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FLASH GENE
Symbol ANGPTL3 contributors: mct/npt/pgu - updated : 06-06-2016
HGNC name angiopoietin-like 3
HGNC id 491
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • a 19 AAs N terminal signal sequence, with a trimeric coiled-coil (CLD)
  • a short linker
  • a globular fibrinogen homology domain (FHD) with four cysteine residues implicated in intramolecular disulfide bonds
  • two potential N-glycosylation sites
  • a C-terminal fibrinogen (FBN)-like domain mediating binding to the TIE2 receptor and regulating blood vessel formation
    • secondary structure
  • an extended helical domain predicted to form dimeric or trimeric coiled-coils
    • conjugated GlycoP
    isoforms Precursor a mature protein of 441 aa for 51.5 kda
    HOMOLOGY
    interspecies homolog to murine Angptl3
    homolog to rattus Angptl3
    homolog to zebrafish angptl3
    intraspecies paralog to ANGPTL8
    Homologene
    FAMILY
  • angiopoietin-like family
    • CATEGORY adhesion , regulatory , signaling growth factor
    SUBCELLULAR LOCALIZATION extracellular
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,organelle,endosome
    basic FUNCTION
  • regulating positively lipid metabolism (activating the lipolysis to stimulate the release of free fatty acid and glycerol from adipocytes)
  • playing a role in the positive regulation of angiogenesis
  • acting as an enzyme inhibitor (inhibiting the activity of lipoprotein lipase)
  • acting as an inhibitor of endothelial lipase and may be involved in the regulation of plasma HDL cholesterol and HDL-phospholipid levels
  • ANGPTL3, 4, and ANGPTL6/angiopoietin-related growth factor also appear to directly regulate lipid, glucose, and energy metabolism independently of angiogenic effects
  • play important roles in modulating lipoprotein metabolism in the body
  • ANGPTL3, ANGPTL4, and ANGPTL5, but not ANGPTL6, play nonredundant roles in triglyceride metabolism
  • involved in cell-matrix adhesion
  • secreted protein that regulate triglyceride (TG) metabolism in part by inhibiting lipoprotein lipase (LPL)
  • ANGPTL3, ANGPTL4, and possibly ANGPTL5 are regulators of lipoprotein metabolism
  • enhances LPL cleavage in the presence of either heparan sulfate proteoglycans or glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1)
  • ANGPTL3 inhibits lipoprotein lipase activity through enhancing its cleavage by PCSK5
  • capable of regulating the motility and permeability of podocytes and the mechanism of its regulation could be associated with the altered expression of nephrin
  • could be involved in proteinuria development and in podocyte injury
  • plays an important role in regulating the expression of nephrin in pathologic conditions
  • ANGPTL3, -4 and ANGPTL6/angiopoietin-related growth factor (AGF) directly regulate lipid, glucose and energy metabolism independent of angiogenic effects
  • act through its coiled-coil domains to enhance survival and replating capacity of human cord blood hematopoietic progenitors
  • possible role of ANGPTL3 at the crossroads of lipoproteins, fatty acids, and glucose metabolism
  • might play a crucial role in podocyte injury
  • inhibits two intravascular lipases, LPL and endothelial lipase, and the low plasma TG and HDL-cholesterol levels in ANGPTL3 deficiency reflect increased activity of these enzymes
  • plays a major role in promoting uptake of circulating very low density lipoprotein-triglycerides (VLDL-TGs) into white adipose tissue (WAT) rather than oxidative tissues (skeletal muscle, heart brown adipose tissue) in the fed state
  • regulates adipose tissue energy homeostasis
  • plays an important role in angiogenesis
  • secretory protein regulating plasma lipid levels via affecting lipoprotein lipase- and endothelial lipase-mediated hydrolysis of triglycerides and phospholipids
    • CELLULAR PROCESS cell migration & motility
    PHYSIOLOGICAL PROCESS development
    text
  • angiogenesis
  • positive regulation of cell migration
    • PATHWAY
    metabolism lipid/lipoprotein
    signaling signal transduction
  • integrin-mediated signaling pathway
  • lipid catabolism, triacylglycerol metabolism
    • a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • ITGAV
  • ITGB3
  • inhibit LPL activity through distinct mechanisms
  • potent inhibitor of LPL
  • FURIN is the primary convertase of ANGPTL3 and endothelial lipase in hepatocytes
  • ANGPTL8 also called betatrophin is a regulator of lipid metabolism through its interaction with ANGPTL3
  • ANGPTL8 has a functional LPL inhibitory motif, but only inhibits LPL and increases plasma TG levels in the presence of ANGPTL3
  • ANGPTL8 requires another member of the ANGPTL family, ANGPTL3, to act on LPL
  • ANGPTL3, much like ANGPTL4, is a physiologically relevant regulator of LPL activity, which causes irreversible inactivation of the enzyme
    • cell & other
    REGULATION
    activated by cleavage
    induced by LXR- or retinoid X receptor-selective agonists
    ASSOCIATED DISORDERS
    corresponding disease(s) FHBL2
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    significantly increased podocyte motility, and dramatically increased the expression of nephrin
    tumoral     --over  
    in esophageal cancer tissues
    constitutional       loss of function
    does not affect the number of APOB-containing lipoproteins secreted by the liver but alters the particles that are made such that they are cleared more rapidly from the circulation via a noncanonical pathway(s)
    constitutional     --over  
    in glomerular podocytes of nephrotic syndrome
    constitutional       loss of function
    results in very low levels of LDL-cholesterol (C), HDL-C and triglyceride (TAG)
    Susceptibility atherosclerosis, coronary artery disease, diabetes mellitus
    Variant & Polymorphism
    Candidate gene
    Marker
  • association of ANGPTL3 expression with the prognosis of subgroups of patients with esophageal cancer
    • Therapy target
    SystemTypeDisorderPubmed
    metabolismlipidcholesterol
    therapeutic antibodies that neutralize ANGPTL4 and ANGPTL3 may be useful for treatment of some forms of hyperlipidemia
    metabolismlipid 
    potential therapeutic target to treat combined hyperlipidemia, a major risk factor for atherosclerotic coronary heart disease
    ANIMAL & CELL MODELS
    KK obese mouse