{"gene":"LIPC","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2001,"finding":"The common -216G→A and -480C→T substitutions in the LIPC promoter reduce promoter activity by ~45% in HepG2 cells. The -480C→T substitution decreases binding affinity of Upstream Stimulatory Factor (USF) protein to its binding site by four-fold, as shown by gel-shift assays. Co-transfection with USF(43) cDNA increases activity of all -650/+48 constructs dose-dependently, maintaining the relative difference between variant and wild-type promoters.","method":"CAT-reporter assays in HepG2 cells, gel-shift (EMSA) assays, co-transfection with USF cDNA","journal":"Atherosclerosis","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro functional reporter assay plus EMSA mutagenesis in a single study with multiple orthogonal methods","pmids":["11257263"],"is_preprint":false},{"year":2006,"finding":"The LIPC promoter is directly regulated by HNF4α via two newly identified direct repeat elements (DR1 and DR4). PGC-1α co-activates HNF4α-dependent LIPC transcription. ARP-1 displaces HNF4α from the DR1 site and represses LIPC promoter activity. HNF1α activates LIPC transcription through its binding site and has an additive effect with HNF4α. In vivo, disruption of Hnf4α in mice abolishes hepatic HL mRNA expression, and the HNF4α antagonist Medica 16 represses endogenous LIPC mRNA in cells.","method":"Luciferase reporter assays, co-transfection experiments in HepG2 cells, Hnf4α knockout mice, RT-PCR for endogenous mRNA","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (reporter assay, co-transfection, KO mouse, pharmacological antagonist) in one study establishing direct transcriptional regulation","pmids":["16603721"],"is_preprint":false},{"year":2022,"finding":"A gain-of-function LIPC variant (E97G) specifically increases the phospholipase activity of hepatic lipase (without altering triglyceride lipase activity) by modifying an evolutionarily conserved motif that controls substrate access to the catalytic site. In vitro cell culture and in vivo mouse overexpression studies showed the increased phospholipase activity promotes catabolism of triglyceride-rich lipoproteins by extrahepatic tissues, resulting in combined hypocholesterolemia (low LDL-C and HDL-C). The lysophospholipid/phospholipid ratio was elevated in plasma of variant carriers, consistent with increased phospholipase activity.","method":"Protein homology modeling, in vitro phospholipase and triglyceride lipase activity assays in cell culture, APOE*3-Leiden.CETP mouse overexpression model, NMR-based lipoprotein profiling, lipidomics","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay, mutagenesis-based structural analysis, and in vivo mouse model with multiple orthogonal methods in one rigorous study","pmids":["35899625"],"is_preprint":false},{"year":2009,"finding":"Two novel LIPC missense variants (G119S/c.421G>A and previously known V73M/L334F) were identified in Thai subjects with hyperalphalipoproteinemia and low hepatic lipase activity, supporting that loss-of-function variants in LIPC cause elevated HDL-C. The G119S variant was judged functionally relevant based on evolutionary conservation and location in a functionally important domain.","method":"Genetic sequencing of LIPC coding regions, measurement of post-heparin hepatic lipase activity in patient plasma","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — enzymatic activity measured in patients carrying identified variants, single lab, no in vitro reconstitution of the specific variant","pmids":["19428034"],"is_preprint":false},{"year":2012,"finding":"Two novel LIPC missense variants (p.G141S/c.421A>G and p.V173M/c.517G>A) reduce hepatic lipase activity in HepG2 cell lysates to 41% and 46% of wild-type, respectively, confirming their loss-of-function effect underlying hyperalphalipoproteinemia.","method":"Site-directed mutagenesis, cDNA cloning and transient expression in HepG2 cells, hepatic lipase activity assay in cell lysates","journal":"Clinica chimica acta","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis and enzymatic activity assay in a single focused study","pmids":["23219720"],"is_preprint":false},{"year":2014,"finding":"Expression of human hepatic lipase (hHL) in primary hepatocytes from Lipc-null mice decreased synthesis and secretion of apoA-I (but not apoE), as shown by metabolic labeling. An HSPG-binding deficient hHL mutant (hHLmt) also inhibited apoA-I production despite impaired ER exit, and both hHL and hHLmt increased microsome-associated apoA-I, indicating an intracellular mechanism for HL's negative impact on apoA-I production independent of cell-surface binding.","method":"Adenovirus-mediated gene transfer in Lipc-null primary hepatocytes, metabolic labeling with 35S, subcellular fractionation","journal":"Journal of biomedical research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO hepatocyte system with adenoviral rescue, metabolic labeling, and fractionation; single lab with multiple methods","pmids":["25013403"],"is_preprint":false},{"year":2022,"finding":"miR-27b negatively regulates LIPC expression and activity in hepatocytes. Using activity-based protein profiling with a serine hydrolase probe and stable isotope labeling/mass spectrometry, LIPC was identified as a direct target of miR-27b. Modulation of miR-27b with mimics or inhibitors altered LIPC levels. Transcription factors Jun, PPARα, and HNF4α (which also regulate LIPC) are themselves regulated by miR-27b. LIPC knockdown decreased intracellular triglyceride degradation and affected HCV life cycle progression.","method":"Activity-based protein profiling with serine hydrolase probe, SILAC mass spectrometry, miRNA mimic/inhibitor transfection, cell-based HCV infection assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — activity-based proteomics plus functional miRNA modulation experiments in single lab with orthogonal methods","pmids":["35483451"],"is_preprint":false},{"year":1998,"finding":"The -514T allele of LIPC is associated with decreased post-heparin hepatic lipase activity in both white and African American men, and this effect is independent of androgen action. Treatment with the anabolic steroid stanozolol increased hepatic lipase activity equally in -514T and -514C homozygous men (45 vs 51 mmol·hr⁻¹·l⁻¹, P=0.5), demonstrating the polymorphism does not modulate androgen responsiveness of HL.","method":"Pharmacological challenge (stanozolol treatment), post-heparin plasma hepatic lipase activity measurement, genotyping","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — controlled pharmacological experiment with direct enzyme activity measurement, single lab but well-controlled design","pmids":["9684756"],"is_preprint":false},{"year":1997,"finding":"Linkage analysis in 218 nuclear families showed that allelic variation at or near the LIPC gene accounts for ~25% of variance in plasma HDL-C concentrations. Sequencing identified four novel 5'-flanking polymorphisms in complete linkage disequilibrium (a single allele) associated with higher HDL-C and apolipoprotein AI levels, establishing LIPC genetic variation as a major determinant of plasma HDL-C.","method":"Linkage analysis, DNA sequencing, association studies in two independent population samples","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — linkage plus sequencing plus replicated association in two independent cohorts; established foundational genotype-phenotype mechanism","pmids":["9114024"],"is_preprint":false},{"year":2022,"finding":"TUSC3 negatively regulates LIPC expression in hepatocellular carcinoma. Co-immunoprecipitation showed a physical interaction between TUSC3 and LIPC. Loss of TUSC3 reduces LIPC levels and activates AKT signaling, promoting epithelial-mesenchymal transition (EMT). Gain- and loss-of-function experiments showed LIPC negatively modulates HCC cell proliferation and migration, acting downstream of TUSC3 to suppress AKT-driven EMT.","method":"Co-immunoprecipitation, immunofluorescence, loss-of-function and gain-of-function experiments in vitro and in vivo, Western blot for EMT markers and AKT pathway","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional rescue experiments in single lab; pathway placement via loss/gain of function with defined molecular readouts","pmids":["36274132"],"is_preprint":false},{"year":2020,"finding":"The LIPC -514C→T promoter variant reduces LIPC promoter activity by ~90% in a luciferase reporter assay in HepG2 cells, providing a direct functional explanation for its association with decreased hepatic lipase activity and increased HDL-C levels.","method":"Luciferase reporter assay in HepG2 cells","journal":"Journal of endocrinological investigation","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — single in vitro reporter assay, single lab, no additional orthogonal validation","pmids":["32617858"],"is_preprint":false},{"year":1986,"finding":"Purified hepatic triglyceride lipase (HTGL/hepatic lipase) added to plasma markedly enhanced anti-Factor Xa clotting activity and caused ~70% inhibition of lipid peroxide-induced thrombin generation in vitro, demonstrating a direct anticoagulant function for HTGL in plasma.","method":"In vitro addition of purified HTGL to plasma, anti-Xa clotting activity assay, thrombin generation assay","journal":"Thrombosis and haemostasis","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct in vitro biochemical assay with purified protein, single study, older methodology","pmids":["2433786"],"is_preprint":false},{"year":2021,"finding":"LIPC gene polymorphisms are associated with plasma phosphatidylethanolamine metabolite levels (glycerophospholipids), as identified by metabolite quantitative trait loci (met-QTL) analysis in AMD patients and controls, supporting a role for LIPC in glycerophospholipid metabolism.","method":"Metabolite QTL analysis using mass spectrometry metabolomics and Illumina SNP array, linear regression, meta-analysis across two cohorts","journal":"Ophthalmology science","confidence":"Low","confidence_rationale":"Tier 4 / Moderate — genomic-metabolomic association without direct enzymatic or biochemical mechanistic experiment on the protein itself","pmids":["34382031"],"is_preprint":false}],"current_model":"LIPC encodes hepatic lipase, a serine hydrolase with both triglyceride lipase and phospholipase activities whose transcription is directly driven by HNF4α (via DR1/DR4 elements), co-activated by PGC-1α, repressed by ARP-1, and additionally activated by HNF1α; the common promoter variants (-480C→T, -514C→T) reduce USF binding and promoter activity, lowering HL expression and elevating plasma HDL-C; a gain-of-function catalytic variant (E97G) that selectively enhances phospholipase activity causes familial combined hypocholesterolemia by promoting phospholipid catabolism and triglyceride-rich lipoprotein clearance; miR-27b downregulates LIPC to reduce intracellular triglyceride degradation; and hepatic lipase intracellularly suppresses apoA-I synthesis in hepatocytes independent of its cell-surface HSPG binding."},"narrative":{"mechanistic_narrative":"LIPC encodes hepatic lipase, a serine hydrolase with both triglyceride lipase and phospholipase activities that is a major determinant of plasma lipoprotein metabolism, with allelic variation at the locus accounting for ~25% of variance in plasma HDL-C [PMID:9114024]. Its hepatic transcription is directly controlled by HNF4α acting through DR1 and DR4 elements, co-activated by PGC-1α and HNF1α and repressed by ARP-1, with HNF4α disruption abolishing hepatic HL mRNA in vivo [PMID:16603721]; common 5'-flanking promoter variants (-480C→T, -514C→T, -216G→A) reduce promoter activity, in part by lowering USF binding affinity, thereby decreasing HL expression and raising HDL-C [PMID:11257263, PMID:9114024, PMID:32617858]. Loss-of-function missense variants that reduce HL enzymatic activity cause hyperalphalipoproteinemia [PMID:23219720], whereas a gain-of-function variant (E97G) that selectively enhances phospholipase activity by altering a conserved motif controlling substrate access promotes catabolism of triglyceride-rich lipoproteins and causes combined hypocholesterolemia [PMID:35899625]. Beyond its secreted lipolytic role, hepatic lipase intracellularly suppresses apoA-I synthesis and secretion in hepatocytes independent of cell-surface heparan sulfate proteoglycan binding [PMID:25013403], and is post-transcriptionally downregulated by miR-27b to reduce intracellular triglyceride degradation [PMID:35483451].","teleology":[{"year":1986,"claim":"Established that hepatic lipase has activities beyond lipolysis, showing purified HTGL exerts a direct anticoagulant effect in plasma.","evidence":"In vitro addition of purified HTGL to plasma with anti-Xa clotting and thrombin generation assays","pmids":["2433786"],"confidence":"Medium","gaps":["Mechanism linking lipase activity to coagulation not defined","Physiological relevance in vivo not established","Older methodology, single study"]},{"year":1997,"claim":"Quantified LIPC as a major genetic determinant of HDL-C, framing the locus as physiologically dominant rather than incidental to lipid metabolism.","evidence":"Linkage analysis and sequencing with replicated association in two independent population samples","pmids":["9114024"],"confidence":"High","gaps":["Causal variant among the linked 5'-flanking polymorphisms not pinned to a molecular mechanism","Did not establish which polymorphism drives the phenotype"]},{"year":1998,"claim":"Tested whether the HDL-associated -514 variant acts via hormonal modulation, showing its effect on HL activity is independent of androgen responsiveness.","evidence":"Stanozolol pharmacological challenge with post-heparin plasma HL activity measurement and genotyping in two ethnic groups","pmids":["9684756"],"confidence":"Medium","gaps":["Did not define the molecular basis of the -514 effect","Single intervention, modest sample"]},{"year":2001,"claim":"Provided a molecular mechanism for promoter variants by showing -480C→T reduces USF transcription factor binding and lowers promoter activity.","evidence":"CAT-reporter assays, EMSA, and USF cDNA co-transfection in HepG2 cells","pmids":["11257263"],"confidence":"High","gaps":["Does not establish in vivo contribution of USF occupancy to HL levels","Other promoter variants in linkage not individually resolved"]},{"year":2006,"claim":"Defined the core transcriptional regulatory circuit of LIPC, identifying direct HNF4α control via DR1/DR4 with PGC-1α and HNF1α activation and ARP-1 repression.","evidence":"Luciferase reporters, co-transfection, Hnf4α knockout mice, and pharmacological HNF4α antagonism","pmids":["16603721"],"confidence":"High","gaps":["Signals that tune HNF4α/PGC-1α activity on LIPC not defined","Interplay with promoter SNP USF site not integrated"]},{"year":2009,"claim":"Linked coding LIPC variants to low HL activity and high HDL-C in patients, extending the loss-of-function genotype-phenotype relationship to the protein-coding sequence.","evidence":"Coding region sequencing and post-heparin HL activity in Thai hyperalphalipoproteinemia subjects","pmids":["19428034"],"confidence":"Medium","gaps":["No in vitro reconstitution of the specific variants","Functional relevance inferred from conservation, not assayed directly"]},{"year":2012,"claim":"Confirmed causality of loss-of-function missense variants by reconstituting reduced enzymatic activity in cells.","evidence":"Site-directed mutagenesis and HL activity assays in HepG2 cell lysates","pmids":["23219720"],"confidence":"High","gaps":["Effect on secretion versus catalysis not separated","Substrate-specific (TG vs phospholipid) consequences not measured"]},{"year":2014,"claim":"Revealed a non-canonical intracellular role, showing hepatic lipase suppresses apoA-I synthesis independent of cell-surface HSPG binding.","evidence":"Adenoviral expression in Lipc-null primary hepatocytes with 35S metabolic labeling and subcellular fractionation","pmids":["25013403"],"confidence":"Medium","gaps":["Molecular mechanism of intracellular apoA-I suppression unknown","Whether catalytic activity is required not resolved","Single lab"]},{"year":2021,"claim":"Associated LIPC genetic variation with plasma glycerophospholipid (phosphatidylethanolamine) levels, hinting at a phospholipid-handling role at the population level.","evidence":"Metabolite QTL analysis with mass spectrometry metabolomics and SNP arrays across two cohorts","pmids":["34382031"],"confidence":"Low","gaps":["No direct enzymatic or biochemical experiment on the protein","Association does not establish causal flux through HL","Confounding by linkage not excluded"]},{"year":2022,"claim":"Dissected the dual catalytic activities, showing a gain-of-function E97G variant selectively boosts phospholipase activity via a conserved substrate-access motif and causes combined hypocholesterolemia.","evidence":"Homology modeling, in vitro phospholipase/TG lipase assays, APOE*3-Leiden.CETP overexpression mice, NMR lipoprotein profiling and lipidomics","pmids":["35899625"],"confidence":"High","gaps":["Structural model not validated by crystallography","Extrahepatic clearance pathway not mechanistically mapped"]},{"year":2022,"claim":"Identified post-transcriptional control of LIPC by miR-27b linking it to intracellular triglyceride turnover and HCV biology.","evidence":"Activity-based serine hydrolase proteomics, SILAC mass spectrometry, miRNA mimic/inhibitor, and HCV infection assays","pmids":["35483451"],"confidence":"Medium","gaps":["Direct miR-27b:LIPC target site not mapped functionally","In vivo relevance of regulation not shown"]},{"year":2022,"claim":"Placed LIPC in a tumor-suppressive axis, showing TUSC3 physically interacts with and positively regulates LIPC to restrain AKT-driven EMT in hepatocellular carcinoma.","evidence":"Co-immunoprecipitation, immunofluorescence, and gain/loss-of-function experiments in vitro and in vivo","pmids":["36274132"],"confidence":"Medium","gaps":["Whether HL catalytic activity mediates the anti-EMT effect unknown","Single Co-IP without reciprocal structural mapping","Mechanism linking LIPC to AKT not defined"]},{"year":null,"claim":"How the secreted lipolytic, intracellular apoA-I-suppressing, and tumor-suppressive functions of hepatic lipase are integrated, and how catalytic versus non-catalytic activities partition across these roles, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model linking the two catalytic activities to distinct physiological outputs","Catalytic requirement for intracellular and tumor-related functions untested","Tissue-specific regulation of the dual activities undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[2,4,11]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[11]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,8]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,0]}],"complexes":[],"partners":["HNF4A","HNF1A","PPARGC1A","USF1","TUSC3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P11150","full_name":"Hepatic triacylglycerol lipase","aliases":["Lipase member C","Lysophospholipase","Phospholipase A1"],"length_aa":499,"mass_kda":55.9,"function":"Catalyzes the hydrolysis of triglycerides and phospholipids present in circulating plasma lipoproteins, including chylomicrons, intermediate density lipoproteins (IDL), low density lipoproteins (LDL) of large size and high density lipoproteins (HDL), releasing free fatty acids (FFA) and smaller lipoprotein particles (PubMed:12032167, PubMed:26193433, PubMed:7592706, PubMed:8798474). Also exhibits lysophospholipase activity (By similarity). Can hydrolyze both neutral lipid and phospholipid substrates but shows a greater binding affinity for neutral lipid substrates than phospholipid substrates (By similarity). In native LDL, preferentially hydrolyzes the phosphatidylcholine species containing polyunsaturated fatty acids at sn-2 position (PubMed:26193433)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P11150/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LIPC","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LIPC","total_profiled":1310},"omim":[{"mim_id":"614025","title":"HEPATIC LIPASE DEFICIENCY","url":"https://www.omim.org/entry/614025"},{"mim_id":"612797","title":"HIGH DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS 12; HDLCQ12","url":"https://www.omim.org/entry/612797"},{"mim_id":"606613","title":"HIGH DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS 1; HDLCQ1","url":"https://www.omim.org/entry/606613"},{"mim_id":"605552","title":"ABDOMINAL OBESITY-METABOLIC SYNDROME 1; AOMS1","url":"https://www.omim.org/entry/605552"},{"mim_id":"603684","title":"LIPASE, ENDOTHELIAL; LIPG","url":"https://www.omim.org/entry/603684"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"liver","ntpm":159.9}],"url":"https://www.proteinatlas.org/search/LIPC"},"hgnc":{"alias_symbol":["HL","HTGL"],"prev_symbol":[]},"alphafold":{"accession":"P11150","domains":[{"cath_id":"3.40.50.1820","chopping":"48-342","consensus_level":"high","plddt":90.6059,"start":48,"end":342},{"cath_id":"2.60.60.20","chopping":"353-425_446-487","consensus_level":"high","plddt":85.2357,"start":353,"end":487}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P11150","model_url":"https://alphafold.ebi.ac.uk/files/AF-P11150-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P11150-F1-predicted_aligned_error_v6.png","plddt_mean":82.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LIPC","jax_strain_url":"https://www.jax.org/strain/search?query=LIPC"},"sequence":{"accession":"P11150","fasta_url":"https://rest.uniprot.org/uniprotkb/P11150.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P11150/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P11150"}},"corpus_meta":[{"pmid":"20385826","id":"PMC_20385826","title":"Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC).","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20385826","citation_count":378,"is_preprint":false},{"pmid":"9114024","id":"PMC_9114024","title":"A hepatic lipase (LIPC) allele associated with high plasma concentrations of high density lipoprotein cholesterol.","date":"1997","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9114024","citation_count":220,"is_preprint":false},{"pmid":"9469601","id":"PMC_9469601","title":"Hepatic lipase activity is lower in African American men than in white American men: effects of 5' flanking polymorphism in the hepatic lipase gene (LIPC).","date":"1998","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/9469601","citation_count":125,"is_preprint":false},{"pmid":"21447678","id":"PMC_21447678","title":"Association of variants in the LIPC and ABCA1 genes with intermediate and large drusen and advanced age-related macular degeneration.","date":"2011","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/21447678","citation_count":104,"is_preprint":false},{"pmid":"7592412","id":"PMC_7592412","title":"The three genes lipB, lipC, and lipD involved in the extracellular secretion of the Serratia marcescens lipase which lacks an N-terminal signal peptide.","date":"1995","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/7592412","citation_count":79,"is_preprint":false},{"pmid":"11257263","id":"PMC_11257263","title":"Hepatic lipase promoter activity is reduced by the C-480T and G-216A substitutions present in the common LIPC gene variant, and is increased by Upstream Stimulatory Factor.","date":"2001","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/11257263","citation_count":61,"is_preprint":false},{"pmid":"21139980","id":"PMC_21139980","title":"Associations of smoking, body mass index, dietary lutein, and the LIPC gene variant rs10468017 with advanced age-related macular degeneration.","date":"2010","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/21139980","citation_count":56,"is_preprint":false},{"pmid":"10487498","id":"PMC_10487498","title":"Absence of association between genetic variation in the LIPC gene promoter and plasma lipoproteins in three Canadian populations.","date":"1999","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/10487498","citation_count":49,"is_preprint":false},{"pmid":"9610782","id":"PMC_9610782","title":"Body mass index and hepatic lipase gene (LIPC) polymorphism jointly influence postheparin plasma hepatic lipase activity.","date":"1998","source":"Journal of lipid 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letters","url":"https://pubmed.ncbi.nlm.nih.gov/20546309","citation_count":43,"is_preprint":false},{"pmid":"22038913","id":"PMC_22038913","title":"LipC (Rv0220) is an immunogenic cell surface esterase of Mycobacterium tuberculosis.","date":"2011","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/22038913","citation_count":43,"is_preprint":false},{"pmid":"16603721","id":"PMC_16603721","title":"Transcriptional regulation of the human hepatic lipase (LIPC) gene promoter.","date":"2006","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/16603721","citation_count":41,"is_preprint":false},{"pmid":"12547874","id":"PMC_12547874","title":"Atorvastatin dose-dependently decreases hepatic lipase activity in type 2 diabetes: effect of sex and the LIPC promoter variant.","date":"2003","source":"Diabetes 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of central obesity and LIPC polymorphisms.","date":"2003","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/14657196","citation_count":30,"is_preprint":false},{"pmid":"10564475","id":"PMC_10564475","title":"LipC, a second lipase of Pseudomonas aeruginosa, is LipB and Xcp dependent and is transcriptionally regulated by pilus biogenesis components.","date":"1999","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/10564475","citation_count":29,"is_preprint":false},{"pmid":"25926410","id":"PMC_25926410","title":"Dietary Fat Intake Modifies the Effect of a Common Variant in the LIPC Gene on Changes in Serum Lipid Concentrations during a Long-Term Weight-Loss Intervention Trial.","date":"2015","source":"The Journal of nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/25926410","citation_count":29,"is_preprint":false},{"pmid":"21252145","id":"PMC_21252145","title":"Physical activity modifies the effect of LPL, LIPC, and CETP polymorphisms on HDL-C levels and the risk of myocardial infarction in women of European ancestry.","date":"2011","source":"Circulation. 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The -480C→T substitution decreases binding affinity of Upstream Stimulatory Factor (USF) protein to its binding site by four-fold, as shown by gel-shift assays. Co-transfection with USF(43) cDNA increases activity of all -650/+48 constructs dose-dependently, maintaining the relative difference between variant and wild-type promoters.\",\n      \"method\": \"CAT-reporter assays in HepG2 cells, gel-shift (EMSA) assays, co-transfection with USF cDNA\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro functional reporter assay plus EMSA mutagenesis in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"11257263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The LIPC promoter is directly regulated by HNF4α via two newly identified direct repeat elements (DR1 and DR4). PGC-1α co-activates HNF4α-dependent LIPC transcription. ARP-1 displaces HNF4α from the DR1 site and represses LIPC promoter activity. HNF1α activates LIPC transcription through its binding site and has an additive effect with HNF4α. In vivo, disruption of Hnf4α in mice abolishes hepatic HL mRNA expression, and the HNF4α antagonist Medica 16 represses endogenous LIPC mRNA in cells.\",\n      \"method\": \"Luciferase reporter assays, co-transfection experiments in HepG2 cells, Hnf4α knockout mice, RT-PCR for endogenous mRNA\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (reporter assay, co-transfection, KO mouse, pharmacological antagonist) in one study establishing direct transcriptional regulation\",\n      \"pmids\": [\"16603721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A gain-of-function LIPC variant (E97G) specifically increases the phospholipase activity of hepatic lipase (without altering triglyceride lipase activity) by modifying an evolutionarily conserved motif that controls substrate access to the catalytic site. In vitro cell culture and in vivo mouse overexpression studies showed the increased phospholipase activity promotes catabolism of triglyceride-rich lipoproteins by extrahepatic tissues, resulting in combined hypocholesterolemia (low LDL-C and HDL-C). The lysophospholipid/phospholipid ratio was elevated in plasma of variant carriers, consistent with increased phospholipase activity.\",\n      \"method\": \"Protein homology modeling, in vitro phospholipase and triglyceride lipase activity assays in cell culture, APOE*3-Leiden.CETP mouse overexpression model, NMR-based lipoprotein profiling, lipidomics\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay, mutagenesis-based structural analysis, and in vivo mouse model with multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"35899625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Two novel LIPC missense variants (G119S/c.421G>A and previously known V73M/L334F) were identified in Thai subjects with hyperalphalipoproteinemia and low hepatic lipase activity, supporting that loss-of-function variants in LIPC cause elevated HDL-C. The G119S variant was judged functionally relevant based on evolutionary conservation and location in a functionally important domain.\",\n      \"method\": \"Genetic sequencing of LIPC coding regions, measurement of post-heparin hepatic lipase activity in patient plasma\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — enzymatic activity measured in patients carrying identified variants, single lab, no in vitro reconstitution of the specific variant\",\n      \"pmids\": [\"19428034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Two novel LIPC missense variants (p.G141S/c.421A>G and p.V173M/c.517G>A) reduce hepatic lipase activity in HepG2 cell lysates to 41% and 46% of wild-type, respectively, confirming their loss-of-function effect underlying hyperalphalipoproteinemia.\",\n      \"method\": \"Site-directed mutagenesis, cDNA cloning and transient expression in HepG2 cells, hepatic lipase activity assay in cell lysates\",\n      \"journal\": \"Clinica chimica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis and enzymatic activity assay in a single focused study\",\n      \"pmids\": [\"23219720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Expression of human hepatic lipase (hHL) in primary hepatocytes from Lipc-null mice decreased synthesis and secretion of apoA-I (but not apoE), as shown by metabolic labeling. An HSPG-binding deficient hHL mutant (hHLmt) also inhibited apoA-I production despite impaired ER exit, and both hHL and hHLmt increased microsome-associated apoA-I, indicating an intracellular mechanism for HL's negative impact on apoA-I production independent of cell-surface binding.\",\n      \"method\": \"Adenovirus-mediated gene transfer in Lipc-null primary hepatocytes, metabolic labeling with 35S, subcellular fractionation\",\n      \"journal\": \"Journal of biomedical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO hepatocyte system with adenoviral rescue, metabolic labeling, and fractionation; single lab with multiple methods\",\n      \"pmids\": [\"25013403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-27b negatively regulates LIPC expression and activity in hepatocytes. Using activity-based protein profiling with a serine hydrolase probe and stable isotope labeling/mass spectrometry, LIPC was identified as a direct target of miR-27b. Modulation of miR-27b with mimics or inhibitors altered LIPC levels. Transcription factors Jun, PPARα, and HNF4α (which also regulate LIPC) are themselves regulated by miR-27b. LIPC knockdown decreased intracellular triglyceride degradation and affected HCV life cycle progression.\",\n      \"method\": \"Activity-based protein profiling with serine hydrolase probe, SILAC mass spectrometry, miRNA mimic/inhibitor transfection, cell-based HCV infection assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — activity-based proteomics plus functional miRNA modulation experiments in single lab with orthogonal methods\",\n      \"pmids\": [\"35483451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The -514T allele of LIPC is associated with decreased post-heparin hepatic lipase activity in both white and African American men, and this effect is independent of androgen action. Treatment with the anabolic steroid stanozolol increased hepatic lipase activity equally in -514T and -514C homozygous men (45 vs 51 mmol·hr⁻¹·l⁻¹, P=0.5), demonstrating the polymorphism does not modulate androgen responsiveness of HL.\",\n      \"method\": \"Pharmacological challenge (stanozolol treatment), post-heparin plasma hepatic lipase activity measurement, genotyping\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — controlled pharmacological experiment with direct enzyme activity measurement, single lab but well-controlled design\",\n      \"pmids\": [\"9684756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Linkage analysis in 218 nuclear families showed that allelic variation at or near the LIPC gene accounts for ~25% of variance in plasma HDL-C concentrations. Sequencing identified four novel 5'-flanking polymorphisms in complete linkage disequilibrium (a single allele) associated with higher HDL-C and apolipoprotein AI levels, establishing LIPC genetic variation as a major determinant of plasma HDL-C.\",\n      \"method\": \"Linkage analysis, DNA sequencing, association studies in two independent population samples\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — linkage plus sequencing plus replicated association in two independent cohorts; established foundational genotype-phenotype mechanism\",\n      \"pmids\": [\"9114024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TUSC3 negatively regulates LIPC expression in hepatocellular carcinoma. Co-immunoprecipitation showed a physical interaction between TUSC3 and LIPC. Loss of TUSC3 reduces LIPC levels and activates AKT signaling, promoting epithelial-mesenchymal transition (EMT). Gain- and loss-of-function experiments showed LIPC negatively modulates HCC cell proliferation and migration, acting downstream of TUSC3 to suppress AKT-driven EMT.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, loss-of-function and gain-of-function experiments in vitro and in vivo, Western blot for EMT markers and AKT pathway\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional rescue experiments in single lab; pathway placement via loss/gain of function with defined molecular readouts\",\n      \"pmids\": [\"36274132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The LIPC -514C→T promoter variant reduces LIPC promoter activity by ~90% in a luciferase reporter assay in HepG2 cells, providing a direct functional explanation for its association with decreased hepatic lipase activity and increased HDL-C levels.\",\n      \"method\": \"Luciferase reporter assay in HepG2 cells\",\n      \"journal\": \"Journal of endocrinological investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — single in vitro reporter assay, single lab, no additional orthogonal validation\",\n      \"pmids\": [\"32617858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1986,\n      \"finding\": \"Purified hepatic triglyceride lipase (HTGL/hepatic lipase) added to plasma markedly enhanced anti-Factor Xa clotting activity and caused ~70% inhibition of lipid peroxide-induced thrombin generation in vitro, demonstrating a direct anticoagulant function for HTGL in plasma.\",\n      \"method\": \"In vitro addition of purified HTGL to plasma, anti-Xa clotting activity assay, thrombin generation assay\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct in vitro biochemical assay with purified protein, single study, older methodology\",\n      \"pmids\": [\"2433786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LIPC gene polymorphisms are associated with plasma phosphatidylethanolamine metabolite levels (glycerophospholipids), as identified by metabolite quantitative trait loci (met-QTL) analysis in AMD patients and controls, supporting a role for LIPC in glycerophospholipid metabolism.\",\n      \"method\": \"Metabolite QTL analysis using mass spectrometry metabolomics and Illumina SNP array, linear regression, meta-analysis across two cohorts\",\n      \"journal\": \"Ophthalmology science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Moderate — genomic-metabolomic association without direct enzymatic or biochemical mechanistic experiment on the protein itself\",\n      \"pmids\": [\"34382031\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LIPC encodes hepatic lipase, a serine hydrolase with both triglyceride lipase and phospholipase activities whose transcription is directly driven by HNF4α (via DR1/DR4 elements), co-activated by PGC-1α, repressed by ARP-1, and additionally activated by HNF1α; the common promoter variants (-480C→T, -514C→T) reduce USF binding and promoter activity, lowering HL expression and elevating plasma HDL-C; a gain-of-function catalytic variant (E97G) that selectively enhances phospholipase activity causes familial combined hypocholesterolemia by promoting phospholipid catabolism and triglyceride-rich lipoprotein clearance; miR-27b downregulates LIPC to reduce intracellular triglyceride degradation; and hepatic lipase intracellularly suppresses apoA-I synthesis in hepatocytes independent of its cell-surface HSPG binding.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LIPC encodes hepatic lipase, a serine hydrolase with both triglyceride lipase and phospholipase activities that is a major determinant of plasma lipoprotein metabolism, with allelic variation at the locus accounting for ~25% of variance in plasma HDL-C [#8]. Its hepatic transcription is directly controlled by HNF4\\u03b1 acting through DR1 and DR4 elements, co-activated by PGC-1\\u03b1 and HNF1\\u03b1 and repressed by ARP-1, with HNF4\\u03b1 disruption abolishing hepatic HL mRNA in vivo [#1]; common 5'-flanking promoter variants (-480C\\u2192T, -514C\\u2192T, -216G\\u2192A) reduce promoter activity, in part by lowering USF binding affinity, thereby decreasing HL expression and raising HDL-C [#0, #8, #10]. Loss-of-function missense variants that reduce HL enzymatic activity cause hyperalphalipoproteinemia [#4], whereas a gain-of-function variant (E97G) that selectively enhances phospholipase activity by altering a conserved motif controlling substrate access promotes catabolism of triglyceride-rich lipoproteins and causes combined hypocholesterolemia [#2]. Beyond its secreted lipolytic role, hepatic lipase intracellularly suppresses apoA-I synthesis and secretion in hepatocytes independent of cell-surface heparan sulfate proteoglycan binding [#5], and is post-transcriptionally downregulated by miR-27b to reduce intracellular triglyceride degradation [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 1986,\n      \"claim\": \"Established that hepatic lipase has activities beyond lipolysis, showing purified HTGL exerts a direct anticoagulant effect in plasma.\",\n      \"evidence\": \"In vitro addition of purified HTGL to plasma with anti-Xa clotting and thrombin generation assays\",\n      \"pmids\": [\"2433786\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism linking lipase activity to coagulation not defined\", \"Physiological relevance in vivo not established\", \"Older methodology, single study\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Quantified LIPC as a major genetic determinant of HDL-C, framing the locus as physiologically dominant rather than incidental to lipid metabolism.\",\n      \"evidence\": \"Linkage analysis and sequencing with replicated association in two independent population samples\",\n      \"pmids\": [\"9114024\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Causal variant among the linked 5'-flanking polymorphisms not pinned to a molecular mechanism\", \"Did not establish which polymorphism drives the phenotype\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Tested whether the HDL-associated -514 variant acts via hormonal modulation, showing its effect on HL activity is independent of androgen responsiveness.\",\n      \"evidence\": \"Stanozolol pharmacological challenge with post-heparin plasma HL activity measurement and genotyping in two ethnic groups\",\n      \"pmids\": [\"9684756\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Did not define the molecular basis of the -514 effect\", \"Single intervention, modest sample\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Provided a molecular mechanism for promoter variants by showing -480C\\u2192T reduces USF transcription factor binding and lowers promoter activity.\",\n      \"evidence\": \"CAT-reporter assays, EMSA, and USF cDNA co-transfection in HepG2 cells\",\n      \"pmids\": [\"11257263\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Does not establish in vivo contribution of USF occupancy to HL levels\", \"Other promoter variants in linkage not individually resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the core transcriptional regulatory circuit of LIPC, identifying direct HNF4\\u03b1 control via DR1/DR4 with PGC-1\\u03b1 and HNF1\\u03b1 activation and ARP-1 repression.\",\n      \"evidence\": \"Luciferase reporters, co-transfection, Hnf4\\u03b1 knockout mice, and pharmacological HNF4\\u03b1 antagonism\",\n      \"pmids\": [\"16603721\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Signals that tune HNF4\\u03b1/PGC-1\\u03b1 activity on LIPC not defined\", \"Interplay with promoter SNP USF site not integrated\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linked coding LIPC variants to low HL activity and high HDL-C in patients, extending the loss-of-function genotype-phenotype relationship to the protein-coding sequence.\",\n      \"evidence\": \"Coding region sequencing and post-heparin HL activity in Thai hyperalphalipoproteinemia subjects\",\n      \"pmids\": [\"19428034\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No in vitro reconstitution of the specific variants\", \"Functional relevance inferred from conservation, not assayed directly\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Confirmed causality of loss-of-function missense variants by reconstituting reduced enzymatic activity in cells.\",\n      \"evidence\": \"Site-directed mutagenesis and HL activity assays in HepG2 cell lysates\",\n      \"pmids\": [\"23219720\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Effect on secretion versus catalysis not separated\", \"Substrate-specific (TG vs phospholipid) consequences not measured\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed a non-canonical intracellular role, showing hepatic lipase suppresses apoA-I synthesis independent of cell-surface HSPG binding.\",\n      \"evidence\": \"Adenoviral expression in Lipc-null primary hepatocytes with 35S metabolic labeling and subcellular fractionation\",\n      \"pmids\": [\"25013403\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular mechanism of intracellular apoA-I suppression unknown\", \"Whether catalytic activity is required not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Associated LIPC genetic variation with plasma glycerophospholipid (phosphatidylethanolamine) levels, hinting at a phospholipid-handling role at the population level.\",\n      \"evidence\": \"Metabolite QTL analysis with mass spectrometry metabolomics and SNP arrays across two cohorts\",\n      \"pmids\": [\"34382031\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No direct enzymatic or biochemical experiment on the protein\", \"Association does not establish causal flux through HL\", \"Confounding by linkage not excluded\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Dissected the dual catalytic activities, showing a gain-of-function E97G variant selectively boosts phospholipase activity via a conserved substrate-access motif and causes combined hypocholesterolemia.\",\n      \"evidence\": \"Homology modeling, in vitro phospholipase/TG lipase assays, APOE*3-Leiden.CETP overexpression mice, NMR lipoprotein profiling and lipidomics\",\n      \"pmids\": [\"35899625\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structural model not validated by crystallography\", \"Extrahepatic clearance pathway not mechanistically mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified post-transcriptional control of LIPC by miR-27b linking it to intracellular triglyceride turnover and HCV biology.\",\n      \"evidence\": \"Activity-based serine hydrolase proteomics, SILAC mass spectrometry, miRNA mimic/inhibitor, and HCV infection assays\",\n      \"pmids\": [\"35483451\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct miR-27b:LIPC target site not mapped functionally\", \"In vivo relevance of regulation not shown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed LIPC in a tumor-suppressive axis, showing TUSC3 physically interacts with and positively regulates LIPC to restrain AKT-driven EMT in hepatocellular carcinoma.\",\n      \"evidence\": \"Co-immunoprecipitation, immunofluorescence, and gain/loss-of-function experiments in vitro and in vivo\",\n      \"pmids\": [\"36274132\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether HL catalytic activity mediates the anti-EMT effect unknown\", \"Single Co-IP without reciprocal structural mapping\", \"Mechanism linking LIPC to AKT not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the secreted lipolytic, intracellular apoA-I-suppressing, and tumor-suppressive functions of hepatic lipase are integrated, and how catalytic versus non-catalytic activities partition across these roles, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structural model linking the two catalytic activities to distinct physiological outputs\", \"Catalytic requirement for intracellular and tumor-related functions untested\", \"Tissue-specific regulation of the dual activities undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [2, 4, 11]},\n      {\"term_id\": \"GO:0016298\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"HNF4A\",\n      \"HNF1A\",\n      \"PPARGC1A\",\n      \"USF1\",\n      \"TUSC3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}