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ANGPTL4
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 6EUB, 6U0A, 6U1U, 6U73
Identifiers
Aliases	ANGPTL4, ANGPTL2, ARP4, FIAF, HARP, HFARP, NL2, PGAR, TGQTL, UNQ171, pp1158, angiopoietin like 4
External IDs	OMIM: 604774, 605910; MGI: 1888999; HomoloGene: 10755; GeneCards: ANGPTL4; OMA:ANGPTL4 - orthologs
Gene location (Human) Chr. Chromosome 19 (human) Band 19p13.2 Start 8,363,289 bp End 8,374,370 bp
Gene location (Mouse) Chr. Chromosome 17 (mouse) Band 17|17 B1 Start 33,992,724 bp End 34,000,804 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in pericardium beta cell sural nerve subcutaneous adipose tissue right lobe of liver vena cava saphenous vein body of pancreas gastric mucosa cartilage tissue Top expressed in brown adipose tissue white adipose tissue tunica adventitia of aorta left lobe of liver subcutaneous adipose tissue lactiferous gland external carotid artery mesenteric lymph nodes right lung lobe proximal tubule More reference expression data BioGPS More reference expression data
Gene ontology Molecular function enzyme inhibitor activity protein binding identical protein binding Cellular component extracellular region blood microparticle extracellular space Biological process multicellular organism development negative regulation of lipoprotein lipase activity cell differentiation negative regulation of endothelial cell apoptotic process negative regulation of apoptotic process response to hypoxia protein homooligomerization angiogenesis triglyceride homeostasis positive regulation of angiogenesis regulation of lipid metabolic process lipid metabolism Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 51129 57875 Ensembl ENSG00000167772 ENSMUSG00000002289 UniProt Q9BY76 Q9Z1P8 RefSeq (mRNA) NM_001039667 NM_016109 NM_139314 NM_020581 RefSeq (protein) NP_001034756 NP_647475 NP_065606 Location (UCSC) Chr 19: 8.36 – 8.37 Mb Chr 17: 33.99 – 34 Mb PubMed search
Wikidata
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Angiopoietin-like 4 is a protein that in humans is encoded by the ANGPTL4 gene. Alternatively spliced transcript variants encoded with different isoforms have been described. This gene was previously referred to as ANGPTL2, HFARP, PGAR, or FIAF but has been renamed ANGPTL4.

This gene is induced under hypoxic (low oxygen) condition in various cell types and is the target of peroxisome proliferator-activated receptors. The encoded protein is a serum hormone directly involved in regulating lipid metabolism.

ANGPTL4 plays an important role in numerous cancers and is implicated in the metastatic process by modulating vascular permeability, cancer cell motility and invasiveness.

Name

The former name, FIAF, stands for Fasting-Induced Adipose Factor.

Structure

This gene is a member of the angiopoietin-like gene family and encodes a glycosylated, secreted protein with a coiled-coil N-terminal domain and a fibrinogen-like C-terminal domain.

Expression

In mice, the highest mRNA expression levels of ANGPTL4 are found in white and brown adipose tissue, followed by liver, kidney, muscle and intestinal tissues. Human ANGPTL4 is most highly expressed in the liver as a hepatokine.

Function

This gene is induced under hypoxic (low oxygen) condition in various cell types and is the target of peroxisome proliferator-activated receptors. The encoded protein is a serum hormone directly involved in regulating lipid metabolism. The native full length ANGPTL4 can form higher order structures via intermolecular disulfide bonds. The N-terminal region of ANGPTL4 (nANGPTL4) is responsible for its assembly. The full length ANGPTL4 undergoes proteolytic cleavage at the linker region, releasing nANGPTL4 and the monomeric C-terminal portion of ANGPTL4 (cANGPTL4). The nANGPTL4 and cANGPTL4 have different biological functions. Monoclonal antibodies targeting the nANGPTL4 and cANGPTL4 have been developed to distinguish their functions.

Clinical significance

ANGPTL4 plays an important role in numerous cancers and is implicated in the metastatic process by modulating vascular permeability, cancer cell motility and invasiveness. ANGPTL4 contributes to tumor growth and protects cells from anoikis, a form of programmed cell death induced when contact-dependent cells detach from the surrounding tissue matrix. ANGPTL4 secreted from tumors can bind to integrins, activating downstream signaling and leading to the production of superoxide to promote tumorigenesis. ANGPTL4 disrupts endothelial cell junctions by directly interacting with integrin, VE-cadherin and claudin-5 in a sequential manner to facilitate metastasis. ANGPTL4, specifically the C-terminal fragment (cANGPTL4), is a key player that coordinates an increase in cellular energy flux crucial for epithelial-mesenchymal transition (EMT) via an ANGPTL4:YWHAG (14-3-3γ) signaling axis. The ANGPTL4:YWHAG signaling axis confers metabolic flexibility and enhances EMT competency through interaction with specific phosphorylation signals on target proteins. A direct consequence is that ANGPTL4 secures ample cellular energy to fuel multiple ABC transporters to confer EMT-mediated chemoresistance.

ANGPTL4 functions as a matricellular protein to facilitate skin wound healing. ANGPTL4-deficient mice exhibit delayed wound reepithelialization with impaired keratinocyte migration, angiogenesis and altered inflammatory response. ANGPTL4 induces nitric oxide production through an integrin/JAK/STAT3-mediated upregulation of iNOS expression in wound epithelia, and enhances angiogenesis to accelerate wound healing in diabetic mice. ANGPTL4 induces a β-catenin-mediated upregulation of ID3 in fibroblasts to reduce scar collagen expression. ANGPTL4 is capable of reversing the fibroblast-to-myofibroblast differentiation induced aligned electrospun fibrous substrates. Cyclic stretching of human tendon fibroblasts stimulated the expression and release of ANGPTL4 protein via TGF-β and HIF-1α signalling, and the released ANGPTL4 was pro-angiogenic. ANGPTL4 is also a potent angiogenic factor whose expression is up-regulated in hypoxic retinal Müller cells in vitro and the ischemic retina in vivo. The expression of ANGPTL4 was increased in the aqueous and vitreous of proliferative diabetic retinopathy patients and localized to areas of retinal neovascularization.

ANGPTL4 has been established as a potent inhibitor of serum triglyceride (TG) clearance, causing elevation of serum TG levels via inhibition of the enzyme lipoprotein lipase (LPL). Biochemical studies indicate that ANGPTL4 disables LPL partly by dissociating the catalytically active LPL dimer into inactive LPL monomers. However, evidence also suggests that ANGPTL4 functions as a conventional, non-competitive inhibitor that binds to LPL to prevent the hydrolysis of substrate as part of reversible mechanism. As a consequence, ANGPTL4 knockout mice have reduced serum triglyceride levels, whereas the opposite is true for mice over-expressing ANGPTL4. ANGPTL4 suppresses foam cell formation to reduce atherosclerosis development. The reduction in LPL activity in adipose tissue during fasting is likely caused by increased local production of ANGPTL4. In other tissues such as heart, production of ANGPTL4 is stimulated by fatty acids and may serve to protect cells against excess fat uptake. ANGPTL4 is more highly induced in nonexercising muscle than in exercising human muscle during acute exercise. ANGPTL4 in nonexercising muscle presumably leads to reduced local uptake of plasma triglyceride-derived fatty acids and their sparing for use by exercising muscle. The induction of ANGPTL4 in exercising muscle likely is counteracted via AMP-activated protein kinase (AMPK)-mediated down-regulation, promoting the use of plasma triglycerides as fuel for active muscles.

High-throughput RNA sequencing of lung tissue samples from the 1918 and 2009 influenza pandemic revealed that ANGPTL4 was one of the most significantly upregulated gene. Murine influenza infection of the lungs stimulated the expression of ANGPTL4 via a STAT3-mediated mechanism. ANGPTL4 enhanced pulmonary tissue leakiness and exacerbated inflammation-induced lung damage. Influenza-infected ANGPTL4-knockout mice displayed diminished lung damage and recovered faster from the infection compared to wild-type mice. The treatment of infected mice with neutralizing anti-ANGPTL4 antibodies significantly accelerated pulmonary recovery and improved lung tissue integrity. It was also shown that antibody treatment against ANGPTL4 reduces pulmonary edema and injury in secondary pneumococcal pneumonia.

References

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2. ^ GRCm38: Ensembl release 89: ENSMUSG00000002289 – Ensembl, May 2017
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4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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7. Kersten S, Mandard S, Tan NS, Escher P, Metzger D, Chambon P, et al. (September 2000). "Characterization of the fasting-induced adipose factor FIAF, a novel peroxisome proliferator-activated receptor target gene" (PDF). The Journal of Biological Chemistry. 275 (37): 28488–93. doi:10.1074/jbc.M004029200. PMID 10862772.
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9. ^ Kim SH, Park YY, Kim SW, Lee JS, Wang D, DuBois RN (November 2011). "ANGPTL4 induction by prostaglandin E2 under hypoxic conditions promotes colorectal cancer progression". Cancer Research. 71 (22): 7010–20. doi:10.1158/0008-5472.CAN-11-1262. PMC 3217078. PMID 21937683.
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12. Desai U, Lee EC, Chung K, Gao C, Gay J, Key B, et al. (July 2007). "Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice". Proceedings of the National Academy of Sciences of the United States of America. 104 (28): 11766–71. Bibcode:2007PNAS..10411766D. doi:10.1073/pnas.0705041104. PMC 1913890. PMID 17609370.
13. ^ Zhu P, Tan MJ, Huang RL, Tan CK, Chong HC, Pal M, et al. (March 2011). "Angiopoietin-like 4 protein elevates the prosurvival intracellular O2(-):H2O2 ratio and confers anoikis resistance to tumors". Cancer Cell. 19 (3): 401–15. doi:10.1016/j.ccr.2011.01.018. hdl:10220/8177. PMID 21397862.
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15. Huang RL, Teo Z, Chong HC, Zhu P, Tan MJ, Tan CK, et al. (October 2011). "ANGPTL4 modulates vascular junction integrity by integrin signaling and disruption of intercellular VE-cadherin and claudin-5 clusters". Blood. 118 (14): 3990–4002. doi:10.1182/blood-2011-01-328716. PMID 21841165.
16. Teo Z, Sng MK, Chan JS, Lim MM, Li Y, Li L, et al. (November 2017). "Elevation of adenylate energy charge by angiopoietin-like 4 enhances epithelial-mesenchymal transition by inducing 14-3-3γ expression". Oncogene. 36 (46): 6408–6419. doi:10.1038/onc.2017.244. PMC 5701092. PMID 28745316.
17. Tan ZW, Teo Z, Tan C, Choo CC, Loo WS, Song Y, et al. (October 2017). "ANGPTL4 T266M variant is associated with reduced cancer invasiveness". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1864 (10): 1525–1536. doi:10.1016/j.bbamcr.2017.06.010. hdl:10220/44354. PMID 28641978.
18. Lim MM, Wee JW, Soong JC, Chua D, Tan WR, Lizwan M, et al. (October 2018). "Targeting metabolic flexibility via angiopoietin-like 4 protein sensitizes metastatic cancer cells to chemotherapy drugs". Molecular Cancer. 17 (1): 152. doi:10.1186/s12943-018-0904-z. PMC 6195749. PMID 30342537.
19. Chong HC, Tan CK, Huang RL, Tan NS (Feb 2012). "Matricellular proteins: a sticky affair with cancers". Journal of Oncology. 2012: 351089. doi:10.1155/2012/351089. PMC 3306981. PMID 22481923.
20. Goh YY, Pal M, Chong HC, Zhu P, Tan MJ, Punugu L, et al. (December 2010). "Angiopoietin-like 4 interacts with integrins beta1 and beta5 to modulate keratinocyte migration". The American Journal of Pathology. 177 (6): 2791–803. doi:10.2353/ajpath.2010.100129. PMC 2993291. PMID 20952587.
21. Goh YY, Pal M, Chong HC, Zhu P, Tan MJ, Punugu L, et al. (October 2010). "Angiopoietin-like 4 interacts with matrix proteins to modulate wound healing". The Journal of Biological Chemistry. 285 (43): 32999–3009. doi:10.1074/jbc.M110.108175. PMC 2963335. PMID 20729546.
22. Chong HC, Chan JS, Goh CQ, Gounko NV, Luo B, Wang X, et al. (September 2014). "Angiopoietin-like 4 stimulates STAT3-mediated iNOS expression and enhances angiogenesis to accelerate wound healing in diabetic mice". Molecular Therapy. 22 (9): 1593–604. doi:10.1038/mt.2014.102. PMC 4435481. PMID 24903577.
23. Teo Z, Chan JS, Chong HC, Sng MK, Choo CC, Phua GZ, et al. (July 2017). "Angiopoietin-like 4 induces a β-catenin-mediated upregulation of ID3 in fibroblasts to reduce scar collagen expression". Scientific Reports. 7 (1): 6303. Bibcode:2017NatSR...7.6303T. doi:10.1038/s41598-017-05869-x. PMC 5524754. PMID 28740178.
24. Chen H, Lui YS, Tan ZW, Lee JY, Tan NS, Tan LP (May 2019). "Migration and Phenotype Control of Human Dermal Fibroblasts by Electrospun Fibrous Substrates". Advanced Healthcare Materials. 8 (9): e1801378. doi:10.1002/adhm.201801378. PMID 30901162. S2CID 85448471.
25. Mousavizadeh R, Scott A, Lu A, Ardekani GS, Behzad H, Lundgreen K, et al. (June 2016). "Angiopoietin-like 4 promotes angiogenesis in the tendon and is increased in cyclically loaded tendon fibroblasts". The Journal of Physiology. 594 (11): 2971–83. doi:10.1113/JP271752. PMC 4887665. PMID 26670924.
26. Babapoor-Farrokhran S, Jee K, Puchner B, Hassan SJ, Xin X, Rodrigues M, et al. (June 2015). "Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy". Proceedings of the National Academy of Sciences of the United States of America. 112 (23): E3030-9. Bibcode:2015PNAS..112E3030B. doi:10.1073/pnas.1423765112. PMC 4466723. PMID 26039997.
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30. Georgiadi A, Lichtenstein L, Degenhardt T, Boekschoten MV, van Bilsen M, Desvergne B, et al. (June 2010). "Induction of cardiac Angptl4 by dietary fatty acids is mediated by peroxisome proliferator-activated receptor beta/delta and protects against fatty acid-induced oxidative stress". Circulation Research. 106 (11): 1712–21. doi:10.1161/CIRCRESAHA.110.217380. PMID 20378851.
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33. Li L, Chong HC, Ng SY, Kwok KW, Teo Z, Tan EH, et al. (February 2015). "Angiopoietin-like 4 Increases Pulmonary Tissue Leakiness and Damage during Influenza Pneumonia". Cell Reports. 10 (5): 654–663. doi:10.1016/j.celrep.2015.01.011. PMC 7185373. PMID 25660016.
34. Li L, Foo BJ, Kwok KW, Sakamoto N, Mukae H, Izumikawa K, et al. (June 2019). "Antibody Treatment against Angiopoietin-Like 4 Reduces Pulmonary Edema and Injury in Secondary Pneumococcal Pneumonia". mBio. 10 (3). doi:10.1128/mBio.02469-18. PMC 6550533. PMID 31164474.

External links

• Human ANGPTL4 genome location and ANGPTL4 gene details page in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: Q9BY76 (Angiopoietin-related protein 4) at the PDBe-KB.

Further reading

• Alex S, Lichtenstein L, Dijk W, Mensink RP, Tan NS, Kersten S (April 2014). "ANGPTL4 is produced by entero-endocrine cells in the human intestinal tract". Histochemistry and Cell Biology. 141 (4): 383–91. doi:10.1007/s00418-013-1157-y. PMID 24141811. S2CID 15092480.
• Grootaert C, Van de Wiele T, Verstraete W, Bracke M, Vanhoecke B (April 2012). "Angiopoietin-like protein 4: health effects, modulating agents and structure-function relationships". Expert Review of Proteomics. 9 (2): 181–99. doi:10.1586/epr.12.12. PMID 22462789. S2CID 5242622.
• Terada LS, Nwariaku FE (March 2011). "Escaping Anoikis through ROS: ANGPTL4 controls integrin signaling through Nox1". Cancer Cell. 19 (3): 297–9. doi:10.1016/j.ccr.2011.02.019. PMID 21397852.
• Pal M, Tan MJ, Huang RL, Goh YY, Wang XL, Tang MB, et al. (2011). "Angiopoietin-like 4 regulates epidermal differentiation". PLOS ONE. 6 (9): e25377. Bibcode:2011PLoSO...625377P. doi:10.1371/journal.pone.0025377. PMC 3178651. PMID 21966511.
• Lichtenstein L, Mattijssen F, de Wit NJ, Georgiadi A, Hooiveld GJ, van der Meer R, et al. (December 2010). "Angptl4 protects against severe proinflammatory effects of saturated fat by inhibiting fatty acid uptake into mesenteric lymph node macrophages". Cell Metabolism. 12 (6): 580–92. doi:10.1016/j.cmet.2010.11.002. PMC 3387545. PMID 21109191.
• Lichtenstein L, Berbée JF, van Dijk SJ, van Dijk KW, Bensadoun A, Kema IP, et al. (November 2007). "Angptl4 upregulates cholesterol synthesis in liver via inhibition of LPL- and HL-dependent hepatic cholesterol uptake". Arteriosclerosis, Thrombosis, and Vascular Biology. 27 (11): 2420–7. doi:10.1161/ATVBAHA.107.151894. PMID 17761937.
• Kersten S (November 2005). "Regulation of lipid metabolism via angiopoietin-like proteins" (PDF). Biochemical Society Transactions. 33 (Pt 5): 1059–62. doi:10.1042/BST20051059. PMID 16246045.
• Le Jan S, Amy C, Cazes A, Monnot C, Lamandé N, Favier J, et al. (May 2003). "Angiopoietin-like 4 is a proangiogenic factor produced during ischemia and in conventional renal cell carcinoma". The American Journal of Pathology. 162 (5): 1521–8. doi:10.1016/S0002-9440(10)64285-X. PMC 1851201. PMID 12707035.
• Mandard S, Zandbergen F, Tan NS, Escher P, Patsouris D, Koenig W, et al. (August 2004). "The direct peroxisome proliferator-activated receptor target fasting-induced adipose factor (FIAF/PGAR/ANGPTL4) is present in blood plasma as a truncated protein that is increased by fenofibrate treatment" (PDF). The Journal of Biological Chemistry. 279 (33): 34411–20. doi:10.1074/jbc.M403058200. PMID 15190076.
• Xu A, Lam MC, Chan KW, Wang Y, Zhang J, Hoo RL, et al. (April 2005). "Angiopoietin-like protein 4 decreases blood glucose and improves glucose tolerance but induces hyperlipidemia and hepatic steatosis in mice". Proceedings of the National Academy of Sciences of the United States of America. 102 (17): 6086–91. Bibcode:2005PNAS..102.6086X. doi:10.1073/pnas.0408452102. PMC 1087912. PMID 15837923.
• Hermann LM, Pinkerton M, Jennings K, Yang L, Grom A, Sowders D, et al. (April 2005). "Angiopoietin-like-4 is a potential angiogenic mediator in arthritis". Clinical Immunology. 115 (1): 93–101. doi:10.1016/j.clim.2004.12.002. PMID 15870027.
• Zhang R (April 2016). "The ANGPTL3-4-8 model, a molecular mechanism for triglyceride trafficking". Open Biology. 6 (4): 150272. doi:10.1098/rsob.150272. PMC 4852456. PMID 27053679.

• Genes on human chromosome 19