ANGPTL4 explained

Angiopoietin-like 4 is a protein that in humans is encoded by the ANGPTL4 gene.[1] [2] [3] 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.[4] [5] [6]

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.[7]

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.[7] Monoclonal antibodies targeting the nANGPTL4[8] and cANGPTL4[9] 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.[4] [5] [6] 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.[9] ANGPTL4 secreted from tumors can bind to integrins, activating downstream signaling and leading to the production of superoxide to promote tumorigenesis.[10] ANGPTL4 disrupts endothelial cell junctions by directly interacting with integrin, VE-cadherin and claudin-5 in a sequential manner to facilitate metastasis.[11] 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.[12] [13] 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.[14]

ANGPTL4 functions as a matricellular protein[15] to facilitate skin wound healing. ANGPTL4-deficient mice exhibit delayed wound reepithelialization with impaired keratinocyte migration, angiogenesis and altered inflammatory response.[16] [17] 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.[18] ANGPTL4 induces a β-catenin-mediated upregulation of ID3 in fibroblasts to reduce scar collagen expression.[19] ANGPTL4 is capable of reversing the fibroblast-to-myofibroblast differentiation induced aligned electrospun fibrous substrates.[20] 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.[21] 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.[22]

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.[23] 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.[24] 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.[25] 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.[26] 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.[27]

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.[28] 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.[29] It was also shown that antibody treatment against ANGPTL4 reduces pulmonary edema and injury in secondary pneumococcal pneumonia.[30]

Further reading

Notes and References

  1. Kim I, Kim HG, Kim H, Kim HH, Park SK, Uhm CS, Lee ZH, Koh GY . Hepatic expression, synthesis and secretion of a novel fibrinogen/angiopoietin-related protein that prevents endothelial-cell apoptosis . The Biochemical Journal . 346 . Pt 3 . 603–10 . March 2000 . 10698685 . 1220891 . 10.1042/0264-6021:3460603 .
  2. Yoon JC, Chickering TW, Rosen ED, Dussault B, Qin Y, Soukas A, Friedman JM, Holmes WE, Spiegelman BM . Peroxisome proliferator-activated receptor gamma target gene encoding a novel angiopoietin-related protein associated with adipose differentiation . Molecular and Cellular Biology . 20 . 14 . 5343–9 . July 2000 . 10866690 . 85983 . 10.1128/MCB.20.14.5343-5349.2000 .
  3. Kersten S, Mandard S, Tan NS, Escher P, Metzger D, Chambon P, Gonzalez FJ, Desvergne B, Wahli W . Characterization of the fasting-induced adipose factor FIAF, a novel peroxisome proliferator-activated receptor target gene . The Journal of Biological Chemistry . 275 . 37 . 28488–93 . September 2000 . 10862772 . 10.1074/jbc.M004029200 . free .
  4. Padua D, Zhang XH, Wang Q, Nadal C, Gerald WL, Gomis RR, Massagué J . TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4 . Cell . 133 . 1 . 66–77 . April 2008 . 18394990 . 2390892 . 10.1016/j.cell.2008.01.046 .
  5. Kim SH, Park YY, Kim SW, Lee JS, Wang D, DuBois RN . ANGPTL4 induction by prostaglandin E2 under hypoxic conditions promotes colorectal cancer progression . Cancer Research . 71 . 22 . 7010–20 . November 2011 . 21937683 . 3217078 . 10.1158/0008-5472.CAN-11-1262 .
  6. Adhikary T, Brandt DT, Kaddatz K, Stockert J, Naruhn S, Meissner W, Finkernagel F, Obert J, Lieber S, Scharfe M, Jarek M, Toth PM, Scheer F, Diederich WE, Reinartz S, Grosse R, Müller-Brüsselbach S, Müller R . Inverse PPARβ/δ agonists suppress oncogenic signaling to the ANGPTL4 gene and inhibit cancer cell invasion . Oncogene . 32 . 44 . 5241–52 . October 2013 . 23208498 . 3938163 . 10.1038/onc.2012.549 .
  7. Zhu P, Goh YY, Chin HF, Kersten S, Tan NS . Angiopoietin-like 4: a decade of research . Bioscience Reports . 32 . 3 . 211–9 . June 2012 . 22458843 . 10.1042/BSR20110102 . 10356/94662 . free .
  8. Desai U, Lee EC, Chung K, Gao C, Gay J, Key B, Hansen G, Machajewski D, Platt KA, Sands AT, Schneider M, Van Sligtenhorst I, Suwanichkul A, Vogel P, Wilganowski N, Wingert J, Zambrowicz BP, Landes G, Powell DR . 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 . July 2007 . 17609370 . 1913890 . 10.1073/pnas.0705041104 . 2007PNAS..10411766D . Machajewski D . free .
  9. Zhu P, Tan MJ, Huang RL, Tan CK, Chong HC, Pal M, Lam CR, Boukamp P, Pan JY, Tan SH, Kersten S, Li HY, Ding JL, Tan NS . Angiopoietin-like 4 protein elevates the prosurvival intracellular O2(-):H2O2 ratio and confers anoikis resistance to tumors . Cancer Cell . 19 . 3 . 401–15 . March 2011 . 21397862 . 10.1016/j.ccr.2011.01.018 . free . 10220/8177 . free .
  10. Tan MJ, Teo Z, Sng MK, Zhu P, Tan NS . Emerging roles of angiopoietin-like 4 in human cancer . Molecular Cancer Research . 10 . 6 . 677–88 . June 2012 . 22661548 . 10.1158/1541-7786.MCR-11-0519 . free . 10356/95626 . free .
  11. Huang RL, Teo Z, Chong HC, Zhu P, Tan MJ, Tan CK, Lam CR, Sng MK, Leong DT, Tan SM, Kersten S, Ding JL, Li HY, Tan NS . ANGPTL4 modulates vascular junction integrity by integrin signaling and disruption of intercellular VE-cadherin and claudin-5 clusters . Blood . 118 . 14 . 3990–4002 . October 2011 . 21841165 . 10.1182/blood-2011-01-328716 . free .
  12. Teo Z, Sng MK, Chan JS, Lim MM, Li Y, Li L, Phua T, Lee JY, Tan ZW, Zhu P, Tan NS . Elevation of adenylate energy charge by angiopoietin-like 4 enhances epithelial-mesenchymal transition by inducing 14-3-3γ expression . Oncogene . 36 . 46 . 6408–6419 . November 2017 . 28745316 . 5701092 . 10.1038/onc.2017.244 .
  13. Tan ZW, Teo Z, Tan C, Choo CC, Loo WS, Song Y, Tam ZY, Ng SP, Koh HZ, Ng YS, Shochat SG, Yau YH, Zhu P, Tan NS . ANGPTL4 T266M variant is associated with reduced cancer invasiveness . Biochimica et Biophysica Acta (BBA) - Molecular Cell Research . 1864 . 10 . 1525–1536 . October 2017 . 28641978 . 10.1016/j.bbamcr.2017.06.010 . free . 10220/44354 . free .
  14. Lim MM, Wee JW, Soong JC, Chua D, Tan WR, Lizwan M, Li Y, Teo Z, Goh WW, Zhu P, Tan NS . Targeting metabolic flexibility via angiopoietin-like 4 protein sensitizes metastatic cancer cells to chemotherapy drugs . Molecular Cancer . 17 . 1 . 152 . October 2018 . 30342537 . 6195749 . 10.1186/s12943-018-0904-z . free .
  15. Chong HC, Tan CK, Huang RL, Tan NS . Matricellular proteins: a sticky affair with cancers . Journal of Oncology . 2012 . 351089 . Feb 2012 . 22481923 . 3306981 . 10.1155/2012/351089 . free .
  16. Goh YY, Pal M, Chong HC, Zhu P, Tan MJ, Punugu L, Lam CR, Yau YH, Tan CK, Huang RL, Tan SM, Tang MB, Ding JL, Kersten S, Tan NS . Angiopoietin-like 4 interacts with integrins beta1 and beta5 to modulate keratinocyte migration . The American Journal of Pathology . 177 . 6 . 2791–803 . December 2010 . 20952587 . 2993291 . 10.2353/ajpath.2010.100129 .
  17. Goh YY, Pal M, Chong HC, Zhu P, Tan MJ, Punugu L, Tan CK, Huang RL, Sze SK, Tang MB, Ding JL, Kersten S, Tan NS . Angiopoietin-like 4 interacts with matrix proteins to modulate wound healing . The Journal of Biological Chemistry . 285 . 43 . 32999–3009 . October 2010 . 20729546 . 2963335 . 10.1074/jbc.M110.108175 . free .
  18. Chong HC, Chan JS, Goh CQ, Gounko NV, Luo B, Wang X, Foo S, Wong MT, Choong C, Kersten S, Tan NS . Angiopoietin-like 4 stimulates STAT3-mediated iNOS expression and enhances angiogenesis to accelerate wound healing in diabetic mice . Molecular Therapy . 22 . 9 . 1593–604 . September 2014 . 24903577 . 4435481 . 10.1038/mt.2014.102 .
  19. Teo Z, Chan JS, Chong HC, Sng MK, Choo CC, Phua GZ, Teo DJ, Zhu P, Choong C, Wong MT, Tan NS . Angiopoietin-like 4 induces a β-catenin-mediated upregulation of ID3 in fibroblasts to reduce scar collagen expression . Scientific Reports . 7 . 1 . 6303 . July 2017 . 28740178 . 5524754 . 10.1038/s41598-017-05869-x . 2017NatSR...7.6303T .
  20. Chen H, Lui YS, Tan ZW, Lee JY, Tan NS, Tan LP . Migration and Phenotype Control of Human Dermal Fibroblasts by Electrospun Fibrous Substrates . Advanced Healthcare Materials . 8 . 9 . e1801378 . May 2019 . 30901162 . 10.1002/adhm.201801378 . 85448471 .
  21. Mousavizadeh R, Scott A, Lu A, Ardekani GS, Behzad H, Lundgreen K, Ghaffari M, McCormack RG, Duronio V . Angiopoietin-like 4 promotes angiogenesis in the tendon and is increased in cyclically loaded tendon fibroblasts . The Journal of Physiology . 594 . 11 . 2971–83 . June 2016 . 26670924 . 4887665 . 10.1113/JP271752 .
  22. Babapoor-Farrokhran S, Jee K, Puchner B, Hassan SJ, Xin X, Rodrigues M, Kashiwabuchi F, Ma T, Hu K, Deshpande M, Daoud Y, Solomon S, Wenick A, Lutty GA, Semenza GL, Montaner S, Sodhi A . 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 . June 2015 . 26039997 . 4466723 . 10.1073/pnas.1423765112 . 2015PNAS..112E3030B . free .
  23. Sukonina V, Lookene A, Olivecrona T, Olivecrona G . Angiopoietin-like protein 4 converts lipoprotein lipase to inactive monomers and modulates lipase activity in adipose tissue . Proceedings of the National Academy of Sciences of the United States of America . 103 . 46 . 17450–5 . November 2006 . 17088546 . 1859949 . 10.1073/pnas.0604026103 . 2006PNAS..10317450S . free .
  24. Lafferty MJ, Bradford KC, Erie DA, Neher SB . Angiopoietin-like protein 4 inhibition of lipoprotein lipase: evidence for reversible complex formation . The Journal of Biological Chemistry . 288 . 40 . 28524–34 . October 2013 . 23960078 . 3789953 . 10.1074/jbc.M113.497602 . free .
  25. Georgiadi A, Wang Y, Stienstra R, Tjeerdema N, Janssen A, Stalenhoef A, van der Vliet JA, de Roos A, Tamsma JT, Smit JW, Tan NS, Müller M, Rensen PC, Kersten S . Overexpression of angiopoietin-like protein 4 protects against atherosclerosis development . Arteriosclerosis, Thrombosis, and Vascular Biology . 33 . 7 . 1529–37 . July 2013 . 23640487 . 10.1161/ATVBAHA.113.301698 . free .
  26. Georgiadi A, Lichtenstein L, Degenhardt T, Boekschoten MV, van Bilsen M, Desvergne B, Müller M, Kersten S . 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 . June 2010 . 20378851 . 10.1161/CIRCRESAHA.110.217380 . free .
  27. Catoire M, Alex S, Paraskevopulos N, Mattijssen F, Evers-van Gogh I, Schaart G, Jeppesen J, Kneppers A, Mensink M, Voshol PJ, Olivecrona G, Tan NS, Hesselink MK, Berbée JF, Rensen PC, Kalkhoven E, Schrauwen P, Kersten S . Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise . Proceedings of the National Academy of Sciences of the United States of America . 111 . 11 . E1043-52 . March 2014 . 24591600 . 3964070 . 10.1073/pnas.1400889111 . 2014PNAS..111E1043C . free .
  28. Xiao YL, Kash JC, Beres SB, Sheng ZM, Musser JM, Taubenberger JK . High-throughput RNA sequencing of a formalin-fixed, paraffin-embedded autopsy lung tissue sample from the 1918 influenza pandemic . The Journal of Pathology . 229 . 4 . 535–45 . March 2013 . 23180419 . 3731037 . 10.1002/path.4145 .
  29. Li L, Chong HC, Ng SY, Kwok KW, Teo Z, Tan EH, Choo CC, Seet JE, Choi HW, Buist ML, Chow VT, Tan NS . Angiopoietin-like 4 Increases Pulmonary Tissue Leakiness and Damage during Influenza Pneumonia . Cell Reports . 10 . 5 . 654–663 . February 2015 . 25660016 . 10.1016/j.celrep.2015.01.011 . 7185373 . free .
  30. Li L, Foo BJ, Kwok KW, Sakamoto N, Mukae H, Izumikawa K, Mandard S, Quenot JP, Lagrost L, Teh WK, Singh Kohli G, Zhu P, Choi H, Buist ML, Seet JE, Yang L, He F, Kwong Chow VT, Tan NS . Antibody Treatment against Angiopoietin-Like 4 Reduces Pulmonary Edema and Injury in Secondary Pneumococcal Pneumonia . mBio . 10 . 3 . June 2019 . 31164474 . 6550533 . 10.1128/mBio.02469-18 .

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "ANGPTL4".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.