LIPG

LIPG encodes endothelial lipase, a cell surface-associated member of the triglyceride lipase family that functions principally as a phospholipase A1 hydrolyzing phosphatidylcholine in HDL, and whose activity governs plasma HDL cholesterol levels in humans and mice (PMID:19436067, PMID:33028621). Both rare and common noncoding regulatory variants in the LIPG promoter and 5' UTR alter promoter activity and track with circulating endothelial lipase protein and HDL-C (PMID:22174694). At the endothelial surface, the enzyme mediates binding, uptake, and transcytosis of both LDL and HDL across aortic endothelial cells; its catalytic activity is required for lipoprotein transport but not for surface association, it acts sequentially with SR-BI for LDL but independently for HDL, and ANGPTL3 selectively inhibits its LDL transcytosis. In hepatocytes its LDL uptake activity depends on heparan sulfate proteoglycans and on its enzymatic function, sufficient to rescue uptake in LDLR-knockout cells. Beyond lipoprotein metabolism, LIPG has a prominent role in cancer cell lipid acquisition: driven by FoxA1/FoxA2 transcription factors, it imports extracellular lipid precursors that fuel intracellular lipid synthesis and tumor cell proliferation (PMID:27045898), and it is induced by oxidative-stress-triggered AMPK activation to drive lipid droplet accumulation supporting survival (PMID:30653260). In triple-negative breast cancer it possesses separable functions—a lipase-dependent activity supporting proliferation and a lipase-independent activity promoting invasiveness, stemness, and EMT—where its protein stability is maintained by the DTX3L E3 ubiquitin ligase via inhibition of proteasomal degradation and it participates in DTX3L-ISG15 interferon signaling (PMID:29350614); pharmacological inhibition of its phospholipase activity with XEN445 selectively blocks proliferative but not invasive phenotypes (PMID:32488004). Its expression is also post-transcriptionally repressed through a ZDHHC1/IGF2BP1 palmitoylation-dependent m6A axis that destabilizes LIPG mRNA (PMID:39069526).

1. 2004 Low

   Established LIPG as a triglyceride-lipase-family enzyme with phospholipase activity whose human genetic variation links it to HDL cholesterol regulation.

   Evidence Resequencing of LIPG across an ethnically diverse population with HDL-C association analysis

   PMID:14984737

   Open questions at the time

   • No direct in vitro enzymatic assay performed in this study
   • Functional role inferred from family membership and association, not causation
2. 2009 Medium

   Demonstrated that Lipg is the causal QTL gene controlling plasma HDL levels, moving the gene-HDL link from association to genetic causality.

   Evidence QTL mapping, haplotype analysis, and quantitative complementation across multiple mouse crosses

   PMID:19436067

   Open questions at the time

   • Mechanism by which Lipg sets HDL levels not resolved at molecular level
   • Single lab
3. 2011 Medium

   Identified the regulatory basis of LIPG-driven HDL variation by showing noncoding promoter/5' UTR variants alter promoter activity and protein levels.

   Evidence Resequencing, luciferase reporter assays, and association with plasma EL protein and HDL-C

   PMID:22174694

   Open questions at the time

   • Does not address enzymatic mechanism on lipoproteins
   • Causal variant effects shown in reporter context only
4. 2016 Medium

   Revealed a cancer-specific role: FoxA-driven LIPG imports extracellular lipid precursors to fuel lipid synthesis and breast cancer proliferation.

   Evidence LIPG and FoxA knockdown in breast cancer lines with proliferation, lipid synthesis, and lipidomic readouts

   PMID:27045898

   Open questions at the time

   • Mechanism of precursor import not biochemically defined
   • Single lab
5. 2018 Medium

   Separated LIPG into lipase-dependent (proliferation) and lipase-independent (invasion/stemness/EMT) functions and identified DTX3L as a stabilizer linking LIPG to ISG15 interferon signaling.

   Evidence In vivo tumorigenicity/metastasis assays, lipase-dead mutants, proteasome inhibition, Co-IP, and siRNA knockdown

   PMID:29350614

   Open questions at the time

   • Molecular basis of the lipase-independent function unresolved
   • DTX3L-LIPG interaction shown by Co-IP without reciprocal structural validation
6. 2019 Medium

   Connected LIPG to stress adaptation by showing oxidative-stress-induced AMPK activation upregulates LIPG to drive protective lipid droplet accumulation.

   Evidence Oxidative stress induction with AMPK measurement, LIPG expression, lipid droplet quantification, and stress neutralization in breast cancer cells

   PMID:30653260

   Open questions at the time

   • Direct transcriptional link between AMPK and LIPG not defined
   • Single lab
7. 2020 Medium

   Confirmed LIPG as a cell-surface phospholipase A1 acting on HDL phosphatidylcholine and extended its tumor role to leukemia via PUFA signaling and antiapoptotic protein stabilization.

   Evidence Liver microenvironment co-culture, PUFA pathway analysis, and apoptotic protein stability assays

   PMID:33028621

   Open questions at the time

   • PUFA-mediated signaling pathway not fully delineated
   • Single lab
8. 2020 Medium

   Pharmacologically dissected LIPG functions, showing its enzymatic activity drives proliferation and CSC self-renewal but not invasiveness.

   Evidence XEN445 enzymatic inhibition of TNBC vs luminal lines, in vitro CSC self-renewal, and in vivo tumor formation assays

   PMID:32488004

   Open questions at the time

   • Substrate consumed in proliferative phenotype not identified
   • Lipase-independent invasion mechanism remains undefined
9. 2024 Medium

   Identified post-transcriptional control of LIPG through a ZDHHC1/IGF2BP1 palmitoylation-m6A axis that destabilizes LIPG mRNA and suppresses colorectal cancer growth.

   Evidence ZDHHC1 perturbation, IGF2BP1 C337 palmitoylation-site mutagenesis, m6A and mRNA stability assays, in vitro/in vivo phenotypes

   PMID:39069526

   Open questions at the time

   • Generality of this regulatory axis across tissues not established
   • Single lab
10. 2025 Medium

    Established LIPG as a transcytosis machine for both LDL and HDL across endothelium, with catalysis required for transport, distinct SR-BI coordination, and selective ANGPTL3 regulation.

    Evidence EL overexpression/knockdown in primary human aortic endothelial cells, fluorescent lipoprotein transport assays, enzymatic inhibition, SR-BI co-perturbation, ex vivo bovine aorta assay (preprint)

    Open questions at the time

    • Preprint, not yet peer-reviewed
    • Mechanistic coupling between catalysis and transcytosis not resolved
11. 2025 Medium

    Demonstrated that EL-mediated LDL uptake is heparan-sulfate-proteoglycan- and enzymatic-activity-dependent and can substitute for LDLR in hepatocytes.

    Evidence LIPG overexpression in LDLR-KO HepG2 cells, FACS LDL uptake, heparin/heparinase treatment, tetrahydrolipstatin inhibition (preprint)

    Open questions at the time

    • Preprint, not yet peer-reviewed
    • Physiological contribution of HSPG-dependent uptake relative to LDLR in vivo not quantified

• The molecular basis of LIPG's lipase-independent functions and the structural mechanism coupling its phospholipase activity to lipoprotein uptake/transcytosis remain unresolved.
• No structural model linking catalysis to transcytosis
• Lipase-independent invasion/stemness mechanism uncharacterized
• Identity of imported lipid species fueling cancer proliferation not fully defined