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FLASH GENE

Symbol

ANGPTL4

contributors: mct/pgu - updated : 21-01-2018

HGNC name	angiopoietin-like 4
HGNC id	16039

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	virus associated
STRUCTURE	10.25 kb     7 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_139314 7 - 1967 NP_647475 45.2 406 - 2003 12707035 a mature peptide of 381 aa (26 - 406) for 43 kda NM_001039667 6 - 1853 NP_001034756 - 368 - 2003 12707035 a mature peptide of 343 aa (26 - 368) for 38.7 kda lacking an alternate in-frame exon compared to variant 1

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive intestine large intestine     moderately Homo sapiens   intestine small intestine     moderately Homo sapiens   liver       highly Homo sapiens Nervous nerve       highly Reproductive female system placenta     predominantly Urinary kidney nephron renal capsule glomerulus   Homo sapiens

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective adipose brown   highly Homo sapiens Connective bone

cells

System Cell Pubmed Species Stage Rna symbol Digestive hepatocyte Lymphoid/Immune macrophage Homo sapiens not specific chondrocyte Homo sapiens

cell lineage
cell lines
fluid/secretion	circulating blood

at STAGE

physiological period

pregnancy

Text

placenta

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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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
	System Type Disorder Pubmed diabete     prime therapeutic candidate for the treatment of diabetic wounds cancer metastases   good therapeutic inhibitor of metastases cardiovascular atheroma   targeted silencing offers a potential therapeutic strategy for the treatment of dyslipidemia and atherosclerosis metabolism lipid triglyceride therapeutic antibodies that neutralize ANGPTL4 and ANGPTL3 may be useful for treatment of some forms of hyperlipidemia neurosensorial visual   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