{"gene":"CIDEC","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2008,"finding":"FSP27/CIDEC localizes to lipid droplets in white adipocytes and promotes formation of unilocular lipid droplets; ablation results in multilocular lipid droplets, increased lipolysis, decreased triacylglycerol storage, and increased mitochondrial biogenesis in white adipose tissue.","method":"FSP27 knockout mice, siRNA depletion in cultured adipocytes, ectopic expression in COS cells, in vivo phenotypic analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KO mice, siRNA, overexpression) with clear mechanistic phenotype, replicated across labs","pmids":["18654663"],"is_preprint":false},{"year":2011,"finding":"Fsp27 is focally enriched at the lipid droplet-lipid droplet contact site (LDCS) and mediates directional net lipid transfer from smaller to larger LDs, driving LD growth via a pressure-difference mechanism.","method":"Live-cell imaging, FRAP/photobleaching, Fsp27-deficient adipocytes, Fsp27-overexpressing cells, biophysical analysis of LD internal pressure","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — live imaging + FRAP + genetic loss-of-function with clear mechanistic model, single rigorous study with multiple orthogonal methods","pmids":["22144693"],"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; CIDE-N homodimerization is required for Fsp27 activity and Plin1 can restore activity of CIDE-N homodimerization-defective mutants.","method":"Co-immunoprecipitation, FRAP, live-cell imaging, domain mutagenesis, siRNA depletion","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — reciprocal Co-IP, mutagenesis, and functional rescue in a single study with multiple orthogonal approaches","pmids":["23481402"],"is_preprint":false},{"year":2013,"finding":"Human FSP27 (CIDEC) interacts with PLIN1 via its C-terminal domain (aa 120–220) in primary human adipocytes, and co-expression of FSP27 and PLIN1 increases average lipid droplet size and promotes unilocular adipocyte formation.","method":"Co-localization by immunofluorescence, co-immunoprecipitation, deletion mapping, triglyceride/glycerol assays in human adipocytes","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 — reciprocal Co-IP and functional assays in human cells, single lab","pmids":["23399566"],"is_preprint":false},{"year":2009,"finding":"A truncation mutation in the CIDE-C domain of human CIDEC (E186X) causes partial lipodystrophy with multilocular lipid droplets; the mutant protein is mistargeted and fails to increase lipid droplet size in transfected cells, establishing the CIDE-C domain as necessary for LD targeting and function.","method":"Human genetics (homozygous truncation mutation), transfection of mutant vs. WT CIDEC in cells, lipid droplet size assay","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 — natural loss-of-function human mutation with cellular mechanistic validation; strong evidence","pmids":["20049731"],"is_preprint":false},{"year":2011,"finding":"FSP27 promotes LD clustering (requiring aa 173–220) followed by their fusion into enlarged droplets (requiring aa 120–210), with LD enlargement—but not clustering—associated with triglyceride accumulation.","method":"GFP-fusion deletion mutants, fluorescence microscopy, triglyceride quantification in HeLa cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — systematic deletion mutagenesis with functional readouts, single lab","pmids":["22194867"],"is_preprint":false},{"year":2009,"finding":"The FSP27 CIDE-C domain (aa 174–192) is required for lipid droplet localization and apoptosis induction (via caspase-9 and mitochondrial cytochrome c release); the CIDE-C domain also mediates heterodimerization with CIDEA.","method":"eGFP-FSP27 deletion constructs, caspase activity assays, cytochrome c release, co-immunoprecipitation, Western blot","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — domain mapping with mutagenesis and multiple functional assays, single lab","pmids":["19843876"],"is_preprint":false},{"year":2014,"finding":"FSP27 (aa 120–220) directly interacts with ATGL (adipose triglyceride lipase) to inhibit its lipolytic activity and promote triglyceride storage; FSP27 depletion increases lipolysis and impairs insulin signaling via reduced AKT phosphorylation.","method":"Co-immunoprecipitation, domain deletion mapping, siRNA knockdown, lipolysis assays, AKT phosphorylation assays in human adipocytes and ATGL KO mouse fibroblasts","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — Co-IP, domain mapping, genetic rescue (ATGL KO cells), multiple functional readouts, replicated mechanistically","pmids":["24627478"],"is_preprint":false},{"year":2017,"finding":"HDAC6 deacetylates CIDEC at K56 (acetylated by PCAF), leading to CIDEC destabilization and reduced lipid droplet fusion; dietary fatty acids promote CIDEC acetylation by dissociating CIDEC from HDAC6 and increasing CIDEC-PCAF association on the ER, requiring conversion of FAs to triacylglycerols.","method":"Co-immunoprecipitation, acetylation site mutagenesis, adipocyte-specific Hdac6 KO mice, lipid droplet fusion assays, in vivo obese animal models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis of acetylation site, KO mouse model, multiple Co-IPs, in vivo and in vitro evidence in single rigorous study","pmids":["28287402"],"is_preprint":false},{"year":2008,"finding":"Fsp27 expression in ob/ob mouse liver is directly transcriptionally activated by PPARγ (functional PPAR response element in the Fsp27 promoter); hepatic Fsp27 promotes triglyceride accumulation and lipid droplet formation.","method":"Chromatin immunoprecipitation, reporter assay, adenovirus-mediated overexpression and shRNA knockdown in hepatocytes in vitro and in vivo","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP + reporter assay + in vivo adenoviral gain/loss-of-function in single study","pmids":["18396136"],"is_preprint":false},{"year":2008,"finding":"Cidec transcription is directly activated by PPARγ2 via a PPRE at −219/−207 of the Cidec promoter in adipocytes.","method":"Chromatin immunoprecipitation, luciferase reporter assay, gel shift assay, promoter mutagenesis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 — ChIP + reporter + mutagenesis, single lab","pmids":["18845124"],"is_preprint":false},{"year":2015,"finding":"CIDEC/Fsp27 is a direct transcriptional target of PPARα in hepatocytes; adenoviral silencing of hepatic Fsp27 abolishes fasting-induced liver steatosis without altering plasma lipids, and synergizes with PPARα agonists to reduce diet-induced hepatosteatosis.","method":"ChIP, reporter assay, adenoviral shRNA silencing in vivo, pharmacological PPARα activation","journal":"Hepatology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 1–2 — ChIP + reporter + in vivo adenoviral knockdown, single lab","pmids":["25418138"],"is_preprint":false},{"year":2015,"finding":"The liver-enriched transcription factor CREBH activates transcription of a liver-specific Fsp27β isoform (10 extra N-terminal amino acids) from a distinct promoter; Fsp27β localizes to lipid droplet surfaces, suppresses lipolysis, and promotes lipid droplet enlargement and TG accumulation in liver.","method":"Promoter identification, reporter assay with constitutively active CREBH, adenoviral overexpression, lipid droplet imaging in hepatocytes","journal":"Hepatology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 — reporter assay + in vivo adenoviral expression + functional LD assays, single lab","pmids":["25125366"],"is_preprint":false},{"year":2012,"finding":"Fsp27/CIDEC is a CREB target gene in the liver; early fasting induction involves the PKA-CREB-CRTC2 signaling pathway (induced by forskolin, blocked by CREB inhibition); pharmacological or genetic inhibition of fatty acid oxidation increases Fsp27 expression during fasting.","method":"Promoter reporter assay with CREB, forskolin stimulation, Sirt1 KO animals, etomoxir/Hmgcs2 interference in vivo and in HepG2 cells","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 — reporter assay + in vivo genetic models + pharmacological manipulation, single lab","pmids":["23220584"],"is_preprint":false},{"year":2021,"finding":"Cidec undergoes phase separation via multivalent homomeric interactions of its N-terminal domain at LD-LD contact sites, forming gel-like condensates that create lipid-permeable fusion plates for LD fusion; phase separation is required for LD fusion activity.","method":"In vitro phase separation reconstitution, live-cell imaging, fluorescence recovery experiments, deletion mutants, in vivo LDCS analysis","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of phase separation + in vivo validation + functional mutant analysis in single rigorous study","pmids":["34508658"],"is_preprint":false},{"year":2023,"finding":"Cidec-mediated lipid transfer between LDs occurs through closely apposed phospholipid monolayers at LD-LD interfaces, follows exponential kinetics, and is slowed by increasing the distance between monolayers, as visualized by electron cryo-tomography.","method":"Electron cryo-tomography, quantitative live fluorescence microscopy of lipid transfer kinetics","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 — cryo-ET structural visualization + quantitative live imaging kinetics, mechanistically rigorous","pmids":["36800289"],"is_preprint":false},{"year":2013,"finding":"Crystal structure of the CIDE-N domain of FSP27 at 2.0 Å resolution reveals a biologically important homodimeric interface similar to the CAD/ICAD heterodimeric complex, providing a structural basis for FSP27-mediated LD growth.","method":"X-ray crystallography at 2.0 Å resolution","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 — crystal structure, but functional validation of homodimer interface was not performed in the same paper","pmids":["24025675"],"is_preprint":false},{"year":2018,"finding":"A polybasic RKKR motif in the linker region of CIDEC interacts with acidic phospholipids via electrostatic attraction to inhibit LD fusion; deletion or mutation of the RKKR motif disrupts protein-lipid interaction and results in enhanced LD fusion and supersized LDs.","method":"Targeted deletion and GFP-fusion constructs, fluorescence microscopy, phospholipid binding assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — domain mutagenesis + protein-lipid binding assays + functional LD imaging, single lab","pmids":["30361435"],"is_preprint":false},{"year":2014,"finding":"AMPK activation induces ubiquitination and proteasomal degradation of FSP27, resulting in LD multilocularization; HSC70 is identified as a novel FSP27-binding protein that promotes FSP27 degradation, while CHIP (E3 ubiquitin ligase) is not required.","method":"AICAR/phenformin treatment, AMPKα1 knockdown, proteasome inhibition, mass spectrometry, co-immunoprecipitation of endogenous proteins, cycloheximide chase, siRNA knockdown of HSC70 and CHIP","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — MS identification + Co-IP + genetic knockdown + functional LD readout, single lab","pmids":["25315694"],"is_preprint":false},{"year":2015,"finding":"Cidec interacts with AMPKα1 and promotes its degradation via the ubiquitin-proteasome pathway, thereby promoting adipocyte differentiation; the interaction was confirmed by yeast two-hybrid, co-immunoprecipitation, and co-localization.","method":"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence co-localization, proteasome inhibition assay","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2–3 — yeast two-hybrid + Co-IP + co-localization + functional assay, single lab","pmids":["26367078"],"is_preprint":false},{"year":2018,"finding":"Growth hormone downregulates FSP27 expression by activating MEK/ERK signaling, which phosphorylates PPARγ at Ser273 and promotes its nuclear-to-cytosol translocation; FSP27 overexpression inhibits PPARγ Ser273 phosphorylation and promotes nuclear retention, thus suppressing GH-induced lipolysis.","method":"Selective inhibitors, constitutively active MEK1 mutant, immunofluorescence, subcellular fractionation, reporter assay, human adipose-derived stromal vascular cells, human subjects","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — multiple signaling inhibitors + nuclear fractionation + reporter assay + human cell model, single lab","pmids":["30325658"],"is_preprint":false},{"year":2016,"finding":"TNF-α downregulates CIDEC transcription through MEK/ERK-dependent phosphorylation and nuclear export of PPARγ in human adipocytes.","method":"MEK/ERK inhibitors, constitutively active MEK1, immunofluorescence, subcellular fractionation, luciferase reporter assay","journal":"Obesity (Silver Spring, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological + reporter + localization assays, single lab","pmids":["27062372"],"is_preprint":false},{"year":2014,"finding":"CIDEC translocates from the ER to lipid droplets in response to fatty acid stimulation; the N-terminal domain (aa 1–173) mediates LD localization while the C-terminal domain (aa 174–238) is necessary for LD fusion; aa 106–173 contains an ER-binding domain.","method":"CIDEC deletion mutant analysis, immunofluorescence, subcellular fractionation in HepG2 cells","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2–3 — domain deletion mutants + subcellular fractionation, single lab","pmids":["25255829"],"is_preprint":false},{"year":2022,"finding":"CIDEC regulates ATGL enzymatic activity by interacting with its activator CGI-58, reducing free fatty acid release and lipotoxicity in adipocytes; adipose-specific CIDEC transgenic mice are protected from HFD-induced glucose intolerance, while the E186X variant abolishes this protection.","method":"Transgenic mouse model (Ad-CIDECtg and Ad-CIDECmut), transcriptomics, lipidomics, Co-IP of CIDEC-CGI-58, recombinant CIDEC treatment of human adipose tissue, triglyceride breakdown assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — transgenic mouse model + Co-IP + lipidomics/transcriptomics + human tissue ex vivo, multiple orthogonal methods","pmids":["35963433"],"is_preprint":false},{"year":2023,"finding":"CIDEC interacts with endothelial VEGFA-VEGFR2 signaling; endothelial-specific CIDEC expression reduces VEGFA and VEGFR2 degradation, increasing VEGFR2 activation, improved insulin signaling/eNOS activation, and vascular relaxation.","method":"Endothelial-specific CIDEC transgenic mice, insulin signaling assays, eNOS activation, vascular relaxation measurements, VEGF pathway analysis","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 — transgenic mouse model with mechanistic pathway identification, single lab","pmids":["36256836"],"is_preprint":false},{"year":2022,"finding":"Small intestine-specific CIDEC knockout reduces body fat, liver TG, and hepatic steatosis; mechanistically, CIDEC promotes phosphatidic acid synthesis by interacting with 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) to accelerate TG accumulation in intestinal cells.","method":"Cre/LoxP intestine-specific KO mice, Co-IP of CIDEC-AGPAT, metabolic phenotyping, phosphatidic acid measurement","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 — tissue-specific KO + Co-IP + biochemical mechanism, single lab","pmids":["36263170"],"is_preprint":false},{"year":2023,"finding":"Paxillin family proteins Hic-5 and LPXN interact with CIDEC and inhibit its proteasomal ubiquitination/degradation, thereby stabilizing CIDEC protein, enlarging LDs, and promoting lipid storage in adipocytes.","method":"HTRF-based high-throughput screening, Co-IP, ubiquitination assays, proteasome inhibition, LD morphology in adipocytes","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP + ubiquitination assays + functional LD readout, single lab","pmids":["38159847"],"is_preprint":false},{"year":2010,"finding":"Insulin upregulates CIDEC expression in human adipocytes via a PI3K-JNK2-dependent pathway, and CIDEC depletion abolishes insulin-induced lipid droplet enlargement and increases glycerol release.","method":"PI3K/Akt/JNK inhibitors, siRNA knockdown of JNK1/JNK2, lipid droplet imaging, glycerol release assay","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 — pathway dissection with selective inhibitors + siRNA + functional assays, single lab","pmids":["20154362","21636835"],"is_preprint":false},{"year":2016,"finding":"FSP27 negatively regulates AMPK activity and ATGL expression in adipocytes; CIDEC knockdown in LPS-treated renal tubular epithelial cells restores phospho-AMPKα and suppresses NF-κB pathway activation and inflammatory cytokine production.","method":"CIDEC siRNA knockdown, Western blot for p-AMPKα, NF-κB pathway reporters, cytokine measurement","journal":"Inflammation","confidence":"Low","confidence_rationale":"Tier 3 — single knockdown study in non-adipocyte cells, indirect pathway evidence","pmids":["29959627"],"is_preprint":false},{"year":2017,"finding":"Gp78 (membrane E3 ubiquitin ligase) co-localizes and physically interacts with CIDEC on the surface of lipid droplets, and this interaction promotes lipid accumulation in hepatocytes.","method":"Co-immunoprecipitation, immunofluorescence co-localization, overexpression/knockdown in AML12 cells","journal":"Molecular medicine reports","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP + co-localization, functional consequence indirect, single lab","pmids":["28656280"],"is_preprint":false},{"year":2016,"finding":"FSP27 negatively regulates the AMPK-signaling axis; negatively charged residues (D215, E218, E219, E220) in the polar C-terminal region of FSP27 are essential for LD enlargement, while the N-terminal domain (aa 1–130) accelerates but is not required for LD growth.","method":"FSP27 domain deletion and charge-reversal mutagenesis, LD size quantification","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — systematic mutagenesis with functional LD readout, single lab","pmids":["26921608"],"is_preprint":false},{"year":2003,"finding":"Human CIDE-3 (CIDEC), a homologue of mouse FSP27, contains conserved CIDE-N and CIDE-C domains and induces apoptosis (DNA fragmentation) upon overexpression in 293T cells; GFP-tagged CIDE-3 localizes to cytosolic corpuscles; an alternative splice isoform (CIDE-3α, lacking exon 3) retains apoptosis-inducing activity.","method":"DNA fragmentation assay, GFP fusion protein localization, RT-PCR, transfection in 293T cells","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 — functional assay (DNA fragmentation) + GFP localization, single lab foundational study","pmids":["12429024"],"is_preprint":false},{"year":2010,"finding":"CIDE-3 (CIDEC) interacts with LITAF (lipopolysaccharide-induced tumor necrosis factor) in hepatic cells, identified by yeast two-hybrid screening; overexpressed CIDE-3 induces apoptosis in hepatocellular carcinoma cells.","method":"Yeast two-hybrid, flow cytometry apoptosis assay, overexpression in SMMC-7721 cells","journal":"Medical oncology (Northwood, London, England)","confidence":"Low","confidence_rationale":"Tier 3 — yeast two-hybrid without biochemical confirmation of endogenous interaction, single lab","pmids":["20957525"],"is_preprint":false},{"year":1992,"finding":"The FSP27 promoter confers adipocyte-specific expression; a palindromic sequence (TTCGAAA) is required for adipocyte-specific expression and is bound by C/EBP and C/EBP-like proteins as demonstrated by DNase I footprinting.","method":"Promoter-reporter transfection, DNase I footprinting with nuclear extracts","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 — functional reporter assays + footprinting, foundational promoter study","pmids":["1339452"],"is_preprint":false},{"year":2025,"finding":"CIDEC acts as a metabolic gatekeeper in liver regeneration: its depletion after peak LD accumulation promotes TG mobilization and fatty acid oxidation-driven regeneration; overexpression of CIDEC or DGAT2 exacerbates TG retention and impairs regeneration.","method":"CIDEC depletion/overexpression in mice, lipidomics, transcriptomics, FAO inhibition experiments, chronic steatosis model","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 — gain- and loss-of-function in vivo + lipidomics + pathway inhibition, single lab","pmids":["41255220"],"is_preprint":false},{"year":2025,"finding":"N-terminal domain of CIDEC (CIDEC-N) undergoes phase separation in vitro; in vitro reconstitution confirmed that multivalent homomeric CIDEC-N interactions are sufficient to drive phase separation, providing a biochemical basis for LDCS condensate formation.","method":"Recombinant protein purification, in vitro phase separation assay, concentration-dependent droplet formation","journal":"STAR protocols","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro reconstitution of phase separation; protocol paper corroborating earlier Developmental Cell study","pmids":["40232936"],"is_preprint":false}],"current_model":"CIDEC/FSP27 is a lipid droplet-associated protein that localizes to LD-LD contact sites where its N-terminal domain undergoes phase separation to form gel-like condensates, facilitating directional pressure-driven transfer of neutral lipids from smaller to larger LDs; its activity is modulated by CIDE-N homodimerization, interaction with Perilipin1 (which activates it), interaction with ATGL and CGI-58 (which it inhibits to suppress lipolysis), acetylation at K56 by PCAF (stabilizing) and deacetylation by HDAC6 (destabilizing), and proteasomal degradation triggered by AMPK/HSC70; transcriptionally it is directly activated by PPARγ, PPARα, and CREBH in a tissue- and isoform-specific manner."},"narrative":{"teleology":[{"year":1992,"claim":"Before CIDEC's lipid droplet function was known, the FSP27 promoter was shown to confer adipocyte-specific expression dependent on C/EBP-binding elements, establishing tissue-restricted transcriptional control as a foundational property.","evidence":"Promoter-reporter transfection and DNase I footprinting with adipocyte nuclear extracts","pmids":["1339452"],"confidence":"Medium","gaps":["Identity of the specific C/EBP family member(s) driving endogenous expression was not resolved","No link to lipid metabolism was established at this stage"]},{"year":2003,"claim":"Cloning of human CIDE-3 (CIDEC) revealed conserved CIDE-N and CIDE-C domains and showed that overexpression induces apoptosis, initially framing the protein within the CIDE cell-death family.","evidence":"DNA fragmentation assay and GFP-fusion localization in 293T cells","pmids":["12429024"],"confidence":"Medium","gaps":["Apoptotic function was based on overexpression; physiological relevance of cell-death activity remained unclear","Lipid droplet association was not yet recognized"]},{"year":2008,"claim":"Genetic ablation in mice and PPARγ-dependent transcriptional activation established CIDEC as a major determinant of unilocular LD formation, triglyceride storage, and lipolytic suppression in white adipose tissue and liver, redefining its primary function from apoptosis to lipid metabolism.","evidence":"FSP27 knockout mice with multilocular LD/lean phenotype; ChIP and reporter assays identifying PPARγ PPRE in the Cidec promoter; adenoviral gain/loss-of-function in hepatocytes","pmids":["18654663","18396136","18845124"],"confidence":"High","gaps":["Mechanism by which CIDEC promotes LD enlargement (fusion vs. transfer vs. synthesis) was unresolved","Relative contribution of lipolysis suppression vs. LD fusion was not separated"]},{"year":2009,"claim":"A human homozygous truncation (E186X) in the CIDE-C domain causing partial lipodystrophy provided genetic proof that the CIDE-C domain is essential for LD targeting and function in humans.","evidence":"Human genetic study with cellular validation showing mislocalization and loss of LD enlargement by mutant CIDEC","pmids":["20049731"],"confidence":"High","gaps":["Whether additional CIDEC mutations cause lipodystrophy in other families was unknown","Structural basis for CIDE-C domain function remained unresolved"]},{"year":2011,"claim":"Live-cell imaging and FRAP revealed that CIDEC concentrates at LD-LD contact sites and mediates directional lipid transfer from smaller to larger LDs driven by Laplace pressure differences, resolving the biophysical mechanism of LD growth.","evidence":"FRAP, live-cell imaging, and biophysical pressure analysis in Fsp27-deficient and Fsp27-overexpressing cells","pmids":["22144693"],"confidence":"High","gaps":["Molecular nature of the pore or channel allowing lipid transfer was unknown","Whether other CIDE family members use the same mechanism was untested"]},{"year":2013,"claim":"Perilipin1 was identified as a direct activator of CIDEC-mediated lipid transfer through interaction with the CIDE-N domain, and CIDE-N homodimerization was shown to be required for function, defining the key protein-protein interactions governing CIDEC activity.","evidence":"Reciprocal Co-IP, FRAP-based lipid transfer quantification, domain mutagenesis, and crystal structure of CIDE-N homodimer at 2.0 Å","pmids":["23481402","23399566","24025675"],"confidence":"High","gaps":["How Plin1 binding mechanistically enhances lipid transfer rate was not determined","Role of CIDE-N dimerization in phase separation was not yet appreciated"]},{"year":2014,"claim":"CIDEC was shown to directly inhibit ATGL lipolytic activity via its C-terminal region (aa 120–220), establishing a dual mechanism — LD fusion plus lipolysis suppression — for triglyceride storage, while AMPK activation was found to trigger CIDEC ubiquitination and proteasomal degradation via HSC70.","evidence":"Co-IP and domain mapping of CIDEC-ATGL interaction in ATGL KO rescue; AICAR/phenformin treatment with cycloheximide chase and HSC70 knockdown","pmids":["24627478","25315694"],"confidence":"High","gaps":["E3 ubiquitin ligase responsible for AMPK-triggered CIDEC degradation was not identified (CHIP was excluded)","Structural basis for CIDEC-ATGL inhibitory interaction was lacking"]},{"year":2015,"claim":"Tissue-specific transcriptional programs were delineated: PPARα directly activates Cidec in hepatocytes during fasting, and CREBH drives a liver-specific Fsp27β isoform from a distinct promoter, explaining how the same gene is induced in both adipose and liver contexts.","evidence":"ChIP, reporter assays, adenoviral shRNA in vivo for PPARα; promoter identification and constitutively active CREBH reporter assays for Fsp27β","pmids":["25418138","25125366"],"confidence":"Medium","gaps":["Functional differences between Fsp27α and Fsp27β isoforms beyond expression pattern were not fully characterized","Whether PPARα and CREBH cooperate on the same promoter was untested"]},{"year":2017,"claim":"Post-translational regulation of CIDEC stability was resolved: PCAF acetylates K56 to stabilize CIDEC, while HDAC6 deacetylates K56 to destabilize it; dietary fatty acids shift the PCAF/HDAC6 balance toward acetylation on the ER, linking nutritional status to CIDEC protein levels.","evidence":"Acetylation site mutagenesis, adipocyte-specific Hdac6 KO mice, Co-IP of CIDEC-PCAF and CIDEC-HDAC6, LD fusion assays in obese animal models","pmids":["28287402"],"confidence":"High","gaps":["Whether K56 acetylation affects CIDEC phase separation or interaction with Plin1/ATGL was not tested","Deacetylation-independent degradation pathways were not addressed"]},{"year":2018,"claim":"A polybasic RKKR motif in the CIDEC linker was found to interact with acidic phospholipids and act as an autoinhibitory element that restrains LD fusion, adding a lipid-dependent regulatory layer to CIDEC activity.","evidence":"Charge-reversal mutagenesis, phospholipid binding assays, and LD size quantification","pmids":["30361435"],"confidence":"Medium","gaps":["How RKKR motif regulation integrates with Plin1 activation or acetylation status was not explored","In vivo significance of this autoinhibitory mechanism was not tested"]},{"year":2021,"claim":"The molecular basis of the LD-LD contact site was resolved: CIDEC-N undergoes phase separation via multivalent homomeric interactions to form gel-like condensates that constitute the lipid-permeable fusion plate, establishing phase separation as the organizing principle for CIDEC-mediated lipid transfer.","evidence":"In vitro reconstitution of CIDEC-N phase separation, live-cell FRAP at LDCS, functional deletion mutants disrupting phase separation","pmids":["34508658"],"confidence":"High","gaps":["Whether Plin1, ATGL, or CGI-58 partition into or are excluded from the condensate was not determined","Structural details of the lipid-permeable pore within the condensate are unknown"]},{"year":2022,"claim":"CIDEC's lipolysis-suppressive function was extended beyond ATGL to its co-activator CGI-58: CIDEC sequesters CGI-58, reducing free fatty acid release and lipotoxicity, with in vivo validation showing adipose-specific CIDEC transgenic mice are protected from HFD-induced glucose intolerance.","evidence":"Co-IP of CIDEC-CGI-58, adipose-specific transgenic and E186X mutant mice, lipidomics, recombinant CIDEC on human adipose tissue ex vivo","pmids":["35963433"],"confidence":"High","gaps":["Whether CIDEC binds CGI-58 and ATGL simultaneously or competitively was not resolved","Stoichiometry of the CIDEC-CGI-58 complex is unknown"]},{"year":2023,"claim":"Cryo-electron tomography visualized the LD-LD interface architecture, showing that CIDEC-mediated lipid transfer occurs through closely apposed phospholipid monolayers with exponential transfer kinetics sensitive to inter-monolayer distance, providing direct structural evidence for the transfer mechanism.","evidence":"Electron cryo-tomography of LD-LD contacts combined with quantitative live fluorescence microscopy of lipid transfer kinetics","pmids":["36800289"],"confidence":"High","gaps":["Atomic-resolution structure of the CIDEC condensate at the contact site is lacking","Whether a proteinaceous pore exists or lipid transfer occurs purely through monolayer proximity remains unresolved"]},{"year":null,"claim":"Key open questions include: (1) the atomic-level structure of the CIDEC phase-separated fusion plate and whether it forms a discrete pore; (2) how post-translational modifications (acetylation, ubiquitination, phospholipid binding) regulate phase separation properties; (3) whether CIDEC condensates selectively partition or exclude regulatory partners such as Plin1, ATGL, and CGI-58.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of the intact CIDEC condensate at LD-LD contacts","Interplay between acetylation/AMPK degradation and phase separation is untested","Comprehensive interactome of the CIDEC condensate is not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[17,22]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[7,23]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,23,19]}],"localization":[{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[0,1,2,5,14,15,22]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[8,22]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[31]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,7,8,9,23,25]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[20,21,27]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,31]}],"complexes":[],"partners":["PLIN1","PNPLA2","ABHD5","HDAC6","KAT2B","HSPA8","CIDEA","TGFB1I1"],"other_free_text":[]},"mechanistic_narrative":"CIDEC (also called FSP27) is a lipid droplet (LD)-associated protein that drives unilocular LD formation in adipocytes and hepatocytes by mediating directional, pressure-driven transfer of neutral lipids from smaller to larger LDs at LD-LD contact sites. At these contact sites, the CIDE-N domain undergoes phase separation to form gel-like condensates that create lipid-permeable fusion plates, while the CIDE-C domain is required for LD targeting and fusion; CIDEC simultaneously suppresses lipolysis by directly inhibiting ATGL and sequestering its co-activator CGI-58, and its protein stability is regulated by PCAF-mediated acetylation at K56 (stabilizing) versus HDAC6-mediated deacetylation and AMPK/HSC70-driven proteasomal degradation [PMID:22144693, PMID:34508658, PMID:36800289, PMID:24627478, PMID:35963433, PMID:28287402, PMID:25315694]. Perilipin1 interaction with CIDEC markedly enhances lipid transfer activity, and CIDE-N homodimerization is required for function [PMID:23481402]. A homozygous truncation mutation (E186X) in the CIDE-C domain causes familial partial lipodystrophy with multilocular white adipocyte LDs [PMID:20049731]. Transcription of CIDEC is directly activated by PPARγ in adipocytes, PPARα and CREBH in hepatocytes (the latter driving a liver-specific Fsp27β isoform), and is modulated by insulin/PI3K-JNK2, TNFα/MEK-ERK, and growth hormone signaling [PMID:18396136, PMID:25418138, PMID:25125366, PMID:20154362]."},"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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developmentally-programmed hepatic steatosis.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31745102","citation_count":10,"is_preprint":false},{"pmid":"33663853","id":"PMC_33663853","title":"Cell death-inducing DNA fragmentation factor-α-like effector C (CIDEC) regulates acetate- and β-hydroxybutyrate-induced milk fat synthesis by increasing FASN expression in mammary epithelial cells of dairy cows.","date":"2021","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/33663853","citation_count":10,"is_preprint":false},{"pmid":"27995415","id":"PMC_27995415","title":"Regulation of PPARγ and CIDEC expression by adenovirus 36 in adipocyte differentiation.","date":"2016","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27995415","citation_count":9,"is_preprint":false},{"pmid":"35859752","id":"PMC_35859752","title":"AMPK-PPARγ-Cidec Axis Drives the Fasting-Induced Lipid Droplet Aggregation in the Liver of Obese Mice.","date":"2022","source":"Frontiers in nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/35859752","citation_count":9,"is_preprint":false},{"pmid":"33685683","id":"PMC_33685683","title":"Inhibition of cell death inducing DNA fragmentation factor-α-like effector c (CIDEC) by tumor necrosis factor-α induces lipolysis and inflammation in calf adipocytes.","date":"2021","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/33685683","citation_count":9,"is_preprint":false},{"pmid":"28656280","id":"PMC_28656280","title":"Role of glycoprotein 78 and cidec in hepatic steatosis.","date":"2017","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/28656280","citation_count":8,"is_preprint":false},{"pmid":"29859472","id":"PMC_29859472","title":"Therapeutic silencing of FSP27 reduces the progression of atherosclerosis in Ldlr-/- mice.","date":"2018","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/29859472","citation_count":8,"is_preprint":false},{"pmid":"26921608","id":"PMC_26921608","title":"Negatively-charged residues in the polar carboxy-terminal region in FSP27 are indispensable for expanding lipid droplets.","date":"2016","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/26921608","citation_count":7,"is_preprint":false},{"pmid":"26189824","id":"PMC_26189824","title":"Haplotypes in the promoter region of the CIDEC gene associated with growth traits in Nanyang cattle.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26189824","citation_count":7,"is_preprint":false},{"pmid":"30792748","id":"PMC_30792748","title":"Involvement of PPARγ/FSP27 in the pathogenic mechanism underlying insulin resistance: tipping the balance between lipogenesis and fat storage in adult catch-up growth rats.","date":"2019","source":"Nutrition & metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/30792748","citation_count":7,"is_preprint":false},{"pmid":"27342423","id":"PMC_27342423","title":"Alcohol and fat promote steatohepatitis: a critical role for fat-specific protein 27/CIDEC.","date":"2016","source":"Journal of investigative medicine : the official publication of the American Federation for Clinical Research","url":"https://pubmed.ncbi.nlm.nih.gov/27342423","citation_count":6,"is_preprint":false},{"pmid":"39872985","id":"PMC_39872985","title":"CIDEC/FSP27 exacerbates obesity-related abdominal aortic aneurysm by promoting perivascular adipose tissue inflammation.","date":"2024","source":"Life metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/39872985","citation_count":6,"is_preprint":false},{"pmid":"28415694","id":"PMC_28415694","title":"Single nucleotide polymorphisms in CIDEC gene are associated with metabolic syndrome components risks and antihypertensive drug efficacy.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28415694","citation_count":6,"is_preprint":false},{"pmid":"39118207","id":"PMC_39118207","title":"Attenuation of brown adipocyte whitening in high-fat diet-induced obese rats: Effects of melatonin and β-hydroxybutyrate on Cidea, Fsp27 and MT1 expression.","date":"2024","source":"Diabetes, obesity & metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/39118207","citation_count":6,"is_preprint":false},{"pmid":"37079518","id":"PMC_37079518","title":"Rare CIDEC coding variants enriched in age-related macular degeneration patients with small low-luminance deficit cause lipid droplet and fat storage defects.","date":"2023","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/37079518","citation_count":5,"is_preprint":false},{"pmid":"35157807","id":"PMC_35157807","title":"Fsp27 plays a crucial role in muscle performance.","date":"2022","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/35157807","citation_count":5,"is_preprint":false},{"pmid":"24065549","id":"PMC_24065549","title":"Cell death-inducing DFFA-like effector c (CIDEC/Fsp27) gene: molecular cloning, sequence characterization, tissue distribution and polymorphisms in Chinese cattles.","date":"2013","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/24065549","citation_count":5,"is_preprint":false},{"pmid":"22790028","id":"PMC_22790028","title":"[Novel mechanism for hepatic lipid accumulation: a physiological role for hepatic PPARγ-fsp27 signal].","date":"2012","source":"Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan","url":"https://pubmed.ncbi.nlm.nih.gov/22790028","citation_count":4,"is_preprint":false},{"pmid":"38159847","id":"PMC_38159847","title":"Paxillin family proteins Hic-5 and LPXN promote lipid storage by regulating the ubiquitination degradation of CIDEC.","date":"2023","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38159847","citation_count":4,"is_preprint":false},{"pmid":"23192040","id":"PMC_23192040","title":"Purification, crystallization and preliminary X-ray crystallographic analysis of the CIDE-N domain of Fsp27.","date":"2012","source":"Acta crystallographica. Section F, Structural biology and crystallization communications","url":"https://pubmed.ncbi.nlm.nih.gov/23192040","citation_count":3,"is_preprint":false},{"pmid":"27716232","id":"PMC_27716232","title":"The role of expression imbalance between adipose synthesis and storage mediated by PPAR-γ/FSP27 in the formation of insulin resistance in catch up growth.","date":"2016","source":"Lipids in health and disease","url":"https://pubmed.ncbi.nlm.nih.gov/27716232","citation_count":3,"is_preprint":false},{"pmid":"29219006","id":"PMC_29219006","title":"Distribution and quantitative analysis of CIDEa and CIDEc in broiler chickens: accounting for differential fat deposition between strains.","date":"2017","source":"British poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/29219006","citation_count":3,"is_preprint":false},{"pmid":"31205943","id":"PMC_31205943","title":"Bariatric Surgery in Rats Upregulates FSP27 Expression in Fat Tissue to Affect Fat Hydrolysis and Metabolism.","date":"2019","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/31205943","citation_count":3,"is_preprint":false},{"pmid":"26345833","id":"PMC_26345833","title":"Polymorphisms in the bovine CIDEC gene are associated with body measurement traits and meat quality traits in Qinchuan cattle.","date":"2015","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/26345833","citation_count":3,"is_preprint":false},{"pmid":"31028911","id":"PMC_31028911","title":"CIDEA and CIDEC are regulated by CREB and are not induced during fasting in grass carp Ctenopharyngodon idella adipocytes.","date":"2019","source":"Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/31028911","citation_count":2,"is_preprint":false},{"pmid":"40633832","id":"PMC_40633832","title":"Partial inhibition of adipose CIDEC improves insulin sensitivity and increases energy expenditure in high-fat diet-fed mice via activating ATGL-PPARα pathway.","date":"2025","source":"Biochimica et biophysica acta. Molecular and cell biology of lipids","url":"https://pubmed.ncbi.nlm.nih.gov/40633832","citation_count":2,"is_preprint":false},{"pmid":"35124674","id":"PMC_35124674","title":"CIDEC: A Potential Factor in Diabetic Vascular Inflammation.","date":"2022","source":"Journal of vascular research","url":"https://pubmed.ncbi.nlm.nih.gov/35124674","citation_count":2,"is_preprint":false},{"pmid":"41255220","id":"PMC_41255220","title":"CIDEC Restricts Liver Regeneration by Disturbing Lipid Droplet Triglyceride Turnover.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41255220","citation_count":2,"is_preprint":false},{"pmid":"16507259","id":"PMC_16507259","title":"[Construction of the prokaryotic expression vector and expression of human CIDE-3 gene].","date":"2006","source":"Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16507259","citation_count":2,"is_preprint":false},{"pmid":"41392209","id":"PMC_41392209","title":"ApoA5-CIDEC axis regulates hepatic lipid metabolism, inflammation, and fibrosis in MASLD.","date":"2025","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41392209","citation_count":1,"is_preprint":false},{"pmid":"31433705","id":"PMC_31433705","title":"A Novel Proangiogenic Function of Fsp27 in Endothelium: You Only Live Thrice?","date":"2019","source":"Journal of the American Heart Association","url":"https://pubmed.ncbi.nlm.nih.gov/31433705","citation_count":1,"is_preprint":false},{"pmid":"41596298","id":"PMC_41596298","title":"Novel Homozygous Variants in CIDEC and WRN in a Young Female with Lipodystrophy and Thyroid Cancer.","date":"2026","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41596298","citation_count":1,"is_preprint":false},{"pmid":"24192364","id":"PMC_24192364","title":"Crystallization and preliminary X-ray crystallographic studies of the CIDE-N domain of CIDE-3.","date":"2013","source":"Acta crystallographica. Section F, Structural biology and crystallization communications","url":"https://pubmed.ncbi.nlm.nih.gov/24192364","citation_count":1,"is_preprint":false},{"pmid":"40305497","id":"PMC_40305497","title":"Comparative effect of high intensity interval training and moderate intensity continuous training on metabolic improvements and regulation of Cidea and Cidec in obese C57BL/6 mice.","date":"2025","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/40305497","citation_count":1,"is_preprint":false},{"pmid":"24229606","id":"PMC_24229606","title":"[Research advances on CIDEC in insulin resistance].","date":"2013","source":"Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/24229606","citation_count":0,"is_preprint":false},{"pmid":"40766532","id":"PMC_40766532","title":"Whole-body Loss of FSP27 Impairs Cognitive Function via Disruption of Neuro-Metabolic Pathways.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40766532","citation_count":0,"is_preprint":false},{"pmid":"40607154","id":"PMC_40607154","title":"CIDEC is most closely associated with fat storage in human adipose tissue among CIDE family isoforms in severely obese subjects: a cross-sectional study.","date":"2025","source":"Diabetology international","url":"https://pubmed.ncbi.nlm.nih.gov/40607154","citation_count":0,"is_preprint":false},{"pmid":"40232936","id":"PMC_40232936","title":"Protocol for in vitro phase separation of N terminus of CIDEC proteins.","date":"2025","source":"STAR protocols","url":"https://pubmed.ncbi.nlm.nih.gov/40232936","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49193,"output_tokens":7751,"usd":0.131922},"stage2":{"model":"claude-opus-4-6","input_tokens":11684,"output_tokens":3710,"usd":0.226755},"total_usd":0.358677,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"FSP27/CIDEC localizes to lipid droplets in white adipocytes and promotes formation of unilocular lipid droplets; ablation results in multilocular lipid droplets, increased lipolysis, decreased triacylglycerol storage, and increased mitochondrial biogenesis in white adipose tissue.\",\n      \"method\": \"FSP27 knockout mice, siRNA depletion in cultured adipocytes, ectopic expression in COS cells, in vivo phenotypic analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KO mice, siRNA, overexpression) with clear mechanistic phenotype, replicated across labs\",\n      \"pmids\": [\"18654663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Fsp27 is focally enriched at the lipid droplet-lipid droplet contact site (LDCS) and mediates directional net lipid transfer from smaller to larger LDs, driving LD growth via a pressure-difference mechanism.\",\n      \"method\": \"Live-cell imaging, FRAP/photobleaching, Fsp27-deficient adipocytes, Fsp27-overexpressing cells, biophysical analysis of LD internal pressure\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — live imaging + FRAP + genetic loss-of-function with clear mechanistic model, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"22144693\"],\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; CIDE-N homodimerization is required for Fsp27 activity and Plin1 can restore activity of CIDE-N homodimerization-defective mutants.\",\n      \"method\": \"Co-immunoprecipitation, FRAP, live-cell imaging, domain mutagenesis, siRNA depletion\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reciprocal Co-IP, mutagenesis, and functional rescue in a single study with multiple orthogonal approaches\",\n      \"pmids\": [\"23481402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Human FSP27 (CIDEC) interacts with PLIN1 via its C-terminal domain (aa 120–220) in primary human adipocytes, and co-expression of FSP27 and PLIN1 increases average lipid droplet size and promotes unilocular adipocyte formation.\",\n      \"method\": \"Co-localization by immunofluorescence, co-immunoprecipitation, deletion mapping, triglyceride/glycerol assays in human adipocytes\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — reciprocal Co-IP and functional assays in human cells, single lab\",\n      \"pmids\": [\"23399566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A truncation mutation in the CIDE-C domain of human CIDEC (E186X) causes partial lipodystrophy with multilocular lipid droplets; the mutant protein is mistargeted and fails to increase lipid droplet size in transfected cells, establishing the CIDE-C domain as necessary for LD targeting and function.\",\n      \"method\": \"Human genetics (homozygous truncation mutation), transfection of mutant vs. WT CIDEC in cells, lipid droplet size assay\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — natural loss-of-function human mutation with cellular mechanistic validation; strong evidence\",\n      \"pmids\": [\"20049731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"FSP27 promotes LD clustering (requiring aa 173–220) followed by their fusion into enlarged droplets (requiring aa 120–210), with LD enlargement—but not clustering—associated with triglyceride accumulation.\",\n      \"method\": \"GFP-fusion deletion mutants, fluorescence microscopy, triglyceride quantification in HeLa cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic deletion mutagenesis with functional readouts, single lab\",\n      \"pmids\": [\"22194867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The FSP27 CIDE-C domain (aa 174–192) is required for lipid droplet localization and apoptosis induction (via caspase-9 and mitochondrial cytochrome c release); the CIDE-C domain also mediates heterodimerization with CIDEA.\",\n      \"method\": \"eGFP-FSP27 deletion constructs, caspase activity assays, cytochrome c release, co-immunoprecipitation, Western blot\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping with mutagenesis and multiple functional assays, single lab\",\n      \"pmids\": [\"19843876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FSP27 (aa 120–220) directly interacts with ATGL (adipose triglyceride lipase) to inhibit its lipolytic activity and promote triglyceride storage; FSP27 depletion increases lipolysis and impairs insulin signaling via reduced AKT phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion mapping, siRNA knockdown, lipolysis assays, AKT phosphorylation assays in human adipocytes and ATGL KO mouse fibroblasts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, domain mapping, genetic rescue (ATGL KO cells), multiple functional readouts, replicated mechanistically\",\n      \"pmids\": [\"24627478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HDAC6 deacetylates CIDEC at K56 (acetylated by PCAF), leading to CIDEC destabilization and reduced lipid droplet fusion; dietary fatty acids promote CIDEC acetylation by dissociating CIDEC from HDAC6 and increasing CIDEC-PCAF association on the ER, requiring conversion of FAs to triacylglycerols.\",\n      \"method\": \"Co-immunoprecipitation, acetylation site mutagenesis, adipocyte-specific Hdac6 KO mice, lipid droplet fusion assays, in vivo obese animal models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis of acetylation site, KO mouse model, multiple Co-IPs, in vivo and in vitro evidence in single rigorous study\",\n      \"pmids\": [\"28287402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Fsp27 expression in ob/ob mouse liver is directly transcriptionally activated by PPARγ (functional PPAR response element in the Fsp27 promoter); hepatic Fsp27 promotes triglyceride accumulation and lipid droplet formation.\",\n      \"method\": \"Chromatin immunoprecipitation, reporter assay, adenovirus-mediated overexpression and shRNA knockdown in hepatocytes in vitro and in vivo\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP + reporter assay + in vivo adenoviral gain/loss-of-function in single study\",\n      \"pmids\": [\"18396136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Cidec transcription is directly activated by PPARγ2 via a PPRE at −219/−207 of the Cidec promoter in adipocytes.\",\n      \"method\": \"Chromatin immunoprecipitation, luciferase reporter assay, gel shift assay, promoter mutagenesis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — ChIP + reporter + mutagenesis, single lab\",\n      \"pmids\": [\"18845124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CIDEC/Fsp27 is a direct transcriptional target of PPARα in hepatocytes; adenoviral silencing of hepatic Fsp27 abolishes fasting-induced liver steatosis without altering plasma lipids, and synergizes with PPARα agonists to reduce diet-induced hepatosteatosis.\",\n      \"method\": \"ChIP, reporter assay, adenoviral shRNA silencing in vivo, pharmacological PPARα activation\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP + reporter + in vivo adenoviral knockdown, single lab\",\n      \"pmids\": [\"25418138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The liver-enriched transcription factor CREBH activates transcription of a liver-specific Fsp27β isoform (10 extra N-terminal amino acids) from a distinct promoter; Fsp27β localizes to lipid droplet surfaces, suppresses lipolysis, and promotes lipid droplet enlargement and TG accumulation in liver.\",\n      \"method\": \"Promoter identification, reporter assay with constitutively active CREBH, adenoviral overexpression, lipid droplet imaging in hepatocytes\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assay + in vivo adenoviral expression + functional LD assays, single lab\",\n      \"pmids\": [\"25125366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Fsp27/CIDEC is a CREB target gene in the liver; early fasting induction involves the PKA-CREB-CRTC2 signaling pathway (induced by forskolin, blocked by CREB inhibition); pharmacological or genetic inhibition of fatty acid oxidation increases Fsp27 expression during fasting.\",\n      \"method\": \"Promoter reporter assay with CREB, forskolin stimulation, Sirt1 KO animals, etomoxir/Hmgcs2 interference in vivo and in HepG2 cells\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assay + in vivo genetic models + pharmacological manipulation, single lab\",\n      \"pmids\": [\"23220584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cidec undergoes phase separation via multivalent homomeric interactions of its N-terminal domain at LD-LD contact sites, forming gel-like condensates that create lipid-permeable fusion plates for LD fusion; phase separation is required for LD fusion activity.\",\n      \"method\": \"In vitro phase separation reconstitution, live-cell imaging, fluorescence recovery experiments, deletion mutants, in vivo LDCS analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of phase separation + in vivo validation + functional mutant analysis in single rigorous study\",\n      \"pmids\": [\"34508658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cidec-mediated lipid transfer between LDs occurs through closely apposed phospholipid monolayers at LD-LD interfaces, follows exponential kinetics, and is slowed by increasing the distance between monolayers, as visualized by electron cryo-tomography.\",\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 — cryo-ET structural visualization + quantitative live imaging kinetics, mechanistically rigorous\",\n      \"pmids\": [\"36800289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure of the CIDE-N domain of FSP27 at 2.0 Å resolution reveals a biologically important homodimeric interface similar to the CAD/ICAD heterodimeric complex, providing a structural basis for FSP27-mediated LD growth.\",\n      \"method\": \"X-ray crystallography at 2.0 Å resolution\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure, but functional validation of homodimer interface was not performed in the same paper\",\n      \"pmids\": [\"24025675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A polybasic RKKR motif in the linker region of CIDEC interacts with acidic phospholipids via electrostatic attraction to inhibit LD fusion; deletion or mutation of the RKKR motif disrupts protein-lipid interaction and results in enhanced LD fusion and supersized LDs.\",\n      \"method\": \"Targeted deletion and GFP-fusion constructs, fluorescence microscopy, phospholipid binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mutagenesis + protein-lipid binding assays + functional LD imaging, single lab\",\n      \"pmids\": [\"30361435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"AMPK activation induces ubiquitination and proteasomal degradation of FSP27, resulting in LD multilocularization; HSC70 is identified as a novel FSP27-binding protein that promotes FSP27 degradation, while CHIP (E3 ubiquitin ligase) is not required.\",\n      \"method\": \"AICAR/phenformin treatment, AMPKα1 knockdown, proteasome inhibition, mass spectrometry, co-immunoprecipitation of endogenous proteins, cycloheximide chase, siRNA knockdown of HSC70 and CHIP\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MS identification + Co-IP + genetic knockdown + functional LD readout, single lab\",\n      \"pmids\": [\"25315694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Cidec interacts with AMPKα1 and promotes its degradation via the ubiquitin-proteasome pathway, thereby promoting adipocyte differentiation; the interaction was confirmed by yeast two-hybrid, co-immunoprecipitation, and co-localization.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence co-localization, proteasome inhibition assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — yeast two-hybrid + Co-IP + co-localization + functional assay, single lab\",\n      \"pmids\": [\"26367078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Growth hormone downregulates FSP27 expression by activating MEK/ERK signaling, which phosphorylates PPARγ at Ser273 and promotes its nuclear-to-cytosol translocation; FSP27 overexpression inhibits PPARγ Ser273 phosphorylation and promotes nuclear retention, thus suppressing GH-induced lipolysis.\",\n      \"method\": \"Selective inhibitors, constitutively active MEK1 mutant, immunofluorescence, subcellular fractionation, reporter assay, human adipose-derived stromal vascular cells, human subjects\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple signaling inhibitors + nuclear fractionation + reporter assay + human cell model, single lab\",\n      \"pmids\": [\"30325658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TNF-α downregulates CIDEC transcription through MEK/ERK-dependent phosphorylation and nuclear export of PPARγ in human adipocytes.\",\n      \"method\": \"MEK/ERK inhibitors, constitutively active MEK1, immunofluorescence, subcellular fractionation, luciferase reporter assay\",\n      \"journal\": \"Obesity (Silver Spring, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological + reporter + localization assays, single lab\",\n      \"pmids\": [\"27062372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CIDEC translocates from the ER to lipid droplets in response to fatty acid stimulation; the N-terminal domain (aa 1–173) mediates LD localization while the C-terminal domain (aa 174–238) is necessary for LD fusion; aa 106–173 contains an ER-binding domain.\",\n      \"method\": \"CIDEC deletion mutant analysis, immunofluorescence, subcellular fractionation in HepG2 cells\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — domain deletion mutants + subcellular fractionation, single lab\",\n      \"pmids\": [\"25255829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CIDEC regulates ATGL enzymatic activity by interacting with its activator CGI-58, reducing free fatty acid release and lipotoxicity in adipocytes; adipose-specific CIDEC transgenic mice are protected from HFD-induced glucose intolerance, while the E186X variant abolishes this protection.\",\n      \"method\": \"Transgenic mouse model (Ad-CIDECtg and Ad-CIDECmut), transcriptomics, lipidomics, Co-IP of CIDEC-CGI-58, recombinant CIDEC treatment of human adipose tissue, triglyceride breakdown assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — transgenic mouse model + Co-IP + lipidomics/transcriptomics + human tissue ex vivo, multiple orthogonal methods\",\n      \"pmids\": [\"35963433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CIDEC interacts with endothelial VEGFA-VEGFR2 signaling; endothelial-specific CIDEC expression reduces VEGFA and VEGFR2 degradation, increasing VEGFR2 activation, improved insulin signaling/eNOS activation, and vascular relaxation.\",\n      \"method\": \"Endothelial-specific CIDEC transgenic mice, insulin signaling assays, eNOS activation, vascular relaxation measurements, VEGF pathway analysis\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transgenic mouse model with mechanistic pathway identification, single lab\",\n      \"pmids\": [\"36256836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Small intestine-specific CIDEC knockout reduces body fat, liver TG, and hepatic steatosis; mechanistically, CIDEC promotes phosphatidic acid synthesis by interacting with 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) to accelerate TG accumulation in intestinal cells.\",\n      \"method\": \"Cre/LoxP intestine-specific KO mice, Co-IP of CIDEC-AGPAT, metabolic phenotyping, phosphatidic acid measurement\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KO + Co-IP + biochemical mechanism, single lab\",\n      \"pmids\": [\"36263170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Paxillin family proteins Hic-5 and LPXN interact with CIDEC and inhibit its proteasomal ubiquitination/degradation, thereby stabilizing CIDEC protein, enlarging LDs, and promoting lipid storage in adipocytes.\",\n      \"method\": \"HTRF-based high-throughput screening, Co-IP, ubiquitination assays, proteasome inhibition, LD morphology in adipocytes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP + ubiquitination assays + functional LD readout, single lab\",\n      \"pmids\": [\"38159847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Insulin upregulates CIDEC expression in human adipocytes via a PI3K-JNK2-dependent pathway, and CIDEC depletion abolishes insulin-induced lipid droplet enlargement and increases glycerol release.\",\n      \"method\": \"PI3K/Akt/JNK inhibitors, siRNA knockdown of JNK1/JNK2, lipid droplet imaging, glycerol release assay\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway dissection with selective inhibitors + siRNA + functional assays, single lab\",\n      \"pmids\": [\"20154362\", \"21636835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FSP27 negatively regulates AMPK activity and ATGL expression in adipocytes; CIDEC knockdown in LPS-treated renal tubular epithelial cells restores phospho-AMPKα and suppresses NF-κB pathway activation and inflammatory cytokine production.\",\n      \"method\": \"CIDEC siRNA knockdown, Western blot for p-AMPKα, NF-κB pathway reporters, cytokine measurement\",\n      \"journal\": \"Inflammation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single knockdown study in non-adipocyte cells, indirect pathway evidence\",\n      \"pmids\": [\"29959627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Gp78 (membrane E3 ubiquitin ligase) co-localizes and physically interacts with CIDEC on the surface of lipid droplets, and this interaction promotes lipid accumulation in hepatocytes.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, overexpression/knockdown in AML12 cells\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP + co-localization, functional consequence indirect, single lab\",\n      \"pmids\": [\"28656280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FSP27 negatively regulates the AMPK-signaling axis; negatively charged residues (D215, E218, E219, E220) in the polar C-terminal region of FSP27 are essential for LD enlargement, while the N-terminal domain (aa 1–130) accelerates but is not required for LD growth.\",\n      \"method\": \"FSP27 domain deletion and charge-reversal mutagenesis, LD size quantification\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic mutagenesis with functional LD readout, single lab\",\n      \"pmids\": [\"26921608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Human CIDE-3 (CIDEC), a homologue of mouse FSP27, contains conserved CIDE-N and CIDE-C domains and induces apoptosis (DNA fragmentation) upon overexpression in 293T cells; GFP-tagged CIDE-3 localizes to cytosolic corpuscles; an alternative splice isoform (CIDE-3α, lacking exon 3) retains apoptosis-inducing activity.\",\n      \"method\": \"DNA fragmentation assay, GFP fusion protein localization, RT-PCR, transfection in 293T cells\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional assay (DNA fragmentation) + GFP localization, single lab foundational study\",\n      \"pmids\": [\"12429024\"],\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, identified by yeast two-hybrid screening; overexpressed CIDE-3 induces apoptosis in hepatocellular carcinoma cells.\",\n      \"method\": \"Yeast two-hybrid, flow cytometry apoptosis assay, overexpression in SMMC-7721 cells\",\n      \"journal\": \"Medical oncology (Northwood, London, England)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — yeast two-hybrid without biochemical confirmation of endogenous interaction, single lab\",\n      \"pmids\": [\"20957525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The FSP27 promoter confers adipocyte-specific expression; a palindromic sequence (TTCGAAA) is required for adipocyte-specific expression and is bound by C/EBP and C/EBP-like proteins as demonstrated by DNase I footprinting.\",\n      \"method\": \"Promoter-reporter transfection, DNase I footprinting with nuclear extracts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — functional reporter assays + footprinting, foundational promoter study\",\n      \"pmids\": [\"1339452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CIDEC acts as a metabolic gatekeeper in liver regeneration: its depletion after peak LD accumulation promotes TG mobilization and fatty acid oxidation-driven regeneration; overexpression of CIDEC or DGAT2 exacerbates TG retention and impairs regeneration.\",\n      \"method\": \"CIDEC depletion/overexpression in mice, lipidomics, transcriptomics, FAO inhibition experiments, chronic steatosis model\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function in vivo + lipidomics + pathway inhibition, single lab\",\n      \"pmids\": [\"41255220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"N-terminal domain of CIDEC (CIDEC-N) undergoes phase separation in vitro; in vitro reconstitution confirmed that multivalent homomeric CIDEC-N interactions are sufficient to drive phase separation, providing a biochemical basis for LDCS condensate formation.\",\n      \"method\": \"Recombinant protein purification, in vitro phase separation assay, concentration-dependent droplet formation\",\n      \"journal\": \"STAR protocols\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of phase separation; protocol paper corroborating earlier Developmental Cell study\",\n      \"pmids\": [\"40232936\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CIDEC/FSP27 is a lipid droplet-associated protein that localizes to LD-LD contact sites where its N-terminal domain undergoes phase separation to form gel-like condensates, facilitating directional pressure-driven transfer of neutral lipids from smaller to larger LDs; its activity is modulated by CIDE-N homodimerization, interaction with Perilipin1 (which activates it), interaction with ATGL and CGI-58 (which it inhibits to suppress lipolysis), acetylation at K56 by PCAF (stabilizing) and deacetylation by HDAC6 (destabilizing), and proteasomal degradation triggered by AMPK/HSC70; transcriptionally it is directly activated by PPARγ, PPARα, and CREBH in a tissue- and isoform-specific manner.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CIDEC (also called FSP27) is a lipid droplet (LD)-associated protein that drives unilocular LD formation in adipocytes and hepatocytes by mediating directional, pressure-driven transfer of neutral lipids from smaller to larger LDs at LD-LD contact sites. At these contact sites, the CIDE-N domain undergoes phase separation to form gel-like condensates that create lipid-permeable fusion plates, while the CIDE-C domain is required for LD targeting and fusion; CIDEC simultaneously suppresses lipolysis by directly inhibiting ATGL and sequestering its co-activator CGI-58, and its protein stability is regulated by PCAF-mediated acetylation at K56 (stabilizing) versus HDAC6-mediated deacetylation and AMPK/HSC70-driven proteasomal degradation [PMID:22144693, PMID:34508658, PMID:36800289, PMID:24627478, PMID:35963433, PMID:28287402, PMID:25315694]. Perilipin1 interaction with CIDEC markedly enhances lipid transfer activity, and CIDE-N homodimerization is required for function [PMID:23481402]. A homozygous truncation mutation (E186X) in the CIDE-C domain causes familial partial lipodystrophy with multilocular white adipocyte LDs [PMID:20049731]. Transcription of CIDEC is directly activated by PPARγ in adipocytes, PPARα and CREBH in hepatocytes (the latter driving a liver-specific Fsp27β isoform), and is modulated by insulin/PI3K-JNK2, TNFα/MEK-ERK, and growth hormone signaling [PMID:18396136, PMID:25418138, PMID:25125366, PMID:20154362].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Before CIDEC's lipid droplet function was known, the FSP27 promoter was shown to confer adipocyte-specific expression dependent on C/EBP-binding elements, establishing tissue-restricted transcriptional control as a foundational property.\",\n      \"evidence\": \"Promoter-reporter transfection and DNase I footprinting with adipocyte nuclear extracts\",\n      \"pmids\": [\"1339452\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the specific C/EBP family member(s) driving endogenous expression was not resolved\", \"No link to lipid metabolism was established at this stage\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Cloning of human CIDE-3 (CIDEC) revealed conserved CIDE-N and CIDE-C domains and showed that overexpression induces apoptosis, initially framing the protein within the CIDE cell-death family.\",\n      \"evidence\": \"DNA fragmentation assay and GFP-fusion localization in 293T cells\",\n      \"pmids\": [\"12429024\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apoptotic function was based on overexpression; physiological relevance of cell-death activity remained unclear\", \"Lipid droplet association was not yet recognized\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Genetic ablation in mice and PPARγ-dependent transcriptional activation established CIDEC as a major determinant of unilocular LD formation, triglyceride storage, and lipolytic suppression in white adipose tissue and liver, redefining its primary function from apoptosis to lipid metabolism.\",\n      \"evidence\": \"FSP27 knockout mice with multilocular LD/lean phenotype; ChIP and reporter assays identifying PPARγ PPRE in the Cidec promoter; adenoviral gain/loss-of-function in hepatocytes\",\n      \"pmids\": [\"18654663\", \"18396136\", \"18845124\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CIDEC promotes LD enlargement (fusion vs. transfer vs. synthesis) was unresolved\", \"Relative contribution of lipolysis suppression vs. LD fusion was not separated\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"A human homozygous truncation (E186X) in the CIDE-C domain causing partial lipodystrophy provided genetic proof that the CIDE-C domain is essential for LD targeting and function in humans.\",\n      \"evidence\": \"Human genetic study with cellular validation showing mislocalization and loss of LD enlargement by mutant CIDEC\",\n      \"pmids\": [\"20049731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether additional CIDEC mutations cause lipodystrophy in other families was unknown\", \"Structural basis for CIDE-C domain function remained unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Live-cell imaging and FRAP revealed that CIDEC concentrates at LD-LD contact sites and mediates directional lipid transfer from smaller to larger LDs driven by Laplace pressure differences, resolving the biophysical mechanism of LD growth.\",\n      \"evidence\": \"FRAP, live-cell imaging, and biophysical pressure analysis in Fsp27-deficient and Fsp27-overexpressing cells\",\n      \"pmids\": [\"22144693\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular nature of the pore or channel allowing lipid transfer was unknown\", \"Whether other CIDE family members use the same mechanism was untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Perilipin1 was identified as a direct activator of CIDEC-mediated lipid transfer through interaction with the CIDE-N domain, and CIDE-N homodimerization was shown to be required for function, defining the key protein-protein interactions governing CIDEC activity.\",\n      \"evidence\": \"Reciprocal Co-IP, FRAP-based lipid transfer quantification, domain mutagenesis, and crystal structure of CIDE-N homodimer at 2.0 Å\",\n      \"pmids\": [\"23481402\", \"23399566\", \"24025675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Plin1 binding mechanistically enhances lipid transfer rate was not determined\", \"Role of CIDE-N dimerization in phase separation was not yet appreciated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"CIDEC was shown to directly inhibit ATGL lipolytic activity via its C-terminal region (aa 120–220), establishing a dual mechanism — LD fusion plus lipolysis suppression — for triglyceride storage, while AMPK activation was found to trigger CIDEC ubiquitination and proteasomal degradation via HSC70.\",\n      \"evidence\": \"Co-IP and domain mapping of CIDEC-ATGL interaction in ATGL KO rescue; AICAR/phenformin treatment with cycloheximide chase and HSC70 knockdown\",\n      \"pmids\": [\"24627478\", \"25315694\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ubiquitin ligase responsible for AMPK-triggered CIDEC degradation was not identified (CHIP was excluded)\", \"Structural basis for CIDEC-ATGL inhibitory interaction was lacking\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Tissue-specific transcriptional programs were delineated: PPARα directly activates Cidec in hepatocytes during fasting, and CREBH drives a liver-specific Fsp27β isoform from a distinct promoter, explaining how the same gene is induced in both adipose and liver contexts.\",\n      \"evidence\": \"ChIP, reporter assays, adenoviral shRNA in vivo for PPARα; promoter identification and constitutively active CREBH reporter assays for Fsp27β\",\n      \"pmids\": [\"25418138\", \"25125366\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional differences between Fsp27α and Fsp27β isoforms beyond expression pattern were not fully characterized\", \"Whether PPARα and CREBH cooperate on the same promoter was untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Post-translational regulation of CIDEC stability was resolved: PCAF acetylates K56 to stabilize CIDEC, while HDAC6 deacetylates K56 to destabilize it; dietary fatty acids shift the PCAF/HDAC6 balance toward acetylation on the ER, linking nutritional status to CIDEC protein levels.\",\n      \"evidence\": \"Acetylation site mutagenesis, adipocyte-specific Hdac6 KO mice, Co-IP of CIDEC-PCAF and CIDEC-HDAC6, LD fusion assays in obese animal models\",\n      \"pmids\": [\"28287402\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether K56 acetylation affects CIDEC phase separation or interaction with Plin1/ATGL was not tested\", \"Deacetylation-independent degradation pathways were not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A polybasic RKKR motif in the CIDEC linker was found to interact with acidic phospholipids and act as an autoinhibitory element that restrains LD fusion, adding a lipid-dependent regulatory layer to CIDEC activity.\",\n      \"evidence\": \"Charge-reversal mutagenesis, phospholipid binding assays, and LD size quantification\",\n      \"pmids\": [\"30361435\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How RKKR motif regulation integrates with Plin1 activation or acetylation status was not explored\", \"In vivo significance of this autoinhibitory mechanism was not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The molecular basis of the LD-LD contact site was resolved: CIDEC-N undergoes phase separation via multivalent homomeric interactions to form gel-like condensates that constitute the lipid-permeable fusion plate, establishing phase separation as the organizing principle for CIDEC-mediated lipid transfer.\",\n      \"evidence\": \"In vitro reconstitution of CIDEC-N phase separation, live-cell FRAP at LDCS, functional deletion mutants disrupting phase separation\",\n      \"pmids\": [\"34508658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Plin1, ATGL, or CGI-58 partition into or are excluded from the condensate was not determined\", \"Structural details of the lipid-permeable pore within the condensate are unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"CIDEC's lipolysis-suppressive function was extended beyond ATGL to its co-activator CGI-58: CIDEC sequesters CGI-58, reducing free fatty acid release and lipotoxicity, with in vivo validation showing adipose-specific CIDEC transgenic mice are protected from HFD-induced glucose intolerance.\",\n      \"evidence\": \"Co-IP of CIDEC-CGI-58, adipose-specific transgenic and E186X mutant mice, lipidomics, recombinant CIDEC on human adipose tissue ex vivo\",\n      \"pmids\": [\"35963433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CIDEC binds CGI-58 and ATGL simultaneously or competitively was not resolved\", \"Stoichiometry of the CIDEC-CGI-58 complex is unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Cryo-electron tomography visualized the LD-LD interface architecture, showing that CIDEC-mediated lipid transfer occurs through closely apposed phospholipid monolayers with exponential transfer kinetics sensitive to inter-monolayer distance, providing direct structural evidence for the transfer mechanism.\",\n      \"evidence\": \"Electron cryo-tomography of LD-LD contacts combined with quantitative live fluorescence microscopy of lipid transfer kinetics\",\n      \"pmids\": [\"36800289\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution structure of the CIDEC condensate at the contact site is lacking\", \"Whether a proteinaceous pore exists or lipid transfer occurs purely through monolayer proximity remains unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include: (1) the atomic-level structure of the CIDEC phase-separated fusion plate and whether it forms a discrete pore; (2) how post-translational modifications (acetylation, ubiquitination, phospholipid binding) regulate phase separation properties; (3) whether CIDEC condensates selectively partition or exclude regulatory partners such as Plin1, ATGL, and CGI-58.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of the intact CIDEC condensate at LD-LD contacts\", \"Interplay between acetylation/AMPK degradation and phase separation is untested\", \"Comprehensive interactome of the CIDEC condensate is not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [17, 22]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [7, 23]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 23, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [0, 1, 2, 5, 14, 15, 22]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [8, 22]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [31]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 7, 8, 9, 23, 25]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [20, 21, 27]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 31]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PLIN1\",\n      \"PNPLA2\",\n      \"ABHD5\",\n      \"HDAC6\",\n      \"KAT2B\",\n      \"HSPA8\",\n      \"CIDEA\",\n      \"TGFB1I1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}