{"gene":"PLIN5","run_date":"2026-04-28T19:45:44","timeline":{"discoveries":[{"year":2006,"finding":"PLIN5 (OXPAT/MLDP/LSDP5) localizes to the surface of lipid droplets in oxidative tissues and its expression is induced by PPARα activation (fasting, insulin deficiency, PPARα agonists). Ectopic expression promotes fatty acid-induced triacylglycerol accumulation and long-chain fatty acid oxidation.","method":"Subcellular fractionation, ectopic expression in cells, GFP-fusion live imaging, PPARα knockout mice, pharmacological PPAR agonist treatment","journal":"Diabetes / Journal of Biological Chemistry / Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 — independently replicated across multiple labs in same year with consistent findings","pmids":["17130488","16571721","17234449"],"is_preprint":false},{"year":2006,"finding":"The N-terminal PAT-1 domain plus a following 33-mer domain of PLIN5 (MLDP) is required for targeting to lipid droplet surfaces, as shown by deletion analysis.","method":"Deletion mutagenesis with GFP-fusion protein localization in cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — direct deletion mutagenesis with clear localization readout, single lab","pmids":["16571721"],"is_preprint":false},{"year":2008,"finding":"PLIN5 (Mldp/LSDP5) directly binds Abhd5 (CGI-58, the protein activator of ATGL) on lipid droplet surfaces; this interaction is dynamic, increases with oleic acid treatment, and is required for efficient ATGL-mediated lipolysis at PLIN5-containing lipid droplets.","method":"Protein-protein interaction assay in transfected fibroblasts, in situ binding on microdissected cardiac muscle fibers, Abhd5 E262K mutant with impaired Mldp binding, cellular lipolysis assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including site-directed mutant, functional lipolysis readout, single rigorous paper","pmids":["19064991"],"is_preprint":false},{"year":2010,"finding":"PLIN5 interacts with both ATGL and its activator Abhd5, but individual PLIN5 molecules bind either ATGL or Abhd5 but not both simultaneously, suggesting oligomeric complexes concentrate these proteins at lipid droplet surfaces. The C-terminal 64 amino acids of PLIN5 (residues 200–463) are necessary and sufficient for differential binding of ATGL to PLIN5 (but not PLIN1).","method":"Protein interaction assays in live cells, in situ binding, chimeric/mutant perilipin analysis, competition experiments, neutral lipid accumulation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including mutagenesis and functional assays in a single rigorous study","pmids":["21148142"],"is_preprint":false},{"year":2012,"finding":"PLIN5 (LSDP5) inhibits lipolysis and fatty acid β-oxidation in hepatocytes; knockdown stimulates lipolysis and increases PPARα expression and mitochondrial β-oxidation. The lipid droplet-targeting and clustering domain maps to the N-terminal 188 amino acids.","method":"Overexpression and siRNA knockdown in AML12 hepatocytes and primary hepatocytes, serial deletion analysis, triglyceride content measurement, lipolysis assay, mitochondrial oxidation measurement","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD/OE with defined cellular phenotype plus domain mapping, single lab","pmids":["22675471"],"is_preprint":false},{"year":2014,"finding":"PLIN5 is found in the mitochondrial fraction of skeletal muscle, and its mitochondrial content increases ~1.6-fold following muscle contraction, consistent with a role in facilitating mitochondrial fatty acid oxidation during lipolysis.","method":"Mitochondrial isolation by differential centrifugation from rat red gastrocnemius, Western blotting, immunofluorescence","journal":"Physiological reports","confidence":"Medium","confidence_rationale":"Tier 2 — direct fractionation with functional context, single lab","pmids":["25318747"],"is_preprint":false},{"year":2019,"finding":"PLIN5 is a fatty-acid-binding protein that preferentially binds lipid droplet-derived monounsaturated fatty acids (MUFAs) and, following cAMP/PKA-mediated lipolytic stimulation, traffics them to the nucleus where MUFAs allosterically activate SIRT1 toward PGC-1α, thereby enhancing PGC-1α/PPARα signaling and oxidative metabolism.","method":"Fatty acid binding assay, cAMP/PKA stimulation, nuclear fractionation, SIRT1 allosteric activation assay with defined substrates, cell and animal model experiments with SIRT1-dependent pathway validation","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including binding assays, nuclear trafficking, in vitro SIRT1 assay, and in vivo validation","pmids":["31901447"],"is_preprint":false},{"year":2020,"finding":"PLIN5 is a substrate of chaperone-mediated autophagy (CMA); its degradation via LAMP2A is required for lipid droplet breakdown in hepatocytes. Disruption of CMA (LAMP2A deletion) stabilizes PLIN5, obstructs LD breakdown, and causes lipid homeostasis imbalance.","method":"Liver-specific LAMP2A-knockout mice, LAMP2A-deficient HepG2 cells, co-localization studies, lipid droplet accumulation assays","journal":"Liver international","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with defined phenotype and substrate identification, single lab","pmids":["32339374"],"is_preprint":false},{"year":2023,"finding":"PLIN5 interacts with the acyl-CoA synthetase FATP4 (ACSVL4) on mitochondria at lipid droplet-mitochondria contact sites; the C-terminal domains of PLIN5 and FATP4 constitute a minimal interaction capable of inducing organelle contacts. Phosphorylation of PLIN5 promotes LD-to-mitochondria fatty acid transfer and β-oxidation during starvation, and an intact PLIN5 mitochondrial tethering domain is required.","method":"Co-immunoprecipitation, proximity ligation assay, domain mapping with minimal constructs, phosphorylation-deficient/mimetic mutants, β-oxidation assays in starved myoblasts, human and murine cell models","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods, functional domain mapping, phosphorylation mutants, human and murine cells","pmids":["37290445"],"is_preprint":false},{"year":2023,"finding":"PLIN5 interacts with SERCA2 (sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2) in cardiomyocytes; cardiac-specific overexpression of PLIN5 increases intracellular Ca2+ release during contraction and Ca2+ removal during relaxation, enhancing SERCA2 function and cardiomyocyte contractility.","method":"Quantitative proteomics of PLIN5-overexpressing hearts, in situ proximity ligation assay, live imaging of Ca2+ dynamics, cardiac-specific transgenic mice (MHC-Plin5)","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 2 — reciprocal protein interaction confirmed by PLA, functional Ca2+ live imaging in transgenic model","pmids":["36717246"],"is_preprint":false},{"year":2022,"finding":"Under basal (non-phosphorylated) conditions, PLIN5 inhibits lipolysis by sequestering CGI-58 (Abhd5), preventing it from activating ATGL. Upon PKA-mediated phosphorylation of PLIN5 (e.g., during fasting, cold, or exercise), PLIN5 releases CGI-58, which then binds and activates ATGL, accelerating lipolysis.","method":"Review synthesizing cell-based phosphorylation experiments and protein interaction studies","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 3 — review synthesis of existing experimental data; mechanism supported by primary studies cited","pmids":["35401929"],"is_preprint":false},{"year":2022,"finding":"PLIN5 interacts with PGC-1α in vascular smooth muscle cells; Plin5 knockdown reduces Plin5-PGC-1α interaction, increases ROS, and promotes VSMC proliferation and migration. PGC-1α overexpression rescues ROS elevation and VSMC dysfunction in Plin5-deficient cells.","method":"Co-immunoprecipitation, wire-injury mouse model, Plin5 knockdown mice (Plin5±), ROS measurement, proliferation/migration assays, PGC-1α overexpression rescue","journal":"Bioengineered","confidence":"Medium","confidence_rationale":"Tier 2-3 — genetic knockdown with defined phenotype and interaction assay, rescue experiment, single lab","pmids":["35470759"],"is_preprint":false},{"year":2025,"finding":"HSD17β11 facilitates the interaction between PLIN5 and ATGL on lipid droplets, enabling efficient PKA-stimulated lipolysis; HSD17β11 deletion impairs this PLIN5-ATGL interaction and reduces lipolysis in human cell lines.","method":"HSD17β11 deletion in human cell lines, lipolysis assays, co-immunoprecipitation of PLIN5 and ATGL, PKA stimulation","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 — genetic deletion with mechanistic interaction assay, single lab, human cells","pmids":["41238190"],"is_preprint":false},{"year":2025,"finding":"TBC1D15 is recruited to mitochondrial membranes in hepatocytes upon alcohol exposure and interacts with PLIN5 through its 10-180 aa domain, promoting mitochondria-lipid droplet contacts and PKA-induced nuclear translocation of PLIN5.","method":"Hepatocyte-specific TBC1D15 overexpression mice, co-immunoprecipitation domain mapping, immunofluorescence of PLIN5 nuclear translocation, PKA inhibition experiments","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 — domain-level interaction mapping with functional nuclear translocation readout, single lab","pmids":["40334909"],"is_preprint":false},{"year":2026,"finding":"PLIN5 phosphorylation at S155 regulates mitochondria-lipid droplet contact formation and hepatic lipid flux: the phosphorylation-resistant S155A variant enhances organelle contacts and LD expansion, while the phosphomimetic S155E variant reduces contacts and yields fewer, smaller LDs. PLIN5 overexpression in Western-diet-fed mice reduces lipotoxicity.","method":"Single-cell tissue imaging (scPhenomics), spatial proteomics, PLIN5 phosphorylation variant overexpression (S155A, S155E, WT) in mice, LD/mitochondria contact quantification, lipid content measurement","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 1-2 — phosphorylation mutagenesis with organelle contact quantification, spatial proteomics, and in vivo functional validation","pmids":["41872512"],"is_preprint":false},{"year":2020,"finding":"Isolated Plin5-deficient cardiomyocytes store fewer lipid droplets than wild-type, primarily because PLIN5 represses ATGL lipase activity; inhibiting ATGL activity normalizes LD levels in Plin5-/- cardiomyocytes to wild-type levels.","method":"Isolated adult cardiomyocytes from Plin5+/+ and Plin5-/- mice, ATGL inhibitor treatment, fatty acid oxidation assays, lipid droplet quantification","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with pharmacological rescue confirming ATGL-dependence, single lab","pmids":["33373698"],"is_preprint":false},{"year":2025,"finding":"PLIN5 regulates lipid metabolism and mitochondrial dynamics in pancreatic β-cells via PGC-1α/Drp1 signaling: PLIN5 knockdown decreases PGC-1α and increases Drp1, causing mitochondrial dysfunction, while PLIN5 overexpression reverses high-glucose-induced damage. PLIN5 also influences PGC-1α binding to the Drp1 promoter.","method":"siRNA knockdown and lentiviral overexpression in INS-1 cells, db/db mice, Western blotting, qPCR, immunofluorescence, chromatin-related promoter binding assay","journal":"Endocrine","confidence":"Medium","confidence_rationale":"Tier 2 — KD/OE with pathway placement via PGC-1α/Drp1, single lab","pmids":["40884681"],"is_preprint":false},{"year":2023,"finding":"PLIN5 expression in liver (Hep3B cells) is induced by IL-6 in a dose- and time-dependent manner through the JAK/STAT3 signaling pathway; this induction can be blocked by TGF-β and TNF-α, and is modulated by IL-6 trans-signaling.","method":"IL-6 treatment of Hep3B cells, JAK/STAT3 inhibitors, TGF-β and TNF-α co-treatment, soluble IL-6R addition, quantitative protein and mRNA analysis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — pathway-level regulation with pharmacological inhibition, single lab","pmids":["37108378"],"is_preprint":false},{"year":2025,"finding":"In an in vitro reconstitution system, PLIN5 promotes stable attachment of lipid droplet monolayers to bilayer membranes (LUVs) while preventing membrane fusion, demonstrating a direct physical role of PLIN5 in mediating organelle contact sites.","method":"In vitro reconstitution with artificial LDs coated with PLIN5, large unilamellar vesicles (LUVs), dual fluorescence labeling to distinguish fusion from stable attachment","journal":"Biochemistry and biophysics reports","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro reconstitution with defined components, single lab","pmids":["41459334"],"is_preprint":false},{"year":2021,"finding":"Leptin promotes FTO-mediated demethylation (reduction in m6A methylation) of Plin5 mRNA, increasing Plin5 protein expression in adipose tissue, which in turn reduces lipid droplet size and promotes triglyceride metabolism.","method":"In vivo leptin treatment of piglets, in vitro porcine adipocyte FTO overexpression/interference, m6A methylation measurement, Plin5 overexpression functional assays","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 — single lab, primarily porcine model, indirect regulation of PLIN5 via m6A","pmids":["34638947"],"is_preprint":false}],"current_model":"PLIN5 is a lipid droplet surface scaffold protein expressed in oxidative tissues (heart, skeletal muscle, liver) under PPARα control that bidirectionally regulates lipolysis by sequestering CGI-58/Abhd5 away from ATGL under basal conditions and releasing it upon PKA-mediated phosphorylation at S155; phospho-PLIN5 also translocates to the nucleus carrying monounsaturated fatty acids that allosterically activate SIRT1/PGC-1α/PPARα signaling, and tethers mitochondria to lipid droplets via an interaction with FATP4, thereby channeling fatty acids from lipid droplet lipolysis directly into mitochondrial β-oxidation."},"narrative":{"teleology":[{"year":2006,"claim":"Identification of PLIN5 as a PPARα-regulated lipid droplet coat protein in oxidative tissues established it as the perilipin family member linking fatty acid storage to oxidative metabolism.","evidence":"Subcellular fractionation, PPARα-knockout mice, ectopic expression, and PPAR agonist treatment across three independent labs","pmids":["17130488","16571721","17234449"],"confidence":"High","gaps":["Mechanism by which PLIN5 simultaneously promotes TAG storage and FA oxidation was unclear","Domain requirements for LD targeting only partially mapped"]},{"year":2008,"claim":"Discovery that PLIN5 directly binds the ATGL co-activator CGI-58/Abhd5 revealed the molecular basis by which PLIN5 gates lipolysis at the lipid droplet surface.","evidence":"Protein interaction assays in transfected fibroblasts, in situ binding on cardiac fibers, Abhd5 E262K mutant analysis, lipolysis assays","pmids":["19064991"],"confidence":"High","gaps":["Whether PLIN5 binds ATGL directly was not yet resolved","Signal that releases CGI-58 from PLIN5 was unknown"]},{"year":2010,"claim":"Demonstration that individual PLIN5 molecules bind either ATGL or CGI-58 but not both simultaneously suggested that oligomeric PLIN5 scaffolds concentrate lipolytic machinery and introduced the C-terminal domain as the ATGL-binding determinant.","evidence":"Chimeric perilipin analysis, competition experiments, and functional assays in live cells","pmids":["21148142"],"confidence":"High","gaps":["Stoichiometry and oligomerization state of PLIN5 on LDs not defined","Phosphorylation-dependent switch not yet shown"]},{"year":2012,"claim":"Hepatocyte loss-of-function studies confirmed that PLIN5 acts as a lipolysis brake, with knockdown increasing ATGL-dependent lipolysis and β-oxidation.","evidence":"siRNA knockdown and overexpression in AML12/primary hepatocytes, lipolysis and oxidation measurements","pmids":["22675471"],"confidence":"Medium","gaps":["Phosphorylation site mediating lipolysis activation not identified","Relationship between LD-association domain and lipolysis-inhibitory function was correlative"]},{"year":2014,"claim":"Detection of PLIN5 in the mitochondrial fraction of skeletal muscle, increasing with contraction, provided the first evidence that PLIN5 physically associates with mitochondria to facilitate FA channeling during exercise.","evidence":"Differential centrifugation and Western blotting from rat skeletal muscle after contraction","pmids":["25318747"],"confidence":"Medium","gaps":["Mitochondrial binding partner not identified","Could not distinguish LD-mitochondria contact sites from free mitochondrial PLIN5"]},{"year":2019,"claim":"The discovery that PLIN5 binds monounsaturated fatty acids and upon PKA stimulation carries them to the nucleus to allosterically activate SIRT1/PGC-1α established a lipid signaling relay from LDs to transcriptional control of oxidative metabolism.","evidence":"FA binding assays, nuclear fractionation, in vitro SIRT1 activation assay, animal model validation","pmids":["31901447"],"confidence":"High","gaps":["Structural basis of FA binding by PLIN5 unknown","Whether nuclear PLIN5 has additional transcriptional targets beyond PGC-1α/PPARα not explored"]},{"year":2020,"claim":"Identification of PLIN5 as a chaperone-mediated autophagy substrate degraded via LAMP2A revealed how PLIN5 protein turnover is coupled to lipid droplet breakdown in hepatocytes.","evidence":"Liver-specific LAMP2A-KO mice and LAMP2A-deficient HepG2 cells with LD accumulation phenotype","pmids":["32339374"],"confidence":"Medium","gaps":["CMA-targeting motif on PLIN5 not mapped","Interplay between CMA-mediated PLIN5 degradation and PKA-mediated PLIN5 phosphorylation not addressed"]},{"year":2020,"claim":"Plin5-knockout cardiomyocytes confirmed that PLIN5 restrains ATGL activity in the heart, as pharmacological ATGL inhibition fully rescued LD depletion in Plin5−/− cells.","evidence":"Isolated adult cardiomyocytes from Plin5-KO mice, ATGL inhibitor rescue, LD quantification","pmids":["33373698"],"confidence":"Medium","gaps":["Heart-specific consequences of chronic PLIN5 loss on mitochondrial function not fully delineated","Phosphorylation-dependent regulation not tested in this system"]},{"year":2022,"claim":"The PKA-phosphorylation model was consolidated: basal PLIN5 sequesters CGI-58 to suppress lipolysis, and phosphorylation releases CGI-58 to activate ATGL, providing a unified regulatory switch.","evidence":"Review synthesis of cell-based phosphorylation and protein interaction studies","pmids":["35401929"],"confidence":"Medium","gaps":["Specific phosphorylation site(s) responsible had not been mutagenized in vivo","Whether additional kinases target PLIN5 was unresolved"]},{"year":2023,"claim":"Identification of FATP4 as the mitochondrial binding partner of PLIN5 at LD–mitochondria contact sites, with phosphorylation promoting FA transfer to β-oxidation, provided the molecular tether linking lipolysis to mitochondrial oxidation.","evidence":"Co-IP, proximity ligation assay, domain mapping with minimal constructs, phospho-mutant β-oxidation assays in starved myoblasts","pmids":["37290445"],"confidence":"High","gaps":["Structure of the PLIN5–FATP4 complex not resolved","Whether PLIN5 also tethers to ER or other organelles via distinct partners unclear"]},{"year":2023,"claim":"Discovery of a PLIN5–SERCA2 interaction in cardiomyocytes, enhancing Ca²⁺ cycling and contractility, expanded PLIN5 function beyond lipid metabolism to excitation-contraction coupling.","evidence":"Quantitative proteomics, proximity ligation assay, live Ca²⁺ imaging in cardiac-specific PLIN5-transgenic mice","pmids":["36717246"],"confidence":"High","gaps":["Direct binding domain on PLIN5 for SERCA2 not mapped","Whether this reflects a lipid-dependent or lipid-independent mechanism is unknown"]},{"year":2025,"claim":"In vitro reconstitution demonstrated that PLIN5 directly mediates stable attachment of lipid droplet monolayers to bilayer membranes without promoting fusion, establishing an intrinsic membrane-tethering activity.","evidence":"Reconstituted artificial LDs coated with PLIN5, LUV bilayers, dual fluorescence to distinguish tethering from fusion","pmids":["41459334"],"confidence":"Medium","gaps":["Physiological relevance to specific organelle contacts not demonstrated in this system","Minimal tethering domain not identified"]},{"year":2026,"claim":"Phosphosite-resolution mutagenesis in vivo demonstrated that S155 is the key PKA site controlling LD–mitochondria contact dynamics and hepatic lipid flux: S155A enhances contacts and LD expansion while S155E reduces them, resolving the phosphoswitch to a single residue.","evidence":"Single-cell tissue imaging, spatial proteomics, PLIN5 S155A/S155E/WT overexpression in Western-diet-fed mice","pmids":["41872512"],"confidence":"High","gaps":["Whether S155 phosphorylation also controls CGI-58 release and nuclear translocation in the same hepatic system was not directly tested","Potential additional phosphorylation sites contributing to PLIN5 regulation not ruled out"]},{"year":null,"claim":"Key unresolved questions include the structural basis of PLIN5 interactions (with CGI-58, ATGL, FATP4, and SERCA2), the full phosphorylation code governing distinct PLIN5 outputs (lipolysis, tethering, nuclear translocation), and whether the SERCA2-mediated Ca²⁺ function is lipid-dependent.","evidence":"","pmids":[],"confidence":"Low","gaps":["No atomic-resolution structure of PLIN5 or any of its complexes","Integrated phosphorylation-dependent regulation of lipolysis vs. tethering vs. nuclear signaling not tested in a single system","Physiological relevance of PLIN5–SERCA2 interaction to cardiac lipotoxicity models not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,3,10,15]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,8]}],"localization":[{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[0,1,2,3,4]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[5,8]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6,13]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,2,3,4,8,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,10,11,17]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6,16]}],"complexes":[],"partners":["ABHD5","PNPLA2","FATP4","SERCA2","PGC1A","SIRT1","TBC1D15","HSD17B11"],"other_free_text":[]},"mechanistic_narrative":"PLIN5 is a lipid droplet coat protein expressed in oxidative tissues that coordinates lipid storage, lipolysis, and mitochondrial fatty acid oxidation through regulated protein–protein interactions and signal-dependent trafficking. Under basal conditions, PLIN5 inhibits lipolysis by sequestering the ATGL co-activator CGI-58/Abhd5 on the lipid droplet surface; PKA-mediated phosphorylation at S155 releases CGI-58 to activate ATGL and simultaneously modulates lipid droplet–mitochondria contact site formation, with the phosphorylation-resistant S155A variant enhancing contacts and the phosphomimetic S155E variant reducing them [PMID:19064991, PMID:21148142, PMID:41872512]. PLIN5 tethers lipid droplets to mitochondria through a C-terminal interaction with FATP4, channeling liberated fatty acids into β-oxidation, and upon lipolytic stimulation traffics monounsaturated fatty acids to the nucleus where they allosterically activate SIRT1 to drive PGC-1α/PPARα-dependent oxidative gene programs [PMID:37290445, PMID:31901447]. PLIN5 expression is transcriptionally induced by PPARα and by IL-6/JAK/STAT3 signaling, and PLIN5 protein turnover is controlled by chaperone-mediated autophagy via LAMP2A [PMID:17130488, PMID:37108378, PMID:32339374]."},"prefetch_data":{"uniprot":{"accession":"Q00G26","full_name":"Perilipin-5","aliases":["Lipid storage droplet protein 5"],"length_aa":463,"mass_kda":50.8,"function":"Lipid droplet-associated protein that maintains the balance between lipogenesis and lipolysis and also regulates fatty acid oxidation in oxidative tissues. Recruits mitochondria to the surface of lipid droplets and is involved in lipid droplet homeostasis by regulating both the storage of fatty acids in the form of triglycerides and the release of fatty acids for mitochondrial fatty acid oxidation. In lipid droplet triacylglycerol hydrolysis, plays a role as a scaffolding protein for three major key lipolytic players: ABHD5, PNPLA2 and LIPE. Reduces the triacylglycerol hydrolase activity of PNPLA2 by recruiting and sequestering PNPLA2 to lipid droplets. Phosphorylation by PKA enables lipolysis probably by promoting release of ABHD5 from the perilipin scaffold and by facilitating interaction of ABHD5 with PNPLA2. Also increases lipolysis through interaction with LIPE and upon PKA-mediated phosphorylation of LIPE (By similarity)","subcellular_location":"Lipid droplet; Cytoplasm; Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q00G26/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PLIN5","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PLIN5","total_profiled":1310},"omim":[{"mim_id":"613248","title":"PERILIPIN 5; PLIN5","url":"https://www.omim.org/entry/613248"},{"mim_id":"609059","title":"PATATIN-LIKE PHOSPHOLIPASE DOMAIN-CONTAINING PROTEIN 2; PNPLA2","url":"https://www.omim.org/entry/609059"},{"mim_id":"604780","title":"ABHYDROLASE DOMAIN-CONTAINING PROTEIN 5, LYSOPHOSPHATIDIC ACID ACYLTRANSFERASE; ABHD5","url":"https://www.omim.org/entry/604780"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Lipid droplets","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":199.6},{"tissue":"skeletal muscle","ntpm":142.3}],"url":"https://www.proteinatlas.org/search/PLIN5"},"hgnc":{"alias_symbol":["LSDP5","LSDA5","OXPAT","MLDP"],"prev_symbol":[]},"alphafold":{"accession":"Q00G26","domains":[{"cath_id":"-","chopping":"23-112","consensus_level":"high","plddt":68.6949,"start":23,"end":112},{"cath_id":"1.20.120.340","chopping":"207-379","consensus_level":"high","plddt":87.0211,"start":207,"end":379}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q00G26","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q00G26-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q00G26-F1-predicted_aligned_error_v6.png","plddt_mean":66.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PLIN5","jax_strain_url":"https://www.jax.org/strain/search?query=PLIN5"},"sequence":{"accession":"Q00G26","fasta_url":"https://rest.uniprot.org/uniprotkb/Q00G26.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q00G26/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q00G26"}},"corpus_meta":[{"pmid":"17130488","id":"PMC_17130488","title":"OXPAT/PAT-1 is a PPAR-induced lipid droplet protein that promotes fatty acid utilization.","date":"2006","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/17130488","citation_count":268,"is_preprint":false},{"pmid":"17234449","id":"PMC_17234449","title":"LSDP5 is a PAT protein specifically expressed in fatty acid oxidizing tissues.","date":"2006","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/17234449","citation_count":203,"is_preprint":false},{"pmid":"21148142","id":"PMC_21148142","title":"Interactions of perilipin-5 (Plin5) with adipose triglyceride lipase.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21148142","citation_count":186,"is_preprint":false},{"pmid":"16571721","id":"PMC_16571721","title":"MLDP, a novel PAT family protein localized to lipid droplets and enriched in the heart, is regulated by peroxisome proliferator-activated receptor alpha.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16571721","citation_count":179,"is_preprint":false},{"pmid":"31901447","id":"PMC_31901447","title":"Lipid Droplet-Derived Monounsaturated Fatty Acids Traffic via PLIN5 to Allosterically Activate SIRT1.","date":"2019","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/31901447","citation_count":134,"is_preprint":false},{"pmid":"19064991","id":"PMC_19064991","title":"Functional interactions between Mldp (LSDP5) and Abhd5 in the control of intracellular lipid accumulation.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19064991","citation_count":122,"is_preprint":false},{"pmid":"37290445","id":"PMC_37290445","title":"PLIN5 interacts with FATP4 at membrane contact sites to promote lipid droplet-to-mitochondria fatty acid transport.","date":"2023","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/37290445","citation_count":105,"is_preprint":false},{"pmid":"19602560","id":"PMC_19602560","title":"Adipocyte differentiation-related protein and OXPAT in rat and human skeletal muscle: involvement in lipid accumulation and type 2 diabetes mellitus.","date":"2009","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/19602560","citation_count":83,"is_preprint":false},{"pmid":"23423172","id":"PMC_23423172","title":"Inactivation of Plin4 downregulates Plin5 and reduces cardiac lipid accumulation in mice.","date":"2013","source":"American journal of physiology. 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its expression is induced by PPARα activation (fasting, insulin deficiency, PPARα agonists). Ectopic expression promotes fatty acid-induced triacylglycerol accumulation and long-chain fatty acid oxidation.\",\n      \"method\": \"Subcellular fractionation, ectopic expression in cells, GFP-fusion live imaging, PPARα knockout mice, pharmacological PPAR agonist treatment\",\n      \"journal\": \"Diabetes / Journal of Biological Chemistry / Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — independently replicated across multiple labs in same year with consistent findings\",\n      \"pmids\": [\"17130488\", \"16571721\", \"17234449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The N-terminal PAT-1 domain plus a following 33-mer domain of PLIN5 (MLDP) is required for targeting to lipid droplet surfaces, as shown by deletion analysis.\",\n      \"method\": \"Deletion mutagenesis with GFP-fusion protein localization in cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct deletion mutagenesis with clear localization readout, single lab\",\n      \"pmids\": [\"16571721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PLIN5 (Mldp/LSDP5) directly binds Abhd5 (CGI-58, the protein activator of ATGL) on lipid droplet surfaces; this interaction is dynamic, increases with oleic acid treatment, and is required for efficient ATGL-mediated lipolysis at PLIN5-containing lipid droplets.\",\n      \"method\": \"Protein-protein interaction assay in transfected fibroblasts, in situ binding on microdissected cardiac muscle fibers, Abhd5 E262K mutant with impaired Mldp binding, cellular lipolysis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including site-directed mutant, functional lipolysis readout, single rigorous paper\",\n      \"pmids\": [\"19064991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PLIN5 interacts with both ATGL and its activator Abhd5, but individual PLIN5 molecules bind either ATGL or Abhd5 but not both simultaneously, suggesting oligomeric complexes concentrate these proteins at lipid droplet surfaces. The C-terminal 64 amino acids of PLIN5 (residues 200–463) are necessary and sufficient for differential binding of ATGL to PLIN5 (but not PLIN1).\",\n      \"method\": \"Protein interaction assays in live cells, in situ binding, chimeric/mutant perilipin analysis, competition experiments, neutral lipid accumulation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including mutagenesis and functional assays in a single rigorous study\",\n      \"pmids\": [\"21148142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PLIN5 (LSDP5) inhibits lipolysis and fatty acid β-oxidation in hepatocytes; knockdown stimulates lipolysis and increases PPARα expression and mitochondrial β-oxidation. The lipid droplet-targeting and clustering domain maps to the N-terminal 188 amino acids.\",\n      \"method\": \"Overexpression and siRNA knockdown in AML12 hepatocytes and primary hepatocytes, serial deletion analysis, triglyceride content measurement, lipolysis assay, mitochondrial oxidation measurement\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD/OE with defined cellular phenotype plus domain mapping, single lab\",\n      \"pmids\": [\"22675471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PLIN5 is found in the mitochondrial fraction of skeletal muscle, and its mitochondrial content increases ~1.6-fold following muscle contraction, consistent with a role in facilitating mitochondrial fatty acid oxidation during lipolysis.\",\n      \"method\": \"Mitochondrial isolation by differential centrifugation from rat red gastrocnemius, Western blotting, immunofluorescence\",\n      \"journal\": \"Physiological reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct fractionation with functional context, single lab\",\n      \"pmids\": [\"25318747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PLIN5 is a fatty-acid-binding protein that preferentially binds lipid droplet-derived monounsaturated fatty acids (MUFAs) and, following cAMP/PKA-mediated lipolytic stimulation, traffics them to the nucleus where MUFAs allosterically activate SIRT1 toward PGC-1α, thereby enhancing PGC-1α/PPARα signaling and oxidative metabolism.\",\n      \"method\": \"Fatty acid binding assay, cAMP/PKA stimulation, nuclear fractionation, SIRT1 allosteric activation assay with defined substrates, cell and animal model experiments with SIRT1-dependent pathway validation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including binding assays, nuclear trafficking, in vitro SIRT1 assay, and in vivo validation\",\n      \"pmids\": [\"31901447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PLIN5 is a substrate of chaperone-mediated autophagy (CMA); its degradation via LAMP2A is required for lipid droplet breakdown in hepatocytes. Disruption of CMA (LAMP2A deletion) stabilizes PLIN5, obstructs LD breakdown, and causes lipid homeostasis imbalance.\",\n      \"method\": \"Liver-specific LAMP2A-knockout mice, LAMP2A-deficient HepG2 cells, co-localization studies, lipid droplet accumulation assays\",\n      \"journal\": \"Liver international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined phenotype and substrate identification, single lab\",\n      \"pmids\": [\"32339374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PLIN5 interacts with the acyl-CoA synthetase FATP4 (ACSVL4) on mitochondria at lipid droplet-mitochondria contact sites; the C-terminal domains of PLIN5 and FATP4 constitute a minimal interaction capable of inducing organelle contacts. Phosphorylation of PLIN5 promotes LD-to-mitochondria fatty acid transfer and β-oxidation during starvation, and an intact PLIN5 mitochondrial tethering domain is required.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, domain mapping with minimal constructs, phosphorylation-deficient/mimetic mutants, β-oxidation assays in starved myoblasts, human and murine cell models\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods, functional domain mapping, phosphorylation mutants, human and murine cells\",\n      \"pmids\": [\"37290445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PLIN5 interacts with SERCA2 (sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2) in cardiomyocytes; cardiac-specific overexpression of PLIN5 increases intracellular Ca2+ release during contraction and Ca2+ removal during relaxation, enhancing SERCA2 function and cardiomyocyte contractility.\",\n      \"method\": \"Quantitative proteomics of PLIN5-overexpressing hearts, in situ proximity ligation assay, live imaging of Ca2+ dynamics, cardiac-specific transgenic mice (MHC-Plin5)\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal protein interaction confirmed by PLA, functional Ca2+ live imaging in transgenic model\",\n      \"pmids\": [\"36717246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Under basal (non-phosphorylated) conditions, PLIN5 inhibits lipolysis by sequestering CGI-58 (Abhd5), preventing it from activating ATGL. Upon PKA-mediated phosphorylation of PLIN5 (e.g., during fasting, cold, or exercise), PLIN5 releases CGI-58, which then binds and activates ATGL, accelerating lipolysis.\",\n      \"method\": \"Review synthesizing cell-based phosphorylation experiments and protein interaction studies\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — review synthesis of existing experimental data; mechanism supported by primary studies cited\",\n      \"pmids\": [\"35401929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PLIN5 interacts with PGC-1α in vascular smooth muscle cells; Plin5 knockdown reduces Plin5-PGC-1α interaction, increases ROS, and promotes VSMC proliferation and migration. PGC-1α overexpression rescues ROS elevation and VSMC dysfunction in Plin5-deficient cells.\",\n      \"method\": \"Co-immunoprecipitation, wire-injury mouse model, Plin5 knockdown mice (Plin5±), ROS measurement, proliferation/migration assays, PGC-1α overexpression rescue\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — genetic knockdown with defined phenotype and interaction assay, rescue experiment, single lab\",\n      \"pmids\": [\"35470759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HSD17β11 facilitates the interaction between PLIN5 and ATGL on lipid droplets, enabling efficient PKA-stimulated lipolysis; HSD17β11 deletion impairs this PLIN5-ATGL interaction and reduces lipolysis in human cell lines.\",\n      \"method\": \"HSD17β11 deletion in human cell lines, lipolysis assays, co-immunoprecipitation of PLIN5 and ATGL, PKA stimulation\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic deletion with mechanistic interaction assay, single lab, human cells\",\n      \"pmids\": [\"41238190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TBC1D15 is recruited to mitochondrial membranes in hepatocytes upon alcohol exposure and interacts with PLIN5 through its 10-180 aa domain, promoting mitochondria-lipid droplet contacts and PKA-induced nuclear translocation of PLIN5.\",\n      \"method\": \"Hepatocyte-specific TBC1D15 overexpression mice, co-immunoprecipitation domain mapping, immunofluorescence of PLIN5 nuclear translocation, PKA inhibition experiments\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain-level interaction mapping with functional nuclear translocation readout, single lab\",\n      \"pmids\": [\"40334909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PLIN5 phosphorylation at S155 regulates mitochondria-lipid droplet contact formation and hepatic lipid flux: the phosphorylation-resistant S155A variant enhances organelle contacts and LD expansion, while the phosphomimetic S155E variant reduces contacts and yields fewer, smaller LDs. PLIN5 overexpression in Western-diet-fed mice reduces lipotoxicity.\",\n      \"method\": \"Single-cell tissue imaging (scPhenomics), spatial proteomics, PLIN5 phosphorylation variant overexpression (S155A, S155E, WT) in mice, LD/mitochondria contact quantification, lipid content measurement\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — phosphorylation mutagenesis with organelle contact quantification, spatial proteomics, and in vivo functional validation\",\n      \"pmids\": [\"41872512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Isolated Plin5-deficient cardiomyocytes store fewer lipid droplets than wild-type, primarily because PLIN5 represses ATGL lipase activity; inhibiting ATGL activity normalizes LD levels in Plin5-/- cardiomyocytes to wild-type levels.\",\n      \"method\": \"Isolated adult cardiomyocytes from Plin5+/+ and Plin5-/- mice, ATGL inhibitor treatment, fatty acid oxidation assays, lipid droplet quantification\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with pharmacological rescue confirming ATGL-dependence, single lab\",\n      \"pmids\": [\"33373698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PLIN5 regulates lipid metabolism and mitochondrial dynamics in pancreatic β-cells via PGC-1α/Drp1 signaling: PLIN5 knockdown decreases PGC-1α and increases Drp1, causing mitochondrial dysfunction, while PLIN5 overexpression reverses high-glucose-induced damage. PLIN5 also influences PGC-1α binding to the Drp1 promoter.\",\n      \"method\": \"siRNA knockdown and lentiviral overexpression in INS-1 cells, db/db mice, Western blotting, qPCR, immunofluorescence, chromatin-related promoter binding assay\",\n      \"journal\": \"Endocrine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD/OE with pathway placement via PGC-1α/Drp1, single lab\",\n      \"pmids\": [\"40884681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PLIN5 expression in liver (Hep3B cells) is induced by IL-6 in a dose- and time-dependent manner through the JAK/STAT3 signaling pathway; this induction can be blocked by TGF-β and TNF-α, and is modulated by IL-6 trans-signaling.\",\n      \"method\": \"IL-6 treatment of Hep3B cells, JAK/STAT3 inhibitors, TGF-β and TNF-α co-treatment, soluble IL-6R addition, quantitative protein and mRNA analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway-level regulation with pharmacological inhibition, single lab\",\n      \"pmids\": [\"37108378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In an in vitro reconstitution system, PLIN5 promotes stable attachment of lipid droplet monolayers to bilayer membranes (LUVs) while preventing membrane fusion, demonstrating a direct physical role of PLIN5 in mediating organelle contact sites.\",\n      \"method\": \"In vitro reconstitution with artificial LDs coated with PLIN5, large unilamellar vesicles (LUVs), dual fluorescence labeling to distinguish fusion from stable attachment\",\n      \"journal\": \"Biochemistry and biophysics reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with defined components, single lab\",\n      \"pmids\": [\"41459334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Leptin promotes FTO-mediated demethylation (reduction in m6A methylation) of Plin5 mRNA, increasing Plin5 protein expression in adipose tissue, which in turn reduces lipid droplet size and promotes triglyceride metabolism.\",\n      \"method\": \"In vivo leptin treatment of piglets, in vitro porcine adipocyte FTO overexpression/interference, m6A methylation measurement, Plin5 overexpression functional assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, primarily porcine model, indirect regulation of PLIN5 via m6A\",\n      \"pmids\": [\"34638947\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PLIN5 is a lipid droplet surface scaffold protein expressed in oxidative tissues (heart, skeletal muscle, liver) under PPARα control that bidirectionally regulates lipolysis by sequestering CGI-58/Abhd5 away from ATGL under basal conditions and releasing it upon PKA-mediated phosphorylation at S155; phospho-PLIN5 also translocates to the nucleus carrying monounsaturated fatty acids that allosterically activate SIRT1/PGC-1α/PPARα signaling, and tethers mitochondria to lipid droplets via an interaction with FATP4, thereby channeling fatty acids from lipid droplet lipolysis directly into mitochondrial β-oxidation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PLIN5 is a lipid droplet coat protein expressed in oxidative tissues that coordinates lipid storage, lipolysis, and mitochondrial fatty acid oxidation through regulated protein–protein interactions and signal-dependent trafficking. Under basal conditions, PLIN5 inhibits lipolysis by sequestering the ATGL co-activator CGI-58/Abhd5 on the lipid droplet surface; PKA-mediated phosphorylation at S155 releases CGI-58 to activate ATGL and simultaneously modulates lipid droplet–mitochondria contact site formation, with the phosphorylation-resistant S155A variant enhancing contacts and the phosphomimetic S155E variant reducing them [PMID:19064991, PMID:21148142, PMID:41872512]. PLIN5 tethers lipid droplets to mitochondria through a C-terminal interaction with FATP4, channeling liberated fatty acids into β-oxidation, and upon lipolytic stimulation traffics monounsaturated fatty acids to the nucleus where they allosterically activate SIRT1 to drive PGC-1α/PPARα-dependent oxidative gene programs [PMID:37290445, PMID:31901447]. PLIN5 expression is transcriptionally induced by PPARα and by IL-6/JAK/STAT3 signaling, and PLIN5 protein turnover is controlled by chaperone-mediated autophagy via LAMP2A [PMID:17130488, PMID:37108378, PMID:32339374].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of PLIN5 as a PPARα-regulated lipid droplet coat protein in oxidative tissues established it as the perilipin family member linking fatty acid storage to oxidative metabolism.\",\n      \"evidence\": \"Subcellular fractionation, PPARα-knockout mice, ectopic expression, and PPAR agonist treatment across three independent labs\",\n      \"pmids\": [\"17130488\", \"16571721\", \"17234449\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which PLIN5 simultaneously promotes TAG storage and FA oxidation was unclear\", \"Domain requirements for LD targeting only partially mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Discovery that PLIN5 directly binds the ATGL co-activator CGI-58/Abhd5 revealed the molecular basis by which PLIN5 gates lipolysis at the lipid droplet surface.\",\n      \"evidence\": \"Protein interaction assays in transfected fibroblasts, in situ binding on cardiac fibers, Abhd5 E262K mutant analysis, lipolysis assays\",\n      \"pmids\": [\"19064991\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PLIN5 binds ATGL directly was not yet resolved\", \"Signal that releases CGI-58 from PLIN5 was unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstration that individual PLIN5 molecules bind either ATGL or CGI-58 but not both simultaneously suggested that oligomeric PLIN5 scaffolds concentrate lipolytic machinery and introduced the C-terminal domain as the ATGL-binding determinant.\",\n      \"evidence\": \"Chimeric perilipin analysis, competition experiments, and functional assays in live cells\",\n      \"pmids\": [\"21148142\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and oligomerization state of PLIN5 on LDs not defined\", \"Phosphorylation-dependent switch not yet shown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Hepatocyte loss-of-function studies confirmed that PLIN5 acts as a lipolysis brake, with knockdown increasing ATGL-dependent lipolysis and β-oxidation.\",\n      \"evidence\": \"siRNA knockdown and overexpression in AML12/primary hepatocytes, lipolysis and oxidation measurements\",\n      \"pmids\": [\"22675471\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphorylation site mediating lipolysis activation not identified\", \"Relationship between LD-association domain and lipolysis-inhibitory function was correlative\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Detection of PLIN5 in the mitochondrial fraction of skeletal muscle, increasing with contraction, provided the first evidence that PLIN5 physically associates with mitochondria to facilitate FA channeling during exercise.\",\n      \"evidence\": \"Differential centrifugation and Western blotting from rat skeletal muscle after contraction\",\n      \"pmids\": [\"25318747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mitochondrial binding partner not identified\", \"Could not distinguish LD-mitochondria contact sites from free mitochondrial PLIN5\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The discovery that PLIN5 binds monounsaturated fatty acids and upon PKA stimulation carries them to the nucleus to allosterically activate SIRT1/PGC-1α established a lipid signaling relay from LDs to transcriptional control of oxidative metabolism.\",\n      \"evidence\": \"FA binding assays, nuclear fractionation, in vitro SIRT1 activation assay, animal model validation\",\n      \"pmids\": [\"31901447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of FA binding by PLIN5 unknown\", \"Whether nuclear PLIN5 has additional transcriptional targets beyond PGC-1α/PPARα not explored\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of PLIN5 as a chaperone-mediated autophagy substrate degraded via LAMP2A revealed how PLIN5 protein turnover is coupled to lipid droplet breakdown in hepatocytes.\",\n      \"evidence\": \"Liver-specific LAMP2A-KO mice and LAMP2A-deficient HepG2 cells with LD accumulation phenotype\",\n      \"pmids\": [\"32339374\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CMA-targeting motif on PLIN5 not mapped\", \"Interplay between CMA-mediated PLIN5 degradation and PKA-mediated PLIN5 phosphorylation not addressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Plin5-knockout cardiomyocytes confirmed that PLIN5 restrains ATGL activity in the heart, as pharmacological ATGL inhibition fully rescued LD depletion in Plin5−/− cells.\",\n      \"evidence\": \"Isolated adult cardiomyocytes from Plin5-KO mice, ATGL inhibitor rescue, LD quantification\",\n      \"pmids\": [\"33373698\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Heart-specific consequences of chronic PLIN5 loss on mitochondrial function not fully delineated\", \"Phosphorylation-dependent regulation not tested in this system\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The PKA-phosphorylation model was consolidated: basal PLIN5 sequesters CGI-58 to suppress lipolysis, and phosphorylation releases CGI-58 to activate ATGL, providing a unified regulatory switch.\",\n      \"evidence\": \"Review synthesis of cell-based phosphorylation and protein interaction studies\",\n      \"pmids\": [\"35401929\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific phosphorylation site(s) responsible had not been mutagenized in vivo\", \"Whether additional kinases target PLIN5 was unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of FATP4 as the mitochondrial binding partner of PLIN5 at LD–mitochondria contact sites, with phosphorylation promoting FA transfer to β-oxidation, provided the molecular tether linking lipolysis to mitochondrial oxidation.\",\n      \"evidence\": \"Co-IP, proximity ligation assay, domain mapping with minimal constructs, phospho-mutant β-oxidation assays in starved myoblasts\",\n      \"pmids\": [\"37290445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the PLIN5–FATP4 complex not resolved\", \"Whether PLIN5 also tethers to ER or other organelles via distinct partners unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery of a PLIN5–SERCA2 interaction in cardiomyocytes, enhancing Ca²⁺ cycling and contractility, expanded PLIN5 function beyond lipid metabolism to excitation-contraction coupling.\",\n      \"evidence\": \"Quantitative proteomics, proximity ligation assay, live Ca²⁺ imaging in cardiac-specific PLIN5-transgenic mice\",\n      \"pmids\": [\"36717246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding domain on PLIN5 for SERCA2 not mapped\", \"Whether this reflects a lipid-dependent or lipid-independent mechanism is unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"In vitro reconstitution demonstrated that PLIN5 directly mediates stable attachment of lipid droplet monolayers to bilayer membranes without promoting fusion, establishing an intrinsic membrane-tethering activity.\",\n      \"evidence\": \"Reconstituted artificial LDs coated with PLIN5, LUV bilayers, dual fluorescence to distinguish tethering from fusion\",\n      \"pmids\": [\"41459334\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance to specific organelle contacts not demonstrated in this system\", \"Minimal tethering domain not identified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Phosphosite-resolution mutagenesis in vivo demonstrated that S155 is the key PKA site controlling LD–mitochondria contact dynamics and hepatic lipid flux: S155A enhances contacts and LD expansion while S155E reduces them, resolving the phosphoswitch to a single residue.\",\n      \"evidence\": \"Single-cell tissue imaging, spatial proteomics, PLIN5 S155A/S155E/WT overexpression in Western-diet-fed mice\",\n      \"pmids\": [\"41872512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether S155 phosphorylation also controls CGI-58 release and nuclear translocation in the same hepatic system was not directly tested\", \"Potential additional phosphorylation sites contributing to PLIN5 regulation not ruled out\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of PLIN5 interactions (with CGI-58, ATGL, FATP4, and SERCA2), the full phosphorylation code governing distinct PLIN5 outputs (lipolysis, tethering, nuclear translocation), and whether the SERCA2-mediated Ca²⁺ function is lipid-dependent.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No atomic-resolution structure of PLIN5 or any of its complexes\", \"Integrated phosphorylation-dependent regulation of lipolysis vs. tethering vs. nuclear signaling not tested in a single system\", \"Physiological relevance of PLIN5–SERCA2 interaction to cardiac lipotoxicity models not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3, 10, 15]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 2, 3, 4, 8, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 10, 11, 17]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ABHD5\", \"PNPLA2\", \"FATP4\", \"SERCA2\", \"PGC1A\", \"SIRT1\", \"TBC1D15\", \"HSD17B11\"],\n    \"other_free_text\": []\n  }\n}\n```"}