id: Q94252
gene_symbol: lipl-4
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: >-
  LIPL-4 is a lysosomal acid lipase in C. elegans with triacylglycerol lipase activity
  (EC 3.1.1.3) that functions as a key signaling enzyme in a lysosome-to-nucleus retrograde
  lipid signaling pathway promoting longevity. LIPL-4 localizes to the lysosomal lumen via
  a signal peptide and is optimally active at acidic pH. Upon fasting or germline loss,
  LIPL-4 is upregulated in the intestine and produces lipid signaling molecules including
  oleoylethanolamide (OEA) and omega-6 polyunsaturated fatty acids (PUFAs such as arachidonic
  acid and DGLA). OEA is carried by the lipid chaperone LBP-8 from the lysosome to the
  nucleus, where it directly binds and activates the nuclear hormone receptor NHR-80
  (with NHR-49 as a cofactor), promoting transcription of longevity and beta-oxidation
  genes. Omega-6 PUFAs produced by LIPL-4 activate autophagy, contributing to lifespan
  extension. Constitutive overexpression of LIPL-4 extends lifespan by approximately 55%,
  an effect that requires lysosomal localization (signal peptide dependent). LIPL-4 expression
  is regulated by the transcription factors MXL-3 and HLH-30 in response to nutrient
  availability, and is induced by TOR inhibition. The protein belongs to the AB hydrolase
  superfamily lipase family and is homologous to human lysosomal acid lipase LIPA.
  Two isoforms exist (a and b), with isoform b lacking the N-terminal 157 residues
  including the signal peptide.
alternative_products:
- name: a {ECO:0000312|WormBase:K04A8.5a}
  id: Q94252-1
- name: b {ECO:0000312|WormBase:K04A8.5b}
  id: Q94252-2
  sequence_note: VSP_060544
existing_annotations:
- term:
    id: GO:0006629
    label: lipid metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation of lipid metabolic process based on phylogenetic inference across
      multiple orthologs including yeast, fly, and mammalian lipases. LIPL-4 is clearly
      involved in lipid metabolism as a lysosomal triacylglycerol lipase that hydrolyzes
      triglycerides and produces fatty acid signaling molecules (PMID:21906946, PMID:25554789).
    action: ACCEPT
    reason: >-
      LIPL-4 is unambiguously involved in lipid metabolic process. While more specific
      terms exist (triglyceride catabolic process, long-chain fatty acid biosynthetic process),
      this broader IBA annotation is appropriate as a phylogenetically supported annotation
      and is not incorrect. Multiple publications confirm lipase activity and lipid metabolism
      roles (PMID:21906946, PMID:23392608, PMID:25554789).
    additional_reference_ids:
    - file:worm/lipl-4/lipl-4-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:21906946
      supporting_text: >-
        Germline removal extends life span in C. elegans via genes such as the lipase LIPL-4
    - reference_id: PMID:25554789
      supporting_text: >-
        We analyzed a C. elegans longevity-promoting lipase, LIPL-4, which has sequence and
        functional similarities to human LIPA
    - reference_id: file:worm/lipl-4/lipl-4-deep-research-falcon.md
      supporting_text: |-
        Savini et al. describe lysosomal acid lipases (including LIPL-4) as releasing **free fatty acids** from **triacylglycerols (TAGs)** and **cholesteryl esters (CEs)**, situating LIPL-4 within TAG/CE lipolysis and FFA generation in intestinal lysosomes.

- term:
    id: GO:0016298
    label: lipase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation of lipase activity based on phylogenetic inference. LIPL-4 has
      experimentally demonstrated lipase activity, specifically triacylglycerol lipase
      activity (PMID:21906946). Lipid hydrolysis activity was confirmed at pH 4.5 in
      worm lysates (PMID:25554789).
    action: ACCEPT
    reason: >-
      Lipase activity is well supported by multiple lines of evidence. While the more
      specific term triacylglycerol lipase activity (GO:0004806) is also annotated,
      this broader IBA annotation is appropriate as a phylogenetically supported
      characterization. The IBA annotation represents the consensus across the lipase
      family tree and is not incorrect.
    additional_reference_ids:
    - file:worm/lipl-4/lipl-4-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:25554789
      supporting_text: >-
        Lipid hydrolysis activity was decreased in lipl-4(tm4417) loss-of-function mutants
        at pH 4.5 but not at pH 7.4
    - reference_id: PMID:21906946
      supporting_text: >-
        autophagy is required to maintain high lipase activity in germline-deficient animals
    - reference_id: file:worm/lipl-4/lipl-4-deep-research-falcon.md
      supporting_text: |-
        mutants have **reduced hydrolysis at pH 4.5 but not pH 7.4**, supporting **acid pH-dependent triglyceride lipase activity** consistent with lysosomal function.

- term:
    id: GO:0004806
    label: triacylglycerol lipase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation of triacylglycerol lipase activity based on Rhea/EC mapping
      (EC:3.1.1.3). This is consistent with the UniProt catalytic activity annotation
      and the experimentally determined IMP annotation from PMID:21906946.
    action: ACCEPT
    reason: >-
      This IEA annotation is correct and consistent with the IMP annotation from
      PMID:21906946. UniProt assigns EC 3.1.1.3 based on experimental evidence from
      multiple publications. The triacylglycerol lipase activity is a core molecular
      function of LIPL-4.
    additional_reference_ids:
    - file:worm/lipl-4/lipl-4-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:21906946
      supporting_text: >-
        Germline removal extends life span in C. elegans via genes such as the lipase LIPL-4
    - reference_id: file:worm/lipl-4/lipl-4-deep-research-falcon.md
      supporting_text: |-
        The direct biochemical assay supports activity against a **triacylglycerol** substrate (triolein).

- term:
    id: GO:0006629
    label: lipid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation of lipid metabolic process based on InterPro domain mapping
      (IPR006693, AB hydrolase lipase domain). This is consistent with the IBA
      annotation for the same term and with experimental evidence.
    action: ACCEPT
    reason: >-
      This IEA annotation is correct and redundant with the IBA annotation. The InterPro
      domain-based inference is sound given the established lipase function of LIPL-4.
      Duplicates with different evidence codes are acceptable.
    supported_by:
    - reference_id: PMID:21906946
      supporting_text: >-
        Germline removal extends life span in C. elegans via genes such as the lipase LIPL-4

- term:
    id: GO:0016788
    label: hydrolase activity, acting on ester bonds
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation of hydrolase activity acting on ester bonds, based on InterPro
      domain mapping (IPR025483, eukaryotic lipase). LIPL-4 has a catalytic triad
      (Ser177, Asp352, His384) characteristic of the AB hydrolase superfamily
      and hydrolyzes ester bonds in triacylglycerols.
    action: ACCEPT
    reason: >-
      This is a correct but general parent term of the more specific triacylglycerol
      lipase activity. The IEA mapping from the eukaryotic lipase InterPro domain is
      appropriate. While broader than other MF annotations, it is not incorrect and
      reflects the domain-level inference.
    supported_by:
    - reference_id: PMID:25554789
      supporting_text: >-
        Lipid hydrolysis activity was decreased in lipl-4(tm4417) loss-of-function mutants
        at pH 4.5 but not at pH 7.4

- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA annotation of lysosomal lumen localization based on UniProt subcellular location
      vocabulary mapping. UniProt annotates LIPL-4 to "Lysosome lumen" based on
      experimental evidence from PMID:25554789 showing FLAG-tagged LIPL-4 co-localizing
      with lysosomal markers in intestinal cells.
    action: ACCEPT
    reason: >-
      Lysosomal lumen localization is strongly supported by experimental evidence.
      LIPL-4 has a signal peptide (residues 1-27) required for lysosomal targeting,
      and its optimal activity at acidic pH is consistent with lysosomal lumen function.
      The signal peptide is required for both lysosomal localization and the longevity
      effect (PMID:25554789). This IEA correctly reflects the experimentally validated
      UniProt subcellular location annotation.
    additional_reference_ids:
    - file:worm/lipl-4/lipl-4-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:25554789
      supporting_text: >-
        FLAG-tagged LIPL-4 protein was localized to intestinal lysosomes (Fig
    - reference_id: PMID:25554789
      supporting_text: >-
        Constitutive expression of LIPL-4 without the signal peptide (lipl-4 Tg no SP),
        which was not targeted to the lysosome, caused little extension of lifespan (fig.
        S4 and table S1), suggesting that the lysosomal activity of LIPL-4 is essential
        for its longevity effect.
    - reference_id: file:worm/lipl-4/lipl-4-deep-research-falcon.md
      supporting_text: |-
        A **signal peptide** required for lysosomal targeting is also required for full downstream signaling and longevity phenotypes, consistent with LIPL-4 acting from the lysosomal lumen/lysosomal compartment.

- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IDA
  original_reference_id: PMID:25554789
  review:
    summary: >-
      IDA annotation of lysosome localization based on direct observation of FLAG-tagged
      LIPL-4 protein co-localizing with lysosomal markers in intestinal cells
      (PMID:25554789). The signal peptide is required for lysosomal targeting and the
      longevity phenotype.
    action: ACCEPT
    reason: >-
      Lysosomal localization is a core aspect of LIPL-4 function, experimentally
      demonstrated by fluorescence microscopy of tagged protein. The requirement of the
      signal peptide for both lysosomal localization and longevity function establishes
      that lysosomal localization is functionally essential (PMID:25554789).
    additional_reference_ids:
    - file:worm/lipl-4/lipl-4-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:25554789
      supporting_text: >-
        FLAG-tagged LIPL-4 protein was localized to intestinal lysosomes (Fig
    - reference_id: PMID:25554789
      supporting_text: >-
        Constitutive expression of LIPL-4 without the signal peptide (lipl-4 Tg no SP),
        which was not targeted to the lysosome, caused little extension of lifespan (fig.
        S4 and table S1), suggesting that the lysosomal activity of LIPL-4 is essential
        for its longevity effect.
    - reference_id: file:worm/lipl-4/lipl-4-deep-research-falcon.md
      supporting_text: |-
        FLAG-tagged LIPL-4 **co-localizes with the lysosomal marker LMP-1** in **intestinal cells**, indicating LIPL-4 is a lysosomal protein in vivo.

- term:
    id: GO:0042759
    label: long-chain fatty acid biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:25554789
  review:
    summary: >-
      IMP annotation of long-chain fatty acid biosynthetic process. PMID:25554789
      identified via high-throughput metabolomic profiling that lipl-4 overexpression
      increases abundance of several long-chain fatty acids including arachidonic acid (AA),
      omega-3 AA, DGLA (C20 fatty acids), and oleoylethanolamide (OEA). PMID:23392608
      showed that lipl-4 induction leads to enrichment of omega-6 PUFAs.
    action: ACCEPT
    reason: >-
      The metabolomic data from PMID:25554789 clearly show that LIPL-4 overexpression
      leads to increased abundance of long-chain fatty acids. While LIPL-4 is primarily
      a lipase (hydrolase), its activity leads to the production/accumulation of
      long-chain fatty acid species and their derivatives. The term captures the
      biological outcome of LIPL-4 activity at the organismal level, even though the
      molecular mechanism is hydrolytic release of fatty acids from triacylglycerols
      rather than de novo biosynthesis.
    additional_reference_ids:
    - file:worm/lipl-4/lipl-4-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:25554789
      supporting_text: >-
        we focused our analysis on three C20 fatty acids—arachidonic acid (AA), omega-3
        arachidonic acid (omega-3 AA), and dihomo-gamma-linolenic acid (DGLA)—and
        oleoylethanolamide (OEA), an N-acylethanolamine fatty acid derivative
    - reference_id: PMID:23392608
      supporting_text: >-
        LIPL-4 overexpression is sufficient to not only enrich omega-6 PUFAs and activate
        autophagy, but also transcriptionally activate nutrient-responsive genes
    - reference_id: file:worm/lipl-4/lipl-4-deep-research-falcon.md
      supporting_text: |-
        LIPL-4 overexpression is associated with increases in several lipid species, including **oleoylethanolamide (OEA)** and PUFAs

- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:23392608
  review:
    summary: >-
      IDA annotation of cytoplasm localization from CACAO curation of PMID:23392608.
      O'Rourke et al. (2013) studied LIPL-4 localization but noted that LIPL-4 does not
      localize to sites of active autophagy. The primary experimentally validated
      localization is lysosomal (PMID:25554789), which is a more specific compartment
      within the cytoplasm.
    action: KEEP_AS_NON_CORE
    reason: >-
      While cytoplasm is technically not incorrect (lysosomes are within the cytoplasm),
      the more specific and functionally relevant localization is lysosomal lumen
      (GO:0043202) as demonstrated by PMID:25554789. The CACAO annotation predates the
      definitive lysosomal localization study. However, it is not wrong per se, so
      keeping as non-core rather than removing. The lysosome annotation (GO:0005764)
      is the core CC annotation.
    supported_by:
    - reference_id: PMID:23392608
      supporting_text: >-
        LIPL-4 does not localize to the sites of active autophagy
    - reference_id: PMID:25554789
      supporting_text: >-
        FLAG-tagged LIPL-4 protein was localized to intestinal lysosomes (Fig

- term:
    id: GO:0010508
    label: positive regulation of autophagy
  evidence_type: IDA
  original_reference_id: PMID:23392608
  review:
    summary: >-
      IDA annotation from CACAO curation of PMID:23392608. O'Rourke et al. showed that
      LIPL-4 overexpression activates autophagy, and that omega-6 PUFAs produced by
      LIPL-4 activity are the mediating signals that activate autophagy. Supplementation
      with omega-6 PUFAs (AA, DGLA) is sufficient to activate autophagy in both C. elegans
      and human cells. This is also supported by PMID:21906946 which showed that autophagy
      is induced in animals overexpressing LIPL-4.
    action: ACCEPT
    reason: >-
      Positive regulation of autophagy is a well-established function of LIPL-4,
      demonstrated in both PMID:23392608 and PMID:21906946. The mechanism involves
      LIPL-4 producing omega-6 PUFAs that serve as metabolic signals activating
      autophagy. This is a core biological process downstream of LIPL-4 activity.
      The evidence code IDA from CACAO is appropriate given that LIPL-4 overexpression
      directly induces autophagy markers.
    additional_reference_ids:
    - file:worm/lipl-4/lipl-4-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:23392608
      supporting_text: >-
        LIPL-4 overexpression is sufficient to not only enrich omega-6 PUFAs and activate
        autophagy, but also transcriptionally activate nutrient-responsive genes
    - reference_id: PMID:21906946
      supporting_text: >-
        autophagy is induced in animals overexpressing LIPL-4 and autophagy is required
        for their long life span
    - reference_id: file:worm/lipl-4/lipl-4-deep-research-falcon.md
      supporting_text: |-
        autophagy is needed for elevated lipase activity in germline-less animals, and LIPL-4 is needed for autophagy induction in that model; TOR inhibition induces **lipl-4** expression and lipase activity, linking LIPL-4 to nutrient sensing and autophagy pathways.

- term:
    id: GO:0004806
    label: triacylglycerol lipase activity
  evidence_type: IMP
  original_reference_id: PMID:21906946
  review:
    summary: >-
      IMP annotation of triacylglycerol lipase activity from WormBase curation of
      PMID:21906946. Lapierre et al. showed that germline-less animals have increased
      lipase activity that depends on lipl-4, and that lipl-4 RNAi reduces lipase activity
      in glp-1 mutant background. LIPL-4 was described as a neutral lipase in this paper.
      Later work (PMID:25554789) confirmed lipid hydrolysis activity at acidic pH and
      UniProt assigns EC 3.1.1.3 based on the catalytic triad.
    action: ACCEPT
    reason: >-
      Triacylglycerol lipase activity is the core molecular function of LIPL-4. The IMP
      evidence is based on the observation that lipl-4 RNAi reduces lipase activity in
      germline-deficient animals. UniProt assigns EC 3.1.1.3 with supporting evidence
      from PMID:21906946 and PMID:25554789.
    additional_reference_ids:
    - file:worm/lipl-4/lipl-4-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:21906946
      supporting_text: >-
        autophagy is required to maintain high lipase activity in germline-deficient animals.
        Reciprocally, lipl-4 is required for autophagy induction.
    - reference_id: PMID:25554789
      supporting_text: >-
        Lipid hydrolysis activity was decreased in lipl-4(tm4417) loss-of-function mutants
        at pH 4.5 but not at pH 7.4
    - reference_id: file:worm/lipl-4/lipl-4-deep-research-falcon.md
      supporting_text: |-
        Experimentally, LIPL-4 shows **acid pH-dependent triglyceride lipase activity** and drives **lysosome-derived lipid signaling** that promotes longevity

- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IMP
  original_reference_id: PMID:21906946
  review:
    summary: >-
      IMP annotation of determination of adult lifespan from WormBase curation of
      PMID:21906946. Lapierre et al. showed that lipl-4 is required for lifespan extension
      in germline-less animals. PMID:25554789 further showed that constitutive
      overexpression of lipl-4 extends lifespan by 55% and that this requires lysosomal
      localization. The lifespan effect operates through OEA/NHR-49/NHR-80 signaling
      and omega-6 PUFA-mediated autophagy activation.
    action: ACCEPT
    reason: >-
      Determination of adult lifespan is a core biological process for LIPL-4. Multiple
      publications demonstrate that LIPL-4 modulates lifespan: it is required for
      germline-loss-mediated longevity (PMID:21906946), its overexpression extends lifespan
      by 55% (PMID:25554789), and the downstream signaling molecules OEA and omega-6 PUFAs
      are sufficient to extend lifespan (PMID:25554789, PMID:23392608).
    additional_reference_ids:
    - file:worm/lipl-4/lipl-4-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:21906946
      supporting_text: >-
        Germline removal extends life span in C. elegans via genes such as the lipase LIPL-4
    - reference_id: PMID:25554789
      supporting_text: >-
        A transgenic strain (lipl-4 Tg) that constitutively expressed lipl-4 in the intestine
        had 55% mean lifespan increase compared to wild-type (WT) animals
    - reference_id: file:worm/lipl-4/lipl-4-deep-research-falcon.md
      supporting_text: |-
        Lapierre et al. established that **germline-less (glp-1)** longevity requires **lipl-4**, and that **intestine-specific lipl-4 overexpression** is sufficient to extend lifespan.
    - reference_id: file:worm/lipl-4/lipl-4-deep-research-falcon.md
      supporting_text: |-
        **+55% mean lifespan** in a constitutive intestinal lipl-4 overexpression strain (lipl-4 Tg) in *Science* 2015.
    - reference_id: PMID:23392608
      supporting_text: >-
        Upon fasting, C. elegans induces the expression of a lipase, which in turn leads to an
        enrichment of omega-6 PUFAs. Supplementing C. elegans culture media with these omega-6
        PUFAs increases their resistance to starvation and extends their life span

- term:
    id: GO:0016239
    label: positive regulation of macroautophagy
  evidence_type: IMP
  original_reference_id: PMID:21906946
  review:
    summary: >-
      IMP annotation of positive regulation of macroautophagy from WormBase curation
      of PMID:21906946. Lapierre et al. showed that lipl-4 is required for autophagy
      induction in germline-less animals and that LIPL-4 overexpression induces autophagy.
      PMID:23392608 further demonstrated that omega-6 PUFAs produced by LIPL-4 are the
      signals that activate autophagy.
    action: ACCEPT
    reason: >-
      This is a more specific child term of GO:0010508 (positive regulation of autophagy),
      and both are annotated. The macroautophagy specification is appropriate given that
      the autophagy markers used (LGG-1/LC3, autophagosomes) specifically report on
      macroautophagy. Both PMID:21906946 and PMID:23392608 provide experimental evidence
      for this annotation. This represents a core biological process for LIPL-4.
    additional_reference_ids:
    - file:worm/lipl-4/lipl-4-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:21906946
      supporting_text: >-
        autophagy is induced in animals overexpressing LIPL-4 and autophagy is required for
        their long life span, recapitulating observations in germline-less animals
    - reference_id: file:worm/lipl-4/lipl-4-deep-research-falcon.md
      supporting_text: |-
        autophagy is needed for elevated lipase activity in germline-less animals, and LIPL-4 is needed for autophagy induction in that model
    - reference_id: PMID:23392608
      supporting_text: >-
        Supplementation of C. elegans or human epithelial cells with these omega-6 PUFAs
        activates autophagy, a cell recycling mechanism that promotes starvation survival
        and slows aging

- term:
    id: GO:0019433
    label: triglyceride catabolic process
  evidence_type: IMP
  original_reference_id: PMID:21906946
  review:
    summary: >-
      IMP annotation of triglyceride catabolic process from WormBase curation of
      PMID:21906946. LIPL-4 has triacylglycerol lipase activity (EC 3.1.1.3),
      hydrolyzing triacylglycerols to diacylglycerols and fatty acids. Lapierre et al.
      showed that lipl-4 contributes to lipase activity in germline-less animals and
      that autophagy and LIPL-4 interdependently modulate lipid homeostasis.
    action: ACCEPT
    reason: >-
      Triglyceride catabolic process is the direct biological process consequence of
      LIPL-4 triacylglycerol lipase activity. The annotation is supported by the
      established catalytic activity (EC 3.1.1.3) and the lipase activity measurements
      in PMID:21906946. This is a core biological process for LIPL-4.
    supported_by:
    - reference_id: PMID:21906946
      supporting_text: >-
        autophagy and the lipase LIPL-4 interdependently modulate aging in germline-deficient
        C. elegans by maintaining lipid homeostasis to prolong life span
    - reference_id: PMID:25554789
      supporting_text: >-
        Lipid hydrolysis activity was decreased in lipl-4(tm4417) loss-of-function mutants
        at pH 4.5 but not at pH 7.4

references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings:
  - statement: >-
      InterPro domains IPR006693 (AB hydrolase lipase) and IPR025483 (eukaryotic lipase) map to
      lipid metabolic process and hydrolase activity acting on ester bonds, respectively.
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings:
  - statement: >-
      Phylogenetic analysis by PANTHER/GO_Central supports lipase activity and lipid metabolic
      process annotations for LIPL-4 based on conservation across eukaryotic lipase family members
      including yeast, fly, and mammalian orthologs.
- id: GO_REF:0000044
  title: >-
    Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary
    mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings:
  - statement: >-
      UniProt subcellular location annotation of lysosome lumen is mapped to GO:0043202.
      This is based on experimental evidence from PMID:25554789.
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings:
  - statement: >-
      Rhea reaction mapping from EC 3.1.1.3 supports triacylglycerol lipase activity annotation.
- id: PMID:21906946
  title: >-
    Autophagy and lipid metabolism coordinately modulate life span in germline-less C. elegans.
  findings:
  - statement: >-
      LIPL-4 has triacylglycerol lipase activity. In germline-less (glp-1) animals, lipl-4
      is required for increased lipase activity and for autophagy induction. Reciprocally,
      autophagy is required to maintain high LIPL-4-dependent lipase activity. LIPL-4
      overexpression induces autophagy and extends lifespan, and autophagy is required for
      this lifespan extension. TOR inhibition induces lipl-4 expression.
    supporting_text: >-
      autophagy is required to maintain high lipase activity in germline-deficient animals.
      Reciprocally, lipl-4 is required for autophagy induction.
- id: PMID:23392608
  title: >-
    ω-6 Polyunsaturated fatty acids extend life span through the activation of autophagy.
  findings:
  - statement: >-
      Upon fasting, LIPL-4 induction leads to enrichment of omega-6 PUFAs (AA, DGLA) that
      serve as metabolic signals activating autophagy. Supplementation with these omega-6
      PUFAs extends C. elegans lifespan and activates autophagy in both worms and human cells.
      LIPL-4 overexpression also transcriptionally activates nutrient-responsive genes
      including fatty acid-binding proteins lbp-3 and lbp-5.
    supporting_text: >-
      LIPL-4 overexpression is sufficient to not only enrich omega-6 PUFAs and activate
      autophagy, but also transcriptionally activate nutrient-responsive genes
  - statement: >-
      LIPL-4 does not localize to sites of active autophagy, suggesting it is not directly
      involved in lipophagy but rather produces signaling lipids that activate autophagy.
    supporting_text: >-
      LIPL-4 does not localize to the sites of active autophagy
- id: PMID:25554789
  title: >-
    Aging. Lysosomal signaling molecules regulate longevity in Caenorhabditis elegans.
  findings:
  - statement: >-
      LIPL-4 localizes to intestinal lysosomes (FLAG-tagged protein). Lipid hydrolysis
      activity is reduced in lipl-4 loss-of-function mutants at pH 4.5 but not pH 7.4,
      confirming acid lipase activity. Constitutive lipl-4 expression extends lifespan by
      55%, requiring the signal peptide for lysosomal targeting. Metabolomic profiling
      identified increased abundance of C20 fatty acids (AA, omega-3 AA, DGLA) and OEA in
      lipl-4 Tg animals. OEA binds LBP-8 and directly activates NHR-80, promoting longevity
      gene transcription through a lysosome-to-nucleus signaling pathway.
    supporting_text: >-
      FLAG-tagged LIPL-4 protein was localized to intestinal lysosomes (Fig. 1, B–D and fig. S2).
  - statement: >-
      The signal peptide is required for lysosomal localization and the longevity effect.
      LIPL-4 without signal peptide is not targeted to lysosomes and causes little lifespan
      extension.
    supporting_text: >-
      Constitutive expression of LIPL-4 without the signal peptide (lipl-4 Tg no SP), which
      was not targeted to the lysosome, caused little extension of lifespan (fig. S4 and table S1),
      suggesting that the lysosomal activity of LIPL-4 is essential for its longevity effect.

- id: file:worm/lipl-4/lipl-4-deep-research-falcon.md
  title: Falcon deep research report on lipl-4 (C. elegans)
  findings:
  - statement: |
      LIPL-4 is a lysosomal acid lipase-like AB-hydrolase expressed prominently in the
      intestine and localized to lysosomes via an N-terminal signal peptide, where it
      shows acid pH-dependent triglyceride lipase activity that drives lysosome-derived
      lipid signaling promoting longevity.
    supporting_text: |-
      **lipl-4** encodes **LIPL-4**, a **lysosomal acid lipase-like** enzyme expressed prominently in the **intestine** (major fat storage tissue) and localized to **lysosomes** via an N-terminal signal peptide. Experimentally, LIPL-4 shows **acid pH-dependent triglyceride lipase activity** and drives **lysosome-derived lipid signaling** that promotes longevity
    reference_section_type: RESULTS
  - statement: |
      Lysosomal acid lipases including LIPL-4 release free fatty acids from
      triacylglycerols and cholesteryl esters in intestinal lysosomes.
    supporting_text: |-
      Savini et al. describe lysosomal acid lipases (including LIPL-4) as releasing **free fatty acids** from **triacylglycerols (TAGs)** and **cholesteryl esters (CEs)**, situating LIPL-4 within TAG/CE lipolysis and FFA generation in intestinal lysosomes.
    reference_section_type: RESULTS
  - statement: |
      FLAG-tagged LIPL-4 co-localizes with the lysosomal marker LMP-1 in intestinal
      cells, and its signal peptide is required for lysosomal targeting and for full
      downstream signaling and longevity.
    supporting_text: |-
      FLAG-tagged LIPL-4 **co-localizes with the lysosomal marker LMP-1** in **intestinal cells**, indicating LIPL-4 is a lysosomal protein in vivo.
    reference_section_type: RESULTS
  - statement: |
      One pro-longevity arm of LIPL-4 signaling acts via the lipid chaperone LBP-8
      and nuclear receptors NHR-49 and NHR-80, with OEA binding LBP-8 with about
      3-fold higher affinity than other LIPL-4-associated lipids.
    supporting_text: |-
      LIPL-4-driven longevity requires **LBP-8** and the nuclear receptors **NHR-49** and **NHR-80**, consistent with a lysosome-generated lipid ligand being chaperoned to the nucleus to alter transcription.
    reference_section_type: RESULTS
  - statement: |
      The LIPL-4/LBP-8 axis links to mitochondrial physiology, increasing beta-oxidation,
      raising mtROS, and activating JUN-1-dependent stress-response transcription that
      improves oxidative stress tolerance and promotes longevity.
    supporting_text: |-
      LIPL-4 signaling also increases mitochondrial β-oxidation and mtROS/JUN-1 responses.
    reference_section_type: RESULTS
  - statement: |
      A second, intestine-to-neuron arm uses the secreted lipid chaperone LBP-3 binding
      specific PUFAs (notably DGLA) and acting through neuronal NHR-49 and the
      neuropeptide NLP-11 to promote longevity.
    supporting_text: |-
      A secreted lipid chaperone, **LBP-3**, binds specific PUFAs and is required for LIPL-4-induced neuronal changes and longevity.
    reference_section_type: RESULTS
  - statement: |
      Intestinal LIPL-4 signaling induces neuronal neuropeptide signaling dependent on
      neuronal NHR-49 and the neuropeptide NLP-11, with DGLA highlighted as a key
      PUFA mediator.
    supporting_text: |-
      Intestinal LIPL-4 signaling induces neuronal **neuropeptide signaling**; functional experiments show dependence on neuronal **NHR-49** and neuropeptide **NLP-11**.
    reference_section_type: RESULTS
  - statement: |
      2024 lysosome immunopurification proteomics shows lipl-4 transgenic worms have
      extensive lysosome proteome remodeling (449 lysosome-enriched proteins, only 39%
      overlap with WT) and perinuclear lysosome clustering in intestinal cells.
    supporting_text: |-
      **449 lysosome-enriched proteins** identified in lipl-4 Tg, with only **39% overlap** vs WT lysosome-enriched proteins; **61%** of proteins enriched on lipl-4 Tg lysosomes were absent from WT lysosomes.
    reference_section_type: RESULTS
  - statement: |
      lipl-4 transgenic longevity depends on nuclear import machinery (npp-6 nucleoporin,
      ima-3 importin-alpha) and lysosome-associated AMPK; impairing AMPK reduces the
      lipl-4 Tg lifespan extension from 72% to 48%.
    supporting_text: |-
      reduces lipl-4 Tg extension from **72% to 48%**.
    reference_section_type: RESULTS

core_functions:
  - description: >-
      LIPL-4 is a lysosomal acid lipase that hydrolyzes triacylglycerols at acidic pH
      in the lysosomal lumen, producing oleoylethanolamide (OEA) and omega-6
      polyunsaturated fatty acids (arachidonic acid, DGLA) as lipid signaling
      molecules. These signals mediate a lysosome-to-nucleus retrograde signaling
      pathway: OEA is transported by LBP-8 to the nucleus where it activates
      NHR-49/NHR-80 to promote beta-oxidation and longevity gene transcription.
    molecular_function:
      id: GO:0004806
      label: triacylglycerol lipase activity
    directly_involved_in:
      - id: GO:0019433
        label: triglyceride catabolic process
      - id: GO:0042759
        label: long-chain fatty acid biosynthetic process
    locations:
      - id: GO:0043202
        label: lysosomal lumen
    supported_by:
      - reference_id: PMID:25554789
        supporting_text: >-
          Lipid hydrolysis activity was decreased in lipl-4(tm4417) loss-of-function
          mutants at pH 4.5 but not at pH 7.4
      - reference_id: PMID:25554789
        supporting_text: >-
          we focused our analysis on three C20 fatty acids—arachidonic acid (AA),
          omega-3 arachidonic acid (omega-3 AA), and dihomo-gamma-linolenic acid
          (DGLA)—and oleoylethanolamide (OEA), an N-acylethanolamine fatty acid
          derivative
      - reference_id: PMID:21906946
        supporting_text: >-
          autophagy is required to maintain high lipase activity in
          germline-deficient animals. Reciprocally, lipl-4 is required for
          autophagy induction.
  - description: >-
      Through production of omega-6 PUFAs (arachidonic acid, DGLA) and OEA in
      the lysosome, LIPL-4 activates macroautophagy and extends adult lifespan.
      Omega-6 PUFAs directly activate autophagy, while OEA signals through the
      LBP-8/NHR-49/NHR-80 pathway to promote longevity gene expression. Both
      pathways require LIPL-4 lysosomal localization (signal peptide dependent).
    molecular_function:
      id: GO:0004806
      label: triacylglycerol lipase activity
    directly_involved_in:
      - id: GO:0016239
        label: positive regulation of macroautophagy
      - id: GO:0008340
        label: determination of adult lifespan
    locations:
      - id: GO:0043202
        label: lysosomal lumen
    supported_by:
      - reference_id: PMID:23392608
        supporting_text: >-
          LIPL-4 overexpression is sufficient to not only enrich omega-6 PUFAs
          and activate autophagy, but also transcriptionally activate
          nutrient-responsive genes
      - reference_id: PMID:21906946
        supporting_text: >-
          autophagy is induced in animals overexpressing LIPL-4 and autophagy is
          required for their long life span
      - reference_id: PMID:25554789
        supporting_text: >-
          A transgenic strain (lipl-4 Tg) that constitutively expressed lipl-4 in
          the intestine had 55% mean lifespan increase compared to wild-type (WT)
          animals