promoter. FSP27 overexpression fully suppresses GH-induced lipolysis and insulin resistance.\",\n      \"method\": \"Pathway-specific inhibitors, transgenic GH overexpression mice, FSP27 overexpression, lipolysis assays\",\n      \"journal\": \"The Journal of endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and transgenic approaches with functional readouts; single lab\",\n      \"pmids\": [\"30400015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FTO promotes SREBP1c nuclear translocation and maturation, which in turn transcriptionally activates CIDEC via its promoter. CIDEC knockdown reduces SREBP1c-induced lipogenesis in HepG2 cells.\",\n      \"method\": \"FTO overexpression/knockdown, SREBP1c overexpression/knockdown, luciferase reporter assay for CIDEC promoter, lipogenesis assays\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay plus genetic gain/loss-of-function; single lab\",\n      \"pmids\": [\"29486327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The polybasic RKKR motif in the linker region between CIDE-N and CIDE-C domains of CIDEC interacts with acidic phospholipids via electrostatic attraction. Deletion of the linker or mutation of RKKR increases formation of supersized LDs; this enhanced LD fusion requires intact CIDE-N domain interaction.\",\n      \"method\": \"Targeted protein deletions and mutations, GFP expression, fluorescence microscopy, lipid droplet size quantification\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic deletion/mutation analysis with defined mechanistic readout; single lab with multiple constructs\",\n      \"pmids\": [\"30361435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cidec undergoes phase separation through homomeric interactions of its multivalent N-terminus, forming gel-like condensates at LD-LD contact sites (LDCS). These condensates generate lipid-permeable fusion plates geometrically constrained by donor LDs, containing stochastic sub-compartments that represent lipid passageways during LD fusion.\",\n      \"method\": \"In vitro phase separation assay, live-cell imaging, super-resolution microscopy, FRAP, genetic deletion constructs\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of phase separation plus live imaging and FRAP in vivo; single paper with multiple orthogonal methods\",\n      \"pmids\": [\"34508658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CIDEC regulates ATGL enzymatic activity via interaction with ATGL's activator CGI-58, reducing free fatty acid release and lipotoxicity. Adipose-specific CIDEC transgenic mice (but not E186X mutant) are protected from HFD-induced glucose intolerance and show reduced serum triglycerides.\",\n      \"method\": \"Transgenic mouse model, transcriptomics, lipidomics, recombinant CIDEC treatment of human adipose tissue, Co-IP\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transgenic model plus Co-IP, lipidomics, and ex vivo human tissue experiments; multiple orthogonal methods\",\n      \"pmids\": [\"35963433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Electron cryo-tomography reveals that Cidec facilitates lipid transfer through closely apposed LD monolayers at LD-LD interfaces. Transfer is slowed by increasing the distance between monolayers and follows exponential kinetics, consistent with pressure-driven transfer through 'leaky' monolayers.\",\n      \"method\": \"Electron cryo-tomography, quantitative live fluorescence microscopy of lipid transfer kinetics\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structural data combined with quantitative live imaging kinetics; single paper with two orthogonal methods\",\n      \"pmids\": [\"36800289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Paxillin family proteins Hic-5 and LPXN bind CIDEC, reduce its ubiquitination, and inhibit its proteasomal degradation, thereby increasing CIDEC protein levels and promoting lipid droplet enlargement and lipid storage in adipocytes.\",\n      \"method\": \"HTRF-based high-throughput screening, Co-IP, siRNA knockdown, proteasome inhibitor experiments, lipid droplet imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirmed interaction plus functional ubiquitination and proteasome assays; single lab\",\n      \"pmids\": [\"38159847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FSP27 negatively regulates acidic residues (D215, E218, E219, E220) in the polar carboxy-terminal region (aa 202–239) of FSP27 are essential for LD enlargement; the amino-terminal domain (aa 1–130) is dispensable but accelerates LD growth. The C-terminal domain (aa 131–239) is required for LD expansion.\",\n      \"method\": \"Deletion and charge-reversal mutagenesis of FSP27 domains, LD morphology assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic deletion and mutagenesis; single lab with defined functional readout\",\n      \"pmids\": [\"26921608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Loss of MKP-1 inhibits PPARγ function by increasing MAPK-dependent phosphorylation at inhibitory serine 112, thereby repressing Fsp27 expression and reducing PPARγ-induced lipid droplet formation in hepatocytes.\",\n      \"method\": \"MKP-1 KO mice (db/db background), microarray, PPARγ phosphorylation assay, hepatocyte lipid droplet formation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO model plus phosphorylation and cell-based lipid droplet readouts; single lab\",\n      \"pmids\": [\"21521693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Insulin increases CIDEC mRNA and protein in human adipocytes, leading to enlargement of lipid droplets; depletion of CIDEC (but not CIDEA) by siRNA abolishes insulin-induced lipid droplet enlargement and significantly increases glycerol release (lipolysis).\",\n      \"method\": \"siRNA knockdown of CIDEC and CIDEA, lipid droplet size measurement, glycerol release assay, insulin treatment\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-selective siRNA with multiple functional readouts in human adipocytes; single lab\",\n      \"pmids\": [\"20154362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Insulin upregulates CIDEC expression via PI3K/JNK2 (not JNK1, MEK, or p38) signaling in human adipocytes. siRNA-mediated depletion of JNK2, but not JNK1, inhibits insulin-induced CIDEC upregulation and lipid droplet enlargement.\",\n      \"method\": \"PI3K, Akt, JNK, MEK, p38 inhibitors; selective JNK1/2 siRNA knockdown; lipid droplet imaging\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-selective siRNA and pharmacological inhibitors with functional readout; single lab\",\n      \"pmids\": [\"21636835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CIDE-3 (CIDEC) interacts with LITAF (lipopolysaccharide-induced tumor necrosis factor) in hepatic cells, as identified by yeast two-hybrid screening; overexpression of CIDE-3 induces apoptosis in HCC cells.\",\n      \"method\": \"Yeast two-hybrid, ectopic overexpression, flow cytometry apoptosis assay\",\n      \"journal\": \"Medical oncology (Northwood, London, England)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid interaction without confirmatory Co-IP; single lab, single method for interaction\",\n      \"pmids\": [\"20957525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CIDEC translocates from the ER to lipid droplets upon fatty acid stimulation. The N-domain (aa 1–173) is involved in LD localization; the C-domain (aa 174–238) is necessary for LD fusion; the 106–173 aa region serves as an ER-binding domain.\",\n      \"method\": \"Ectopic expression of CIDEC domain mutants in HepG2 cells, fluorescence microscopy, fatty acid stimulation\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic domain deletion with co-localization imaging; single lab\",\n      \"pmids\": [\"25255829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CIDEC interacts with 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) in intestinal cells to accelerate phosphatidic acid synthesis and promote TG accumulation. Small intestine-specific CIDEC knockout mice on HFD have lower body fat, liver TG, and higher fecal TG than wild-type.\",\n      \"method\": \"Small intestine-specific Cre/LoxP CIDEC KO mice, Co-IP with AGPAT, lipid/metabolic phenotyping\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO with metabolic phenotyping plus Co-IP for mechanistic interaction; single lab\",\n      \"pmids\": [\"36263170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Endothelial CIDEC interacts with VEGFA-VEGFR2 signaling to reduce VEGFA and VEGFR2 degradation, thereby increasing VEGFR2 activation and improving angiogenesis and insulin signaling in endothelial cells.\",\n      \"method\": \"Endothelial-specific CIDEC transgenic mice, endothelial VEGFR2 activation assays, HFD metabolic phenotyping, vascular relaxation assays\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic model with functional vascular readouts and mechanistic VEGF pathway analysis; single lab\",\n      \"pmids\": [\"36256836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FSP27/CIDEC promotes alcoholic steatohepatitis: chronic-plus-binge ethanol feeding upregulates Fsp27 via PPARγ (for Fsp27α) and CREBH (for Fsp27β); hepatocyte-specific Fsp27 KO or adenoviral Fsp27 shRNA markedly reduces ASH. FSP27 overexpression and ethanol synergistically increase mitochondrial reactive oxygen species and hepatocyte damage.\",\n      \"method\": \"Hepatocyte-specific Fsp27 KO mice (Fsp27Hep−/−), adenoviral shRNA, PPARγ inhibitor (GW9662), mitochondrial ROS assay, ethanol feeding model\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO, adenoviral knockdown, and pharmacological inhibition with mechanistic ROS readouts; multiple orthogonal methods\",\n      \"pmids\": [\"26099526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FSP27 deficiency in adipocytes reduces CCL2 expression and secretion through a JNK-dependent pathway, thereby reducing macrophage migration and PVAT inflammation in obesity-associated abdominal aortic aneurysm. Cidec overexpression rescues CCL2 secretion after Fsp27 knockdown.\",\n      \"method\": \"Global and adipose-specific FSP27 KO mice, 3T3-L1 adipocyte knockdown/overexpression, CCL2 ELISA, macrophage migration assay, JNK inhibition\",\n      \"journal\": \"Life metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two genetic KO models plus cell-based rescue experiments with specific pathway inhibition; single lab\",\n      \"pmids\": [\"39872985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CIDEC depletion after peak LD accumulation in regenerating liver promotes TG mobilization via fatty acid oxidation (FAO), supporting liver regeneration. CIDEC overexpression or DGAT2 overexpression exacerbates TG retention and impairs regeneration. FAO inhibition abolishes the pro-regenerative effect of CIDEC depletion.\",\n      \"method\": \"CIDEC KO and overexpression in mice, DGAT2 overexpression, FAO inhibitor (etomoxir), lipidomics, transcriptomics, partial hepatectomy model\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic perturbations (KO, OE) plus pharmacological FAO inhibition with lipidomics and functional liver regeneration readout; single paper with multiple orthogonal methods\",\n      \"pmids\": [\"41255220\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CIDEC/FSP27 is a lipid droplet (LD)-associated protein that promotes LD fusion and unilocular LD formation by enriching at LD-LD contact sites where its N-terminal phase separation generates lipid-permeable fusion plates; it forms CIDE-N homodimers to drive directional, pressure-dependent lipid transfer from smaller to larger LDs, is activated by perilipin1 interaction, inhibited by an internal RKKR–acidic phospholipid interaction and by HDAC6-mediated deacetylation at K56, regulated transcriptionally by PPARγ2/PPARα/CREBH depending on tissue context, targeted for proteasomal degradation by AMPK via HSC70, and interacts with ATGL/CGI-58 to suppress lipolysis and maintain insulin sensitivity in adipocytes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CIDEC (FSP27) is a lipid droplet (LD)-associated protein that drives the formation of unilocular, enlarged LDs and promotes triglyceride storage in adipocytes and hepatocytes; its loss in mice produces multilocular LDs, elevated lipolysis, reduced TG storage, and a 'browning' of white adipose tissue with increased mitochondrial activity [#0, #2]. Mechanistically, CIDEC enriches at LD–LD contact sites and mediates directional, pressure-driven net lipid transfer from smaller to larger LDs, leading to clustering and fusion [#9, #10]. This activity depends on homodimerization of its CIDE-N domain—whose crystal structure reveals a CAD/ICAD-like dimeric interface—and on phase separation of its multivalent N-terminus, which forms gel-like condensates that create lipid-permeable 'fusion plates' between closely apposed LD monolayers [#11, #13, #25, #27]. The fusogenic activity is amplified by interaction with perilipin1 (PLIN1) through the CIDE-N domain and is autoinhibited by a polybasic RKKR linker motif that binds acidic phospholipids [#11, #24]. CIDEC suppresses lipolysis by binding the lipase ATGL and its activator CGI-58, thereby limiting free fatty acid release, protecting against lipotoxicity and free-fatty-acid-induced insulin resistance, and maintaining insulin sensitivity [#14, #26]. CIDEC expression is transcriptionally controlled in a tissue-specific manner by PPARγ during adipogenesis and in liver, by CREBH (Fsp27β) and PPARα in hepatocytes, and is down-regulated by TNF-α/growth hormone via MEK/ERK-driven PPARγ Ser273 phosphorylation [#3, #1, #16, #17, #19, #21]. CIDEC protein stability is set by post-translational mechanisms: AMPK activation triggers ubiquitin-proteasome degradation (with HSC70 as a stabilizing chaperone), HDAC6-mediated deacetylation at K56 destabilizes it while PCAF acetylation stabilizes it, and paxillin-family proteins Hic-5/LPXN reduce its ubiquitination [#15, #20, #28]. A homozygous nonsense CIDEC mutation (E186X) disrupting the CIDE-C domain causes protein mislocalization, failure of LD enlargement, and partial lipodystrophy with multiloculated adipocyte LDs in humans [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Before any functional role was known, the question was what restricts FSP27 expression to fat cells; identifying the adipocyte-specific promoter element established it as a differentiation-linked gene.\",\n      \"evidence\": \"Reporter transfection, DNase I footprinting, and gel shift with adipocyte nuclear extracts identifying a C/EBP-bound palindromic element\",\n      \"pmids\": [\"1339452\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect promoter activity to a protein function\", \"C/EBP regulation not linked to later PPARγ axis\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"An early functional annotation tested whether the human ortholog (CIDE-3) acted in cell death, framing CIDEC initially as a pro-apoptotic factor rather than a lipid regulator.\",\n      \"evidence\": \"DNA fragmentation assay and GFP localization after ectopic expression in 293T cells, including a splice isoform\",\n      \"pmids\": [\"12429024\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apoptosis seen only on overexpression in non-adipose cells\", \"No endogenous role demonstrated\", \"Relationship to lipid storage not addressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The defining question—what does CIDEC do physiologically—was answered by showing it is required for unilocular LD formation and TG storage, with knockout causing multilocular droplets and increased lipolysis.\",\n      \"evidence\": \"FSP27 knockout mice, adipocyte siRNA, ectopic expression in COS cells with LD morphology and lipolysis assays\",\n      \"pmids\": [\"18654663\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of LD enlargement unknown\", \"Direct binding partners not yet identified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Parallel work established CIDEC's transcriptional control and tissue reach, showing it is a direct PPARγ target driving hepatic TG accumulation and a regulator of WAT identity whose loss browns adipose tissue.\",\n      \"evidence\": \"PPRE identification, ChIP/reporter assays, adenoviral gain/loss-of-function in hepatocytes, and KO mouse mitochondrial/gene-expression analyses\",\n      \"pmids\": [\"18396136\", \"18682832\", \"18845124\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TG storage feeds back on mitochondrial/browning genes unresolved\", \"Tissue-specific promoter usage not yet distinguished\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Domain dissection and human genetics localized function to the CIDE-C domain, establishing it as essential for LD targeting and enlargement and causally linking CIDEC loss to human lipodystrophy.\",\n      \"evidence\": \"Deletion constructs/LD localization in HeLa, co-IP with CIDEA, and an E186X nonsense mutation in a partial lipodystrophy patient\",\n      \"pmids\": [\"19843876\", \"20049731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CIDE-C anchors to LD not defined\", \"Apoptosis vs. lipid functions of the domain not separated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The central mechanistic advance defined CIDEC as a lipid-transfer/fusion machine: it enriches at LD–LD contact sites and mediates directional, pressure-driven net lipid transfer from small to large LDs, with domains mapped for clustering versus fusion.\",\n      \"evidence\": \"FRAP and live-cell imaging in KO vs. expressing adipocytes, plus systematic GFP-deletion domain mapping\",\n      \"pmids\": [\"22144693\", \"22194867\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the transfer conduit not yet resolved\", \"How directionality is set beyond pressure inference unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The molecular requirements for lipid transfer were defined: CIDE-N homodimerization (with a crystal structure) drives transfer, and PLIN1 binding to CIDE-N markedly potentiates it.\",\n      \"evidence\": \"Reciprocal co-IP, FRAP, mutagenesis of the dimer interface, rescue by PLIN1, and a 2.0 Å CIDE-N crystal structure\",\n      \"pmids\": [\"23481402\", \"23399566\", \"24025675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How dimerization couples to monolayer permeabilization unknown\", \"Stoichiometry at contact sites not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"CIDEC's anti-lipolytic mechanism was identified—direct interaction with ATGL inhibits lipolysis and protects against free-fatty-acid-induced insulin resistance—connecting LD storage to metabolic health.\",\n      \"evidence\": \"Co-IP, FSP27/ATGL siRNA, ATGL-KO fibroblasts, lipolysis assays, and phospho-AKT readouts\",\n      \"pmids\": [\"24627478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether inhibition is steric or allosteric unclear\", \"CGI-58 involvement not yet addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Protein stability was shown to be actively regulated: AMPK activation drives ubiquitin-proteasome degradation of CIDEC while HSC70 stabilizes it, providing a route to dynamically control LD architecture.\",\n      \"evidence\": \"Co-IP/MS, cycloheximide chase, siRNA, and ubiquitination assays under AICAR/phenformin\",\n      \"pmids\": [\"25315694\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase not identified\", \"Link between degradation and metabolic state incomplete\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Tissue-specific transcriptional logic was extended in liver, where CREBH drives the Fsp27β promoter and PPARα drives fasting-induced hepatic CIDEC, defining context-dependent isoform control of steatosis.\",\n      \"evidence\": \"Promoter reporter assays, CREBH-KO and PPARα ChIP/reporter, in vivo adenoviral/ASO silencing in fasting models\",\n      \"pmids\": [\"25125366\", \"25418138\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How α vs. β isoforms differ functionally beyond promoter usage unclear\", \"Cross-talk between hepatic and adipose programs unaddressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Acetylation was added as a stability switch: PCAF acetylation at K56 stabilizes CIDEC and promotes LD fusion, while HDAC6 deacetylation destabilizes it, with fatty acids biasing toward acetylation.\",\n      \"evidence\": \"Adipocyte Hdac6-KO mice, co-IP/MS, K56 mutagenesis, and LD fusion assays\",\n      \"pmids\": [\"28287402\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How K56 acetylation alters fusion mechanistically unclear\", \"Interplay with AMPK/ubiquitin pathway not integrated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The fusion machinery was shown to be autoinhibited: a polybasic RKKR linker binds acidic phospholipids to limit fusion, defining a built-in brake on supersized LD formation.\",\n      \"evidence\": \"Deletion/charge mutation of the RKKR linker with LD-size quantification\",\n      \"pmids\": [\"30361435\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phospholipid binding is relieved physiologically unclear\", \"Relationship to PLIN1 activation not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The physical mechanism of fusion-plate formation was revealed: CIDEC undergoes phase separation via its multivalent N-terminus to form gel-like condensates that create lipid-permeable passageways between LDs.\",\n      \"evidence\": \"In vitro phase-separation reconstitution, super-resolution and live imaging, FRAP, and deletion constructs\",\n      \"pmids\": [\"34508658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Composition of the permeable sub-compartments incompletely defined\", \"Regulation of condensate state by PTMs unaddressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"High-resolution structural and kinetic analysis confirmed pressure-driven lipid transfer through closely apposed, 'leaky' monolayers, with transfer rate set by inter-monolayer distance.\",\n      \"evidence\": \"Electron cryo-tomography of LD–LD interfaces with quantitative live transfer kinetics\",\n      \"pmids\": [\"36800289\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic structure of the pore/passage not resolved\", \"How CIDEC sculpts monolayer apposition unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Stability regulation was broadened by identifying paxillin-family proteins Hic-5 and LPXN as binders that reduce CIDEC ubiquitination, promoting LD enlargement.\",\n      \"evidence\": \"HTRF screen, co-IP, siRNA, proteasome inhibition, and LD imaging\",\n      \"pmids\": [\"38159847\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab interaction without reciprocal in vivo validation\", \"Mechanism of ubiquitination protection unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The anti-lipolytic mechanism was refined and tied to metabolic protection: CIDEC engages ATGL's activator CGI-58 to limit free fatty acid release, and transgenic CIDEC (not E186X) protects against diet-induced glucose intolerance.\",\n      \"evidence\": \"Adipose-specific CIDEC transgenic mice, co-IP, lipidomics, and recombinant CIDEC on human adipose tissue\",\n      \"pmids\": [\"35963433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CGI-58 sequestration is the sole anti-lipolytic route unclear\", \"Quantitative contribution vs. direct ATGL binding not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Beyond storage, CIDEC was placed in dynamic lipid mobilization: its depletion after peak LD accumulation promotes TG mobilization via fatty acid oxidation to support liver regeneration.\",\n      \"evidence\": \"CIDEC KO/overexpression mice, DGAT2 overexpression, etomoxir FAO inhibition, lipidomics in a partial hepatectomy model\",\n      \"pmids\": [\"41255220\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CIDEC down-regulation is timed during regeneration unclear\", \"Direct link between LD architecture and FAO substrate availability not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple stability/PTM inputs (AMPK-ubiquitin, K56 acetylation, paxillin binding), the RKKR autoinhibition, and PLIN1 activation are integrated to set CIDEC condensate state and fusion output at a given metabolic state remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified model coupling PTM state to phase-separation/fusion activity\", \"E3 ligase for AMPK-driven degradation unidentified\", \"Atomic structure of the lipid-transfer conduit lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [9, 24, 25, 27]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [9, 27]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [14, 26]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [11, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [0, 9, 10, 16, 34]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [20, 34]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 14, 26, 39]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [9, 10, 25]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 3, 16, 17]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [15, 20, 28]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PLIN1\", \"ATGL\", \"CGI-58\", \"HSC70\", \"HDAC6\", \"CIDEA\", \"LPXN\", \"AGPAT\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}