ANGPTL4

Angiopoietin-like 4
Identifiers
Symbols ANGPTL4 ; ARP4; FIAF; HARP; HFARP; NL2; PGAR; TGQTL; UNQ171; pp1158
External IDs OMIM: 605910 MGI: 1888999 HomoloGene: 10755 GeneCards: ANGPTL4 Gene
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 51129 57875
Ensembl ENSG00000167772 ENSMUSG00000002289
UniProt Q9BY76 Q9Z1P8
RefSeq (mRNA) NM_001039667 NM_020581
RefSeq (protein) NP_001034756 NP_065606
Location (UCSC) Chr 19:
8.36 – 8.37 Mb		 Chr 17:
33.77 – 33.78 Mb
PubMed search

Angiopoietin-like 4 is a protein that in human is encoded by the ANGPTL4 gene.[1][2][3] Alternatively spliced transcript variants encoding different isoforms have been described. This gene was previously referred to as ANGPTL2, HFARP, PGAR, or FIAF but has been renamed ANGPTL4.

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.[4]

Expression

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

Function

Picture depicts role of ANGPTL4 as endogenous inhibitor of lipoprotein lipase and its regulation by fatty acids via Peroxisome Proliferator Activated Receptors

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.[4] Monoclonal antibodies targeting the nANGPTL4[5] and cANGPTL4[6] 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.[7][8][9] 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.[6] 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 functions as a matricellular protein[12] to facilitate skin wound healing. ANGPTL4-deficient mice exhibit delayed wound reepithelialization with impaired keratinocyte migration, angiogenesis and altered inflammatory response.[13][14] 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.[15] 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.[16] 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. [17]

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.[18] 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.[19] 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.[20] 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.[21] 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.[22]

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.[23] 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. [24]

References

  1. ↑ Kim I, Kim HG, Kim H, Kim HH, Park SK, Uhm CS, Lee ZH, Koh GY (May 2000). "Hepatic expression, synthesis and secretion of a novel fibrinogen/angiopoietin-related protein that prevents endothelial-cell apoptosis". Biochem J 346 (Pt 3): 603–10. doi:10.1042/0264-6021:3460603. PMC 1220891. PMID 10698685.
  2. ↑ Yoon JC, Chickering TW, Rosen ED, Dussault B, Qin Y, Soukas A, Friedman JM, Holmes WE, Spiegelman BM (Jul 2000). "Peroxisome proliferator-activated receptor gamma target gene encoding a novel angiopoietin-related protein associated with adipose differentiation". Mol Cell Biol 20 (14): 5343–5349. doi:10.1128/MCB.20.14.5343-5349.2000. PMC 85983. PMID 10866690.
  3. ↑ Kersten S, Mandard S, Tan NS, Escher P, Metzger D, Chambon P, Gonzalez FJ, Desvergne B, Wahli W (Sep 2000). "Characterization of the fasting-induced adipose factor FIAF, a novel peroxisome proliferator-activated receptor target gene.". J. Biol. Chem. 275 (37): 28488–93. doi:10.1074/jbc.M004029200. PMID 10862772.
  4. 1 2 Zhu P, Goh YY, Chin HF, Kersten S, Tan NS. (2012). "Angiopoietin-like 4: a decade of research". Biosci. Rep. 32 (3): 211–9. doi:10.1042/BSR20110102. PMID 22458843.
  5. ↑ 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. (2007). "Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice.". Proc Natl Acad Sci U S A. 104 (28): 11766–11771. doi:10.1073/pnas.0705041104. PMID 17609370.
  6. 1 2 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. (2011). "Angiopoietin-like 4 protein elevates the prosurvival intracellular O2(-):H2O2 ratio and confers anoikis resistance to tumors.". Cancer Cell 19 (3): 401–415. doi:10.1016/j.ccr.2011.01.018. PMID 21397862.
  7. ↑ Padua D, Zhang XH, Wang Q, Nadal C, Gerald WL, Gomis RR, Massagué J. (2008). "TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4.". Cell 133 (1): 66–77. doi:10.1016/j.cell.2008.01.046. PMID 18394990.
  8. ↑ Kim SH, Park YY, Kim SW, Lee JS, Wang D, DuBois RN. (2011). "ANGPTL4 induction by prostaglandin E2 under hypoxic conditions promotes colorectal cancer progression.". Cancer Res. 71 (22): 7010–7020. doi:10.1158/0008-5472.CAN-11-1262. PMID 21937683.
  9. ↑ 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. (2012). "Inverse PPARβ/δ agonists suppress oncogenic signaling to the ANGPTL4 gene and inhibit cancer cell invasion.". Oncogene 32 (44): 5241–52. doi:10.1038/onc.2012.549. PMID 23208498.
  10. ↑ Tan MJ, Teo Z, Sng MK, Zhu P, Tan NS. (2012). "Emerging Roles of Angiopoietin-like 4 in Human Cancer". Mol. Cancer Res. 10 (6): 1–12. doi:10.1158/1541-7786.MCR-11-0519. PMID 22661548.
  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. (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.
  12. ↑ Chong HC, Tan CK, Huang RL, Tan NS (Feb 2012). "Matricellular proteins: a sticky affair with cancers". J. Oncol. 2012: 351089. doi:10.1155/2012/351089. PMC 3306981. PMID 22481923.
  13. ↑ 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. (2010). "Angiopoietin-like 4 interacts with integrins beta1 and beta5 to modulate keratinocyte migration.". Am J Pathol. 177 (6): 2791–2803. doi:10.2353/ajpath.2010.100129. PMC 2993291. PMID 20952587.
  14. ↑ 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. (2010). "Angiopoietin-like 4 interacts with matrix proteins to modulate wound healing.". J Biol Chem. 285 (43): 32999–33009. doi:10.1074/jbc.M110.108175. PMC 2963335. PMID 20729546.
  15. ↑ Chong HC, Chan JS, Goh CQ, Gounko NV, Luo B, Wang X, Foo S, Wong MT, Choong C, Kersten S, Tan NS. (2014). "Angiopoietin-like 4 stimulates STAT3-mediated iNOS expression and enhances angiogenesis to accelerate wound healing in diabetic mice.". Mol Ther. 22: 1593–1604. doi:10.1038/mt.2014.102. PMID 24903577.
  16. ↑ Mousavizadeh R, Scott A, Lu A, Ardekani GS, Behzad H, Lundgreen K, Ghaffari M, McCormack RG, Duronio V. (2015). "Angiopoietin-like 4 (ANGPTL4) promotes angiogenesis in tendon and is increased in cyclically loaded tendon fibroblasts.". J Physiol. doi:10.1113/JP271752. PMID 26670924.
  17. ↑ 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. (2015). "Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy.". Proc Natl Acad Sci U S A. 112: E3030–9. doi:10.1073/pnas.1423765112. PMID 26039997.
  18. ↑ Sukonina V, Lookene A, Olivecrona T, Olivecrona G. (2006). "Angiopoietin-like protein 4 converts lipoprotein lipase to inactive monomers and modulates lipase activity in adipose tissue.". Proc. Natl. Acad. Sci. U.S.A. 104 (46): 17450–5. doi:10.1073/pnas.0604026103. PMID 17088546.
  19. ↑ Lafferty MJ, Bradford KC, Erie DA, Neher SB. (Jul 2013). "Angiopoietin-like protein 4 inhibition of lipoprotein lipase: evidence for reversible complex formation.". J. Biol. Chem. 33 (7): 1529–37. doi:10.1161/ATVBAHA.113.301698. PMID 23960078.
  20. ↑ 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, Kersten S. (Oct 2013). "Overexpression of Angiopoietin-like Protein 4 Protects Against Atherosclerosis.". Arterioscler. Thromb. Vasc. Biol. 288 (40): 28524–34. doi:10.1074/jbc.M113.497602. PMID 23640487.
  21. ↑ Georgiadi A, Lichtenstein L, Degenhardt T, Boekschoten MV, van Bilsen M, Desvergne B, Müller M, Kersten S. (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.". Circ. Res. 106: 1712–1721. doi:10.1161/CIRCRESAHA.110.217380. PMID 20378851.
  22. ↑ 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. (2014). "Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise.". Proc Natl Acad Sci U S A. 111: E1043–52. doi:10.1073/pnas.1400889111. PMID 24591600.
  23. ↑ Xiao YL, Kash JC, Beres SB, Sheng ZM, Musser JM, Taubenberger JK. (Mar 2013). "High-throughput RNA sequencing of a formalin-fixed, paraffin-embedded autopsy lung tissue sample from the 1918 influenza pandemic.". J Pathol. 229 (4): 535–45. doi:10.1002/path.4145. PMID 23180419.
  24. ↑ Li L, Chong HC, Ng SY, Kwok KW, Teo Z, Tan EH, Choo CC, Seet JE, Choi HW, Buist ML, Chow VT, Tan NS. (2015). "Angiopoietin-like 4 Increases Pulmonary Tissue Leakiness and Damage during Influenza Pneumonia.". Cell Rep. 10 (5): 654–663. doi:10.1016/j.celrep.2015.01.011. PMID 25660016.

Further reading

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