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FLASH GENE
Symbol ANGPTL4 contributors: mct/pgu - updated : 21-01-2018
HGNC name angiopoietin-like 4
HGNC id 16039
PROTEIN
PHYSICAL PROPERTIES Hydrophobic
STRUCTURE
motifs/domains
  • a N-terminal coiled-coil domain, binding transiently to LPL and this interaction results in the conversion of the enzyme from catalytically active dimers to an inactive
  • a 25 aa secretory signal peptide
  • three potential N-glycosylation sites
  • four cysteines involved in intramolecular disulfide bonding
  • a C-terminal fibrinogen like domain
    • conjugated GlycoP
    mono polymer homomer , dimer , tetramer , oligo
    isoforms Precursor the homooligomer undergoes proteolytic processing to release its carboxyl fibrinogen-like domain, which circulates as a monomer
    HOMOLOGY
    interspecies ortholog to rattus Angptl4
    ortholog to murine Angptl4
    intraspecies homolog to ANGPT2
    Homologene
    FAMILY
  • vascular endothelial growth factors family
  • angiopoietin family
    • CATEGORY regulatory , signaling hormone growth factor
    SUBCELLULAR LOCALIZATION extracellular
    text secreted protein
    basic FUNCTION
  • acting as an apoptosis survival factor for vascular endothelial cells through an endocrine action (negative regulation of apoptosis)
  • might modulate cartilage metabolism by regulating MMPs
  • ANGPTL3, ANGPTL4, and ANGPTL5, but not ANGPTL6, play nonredundant roles in triglyceride metabolism
  • directly regulates lipid, glucose and energy metabolism independently of angiogenic effects
  • acting as a positive regulator of angiogenesis
  • modulating tumorgenesis
  • inhibiting proliferation, migration, and tubule formation of endothelial cells and reducing vascular leakage
  • involved in regulating glucose homeostasis, systemic lipid metabolism (positive regulation of lipid metabolism), and insulin sensitivity
  • acting as an enzyme inhibitor for the lipoprotein lipase
  • playing a role in the reponse to hypoxia
  • through its action on both vascular and tumor compartments, prevents the metastatic process by inhibiting vascular activity as well as tumor cell motility and invasiveness
  • ANGPTL3, 4, and ANGPTL6/angiopoietin-related growth factor also appear to directly regulate lipid, glucose, and energy metabolism independently of angiogenic effects
  • regulate lipid metabolism mainly by inhibiting LPL activity
  • may also act as an inhibitor of endothelial lipase
  • modulates the disposition of circulating triglycerides by inhibiting LPL, upon oligomerization
  • play important roles in modulating lipoprotein metabolism in the body
  • secreted protein that regulate triglyceride (TG) metabolism in part by inhibiting lipoprotein lipase (LPL)
  • ANGPTL3, ANGPTL4, and possibly ANGPTL5 are regulators of lipoprotein metabolism
  • role during wound healing and stimulates intracellular signaling mechanisms to coordinate cellular behavior
  • podocyte-secreted ANGPTL4 is involved in proteinuria, and has potentially a key role in nephrotic syndrome
  • ANGPTL3, -4 and ANGPTL6/angiopoietin-related growth factor (AGF) directly regulate lipid, glucose and energy metabolism independent of angiogenic effects
  • endogenous inhibitor of lipoprotein lipase (LPL), and modulates lipid deposition and energy homeostasis
  • one of the factors involved in the progression of human colorectal cancer, especially venous invasion and distant metastasis
  • plays an important role in protecting macrophages in mesenteric lymph nodes from the toxic effects of dietary saturated fat
  • ANGPTL4 and ANGPTL5 can lead to increased engraftment capacity of NOD/SCID-repopulating cells (SRCs)
  • is a genetically and epigenetically inactivated secreted tumor suppressor that inhibits tumor angiogenesis
  • may play an important role in promoting vessel permeability in ischemic retinopathies
  • secreted factor involved in regulation of lipid homeostasis
  • promotes cartilage matrix remodeling by inhibiting expression of its two key components and by up-regulating the level of certain MMPs
  • nonexercising muscle and the local regulation of ANGPTL4 via AMPK and free fatty acids have key roles in governing lipid homeostasis during exercise
  • is an important regulator of plasma lipid partitioning during sustained cold
  • promotes angiogenesis in tendon and is increased in cyclically loaded tendon fibroblasts
    • CELLULAR PROCESS cell life, differentiation
    cell life, antiapoptosis
    PHYSIOLOGICAL PROCESS development
    text
  • glucose homeostasis
  • angiogenesis
    • PATHWAY
    metabolism lipid/lipoprotein
    signaling hormonal
    a component
  • forming dimer and tetramer before secretion and cleavage of the protein
    • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • inhibit LPL activity through distinct mechanisms
  • interacts with vitronectin and fibronectin in the wound bed, delaying their proteolytic degradation by metalloproteinases
  • ANGPTL4 induction by prostaglandin E2 under hypoxic conditions promotes colorectal cancer progression
  • binds to lipoprotein lipase (LPL) through its N-terminal coiled-coil domain (ccd-ANGPTL4) inducing dissociation of the dimeric enzyme to inactive monomers
  • is one of the major targets of PPARD in skeletal muscle cells
  • PPARD-ANGPTL4 pathway is involved in the regulation of tumor cell invasion
  • both NR3C1 and FOXO1 are required for ANGPTL4 transcription activation, and FOXO1 negatively mediates the suppressive effect of insulin
  • ANGPTL4 was capable of binding and inactivating LPL complexed to GPIHBP1 on the surface of endothelial cells, and inactivation of LPL by ANGPTL4 greatly reduces the affinity of LPL for GPIHBP1
  • LPL inhibition is made possible by a free fatty acids, FA-induced activation of PPARB/PPARD, which augments angiopoietin-like 4 (ANGPTL4), an inhibitor of LPL activity
  • inhibits lipoprotein lipase (LPL) activity
  • FTO bound to ANGPTL4, which encodes an adipokine that stimulates intracellular lipolysis in adipocytes
  • ANGPTL4 promotes PCSK1-mediated intracellular cleavage of LPL in adipocytes, likely contributing to regulation of LPL in adipose tissue
  • ANGPTL4 binds LPL near the active site at the lid domain and a nearby alpha-helix
  • ANGPTL4 specifically inhibits LPL by binding the lid domain, which could prevent substrate catalysis at the active site
  • ANGPTL8 may function as an important metabolic switch, by forming complexes with ANGPTL3, or with ANGPTL4, in order to direct the flow of energy from triglycerides in blood according to the needs of the body
    • cell & other
    REGULATION
    activated by glucocorticoids that increase ANGPTLl4 expression in adipose tissue, and could potentially increase levels in the circulation
    induced by PPARG ligand and hormone-dependant adipocyte differentiation
    hypoxic conditions in endothelial cells, and in both tumor and endothelial cells as well as in hypoxic perinecrotic areas of numerous cancers
    inflammatory saturated fatty acids
    high glucose in RPE cells and exhibited potent angiogenic activity on retinal endothelial (RE) cells
    Other produced by EEC in human intestine and expression may be regulated by short chain fatty acids and bile acids
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral        
    aberrant methylation of this gene is associated with human gastric cancers
    tumoral     --over  
    increased expression of the protein is associated with breast cancer metastasis to the lungs
    constitutional     --low  
    decreased expression of this protein is associated with type 2 diabetes
    constitutional     --low  
    protects against the development and progression of atherosclerosis
    constitutional     --over  
    higher in patients with the metabolic syndrome than in subjects without the metabolic syndrome
    constitutional     --low  
    in macrophages by TLR activators could lead to a variety of down-stream effects important in host defense and wound repair
    Susceptibility to lower plasma levels of triglyceride and higher levels of high-density lipoprotein cholesterol
    Variant & Polymorphism other
  • variant E40K increase suceptibility to the lower plasma levels of triglyceride and higher levels of high-density lipoprotein cholesterol
  • variant E40K destabilizes the protein after secretion, preventing the extracellular accumulation of oligomers and abolishing the ability of the protein to inhibit LPL activity
    • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    diabete  
    prime therapeutic candidate for the treatment of diabetic wounds
    cancermetastases 
    good therapeutic inhibitor of metastases
    cardiovascularatheroma 
    targeted silencing offers a potential therapeutic strategy for the treatment of dyslipidemia and atherosclerosis
    metabolismlipidtriglyceride
    therapeutic antibodies that neutralize ANGPTL4 and ANGPTL3 may be useful for treatment of some forms of hyperlipidemia
    neurosensorialvisual 
    could be an important target for the treatment of macular edema
    ANIMAL & CELL MODELS
  • Angptl4-deficient mice exhibit delayed wound reepithelialization with impaired keratinocyte migration