Biology:ANGPTL4

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.

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, 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 as a hepatokine.

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.[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]

References

  1. ↑ "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. doi:10.1042/0264-6021:3460603. PMID 10698685. 
  2. ↑ "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. doi:10.1128/MCB.20.14.5343-5349.2000. PMID 10866690. 
  3. ↑ "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. doi:10.1074/jbc.M004029200. PMID 10862772. 
  4. ↑ 4.0 4.1 "TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4". Cell 133 (1): 66–77. April 2008. doi:10.1016/j.cell.2008.01.046. PMID 18394990. 
  5. ↑ 5.0 5.1 "ANGPTL4 induction by prostaglandin E2 under hypoxic conditions promotes colorectal cancer progression". Cancer Research 71 (22): 7010–20. November 2011. doi:10.1158/0008-5472.CAN-11-1262. PMID 21937683. 
  6. ↑ 6.0 6.1 "Inverse PPARβ/δ agonists suppress oncogenic signaling to the ANGPTL4 gene and inhibit cancer cell invasion". Oncogene 32 (44): 5241–52. October 2013. doi:10.1038/onc.2012.549. PMID 23208498. 
  7. ↑ 7.0 7.1 "Angiopoietin-like 4: a decade of research". Bioscience Reports 32 (3): 211–9. June 2012. doi:10.1042/BSR20110102. PMID 22458843. 
  8. ↑ "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. doi:10.1073/pnas.0705041104. PMID 17609370. 
  9. ↑ 9.0 9.1 "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. doi:10.1016/j.ccr.2011.01.018. PMID 21397862. 
  10. ↑ "Emerging roles of angiopoietin-like 4 in human cancer". Molecular Cancer Research 10 (6): 677–88. June 2012. doi:10.1158/1541-7786.MCR-11-0519. PMID 22661548. 
  11. ↑ "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. doi:10.1182/blood-2011-01-328716. PMID 21841165. 
  12. ↑ "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. doi:10.1038/onc.2017.244. PMID 28745316. 
  13. ↑ "ANGPTL4 T266M variant is associated with reduced cancer invasiveness". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1864 (10): 1525–1536. October 2017. doi:10.1016/j.bbamcr.2017.06.010. PMID 28641978. 
  14. ↑ "Targeting metabolic flexibility via angiopoietin-like 4 protein sensitizes metastatic cancer cells to chemotherapy drugs". Molecular Cancer 17 (1): 152. October 2018. doi:10.1186/s12943-018-0904-z. PMID 30342537. 
  15. ↑ "Matricellular proteins: a sticky affair with cancers". Journal of Oncology 2012: 351089. Feb 2012. doi:10.1155/2012/351089. PMID 22481923. 
  16. ↑ "Angiopoietin-like 4 interacts with integrins beta1 and beta5 to modulate keratinocyte migration". The American Journal of Pathology 177 (6): 2791–803. December 2010. doi:10.2353/ajpath.2010.100129. PMID 20952587. 
  17. ↑ "Angiopoietin-like 4 interacts with matrix proteins to modulate wound healing". The Journal of Biological Chemistry 285 (43): 32999–3009. October 2010. doi:10.1074/jbc.M110.108175. PMID 20729546. 
  18. ↑ "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. doi:10.1038/mt.2014.102. PMID 24903577. 
  19. ↑ "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. doi:10.1038/s41598-017-05869-x. PMID 28740178. 
  20. ↑ "Migration and Phenotype Control of Human Dermal Fibroblasts by Electrospun Fibrous Substrates". Advanced Healthcare Materials 8 (9): e1801378. May 2019. doi:10.1002/adhm.201801378. PMID 30901162. 
  21. ↑ "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. doi:10.1113/JP271752. PMID 26670924. 
  22. ↑ "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. doi:10.1073/pnas.1423765112. PMID 26039997. 
  23. ↑ "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. doi:10.1073/pnas.0604026103. PMID 17088546. 
  24. ↑ "Angiopoietin-like protein 4 inhibition of lipoprotein lipase: evidence for reversible complex formation". The Journal of Biological Chemistry 288 (40): 28524–34. October 2013. doi:10.1074/jbc.M113.497602. PMID 23960078. 
  25. ↑ "Overexpression of angiopoietin-like protein 4 protects against atherosclerosis development". Arteriosclerosis, Thrombosis, and Vascular Biology 33 (7): 1529–37. July 2013. doi:10.1161/ATVBAHA.113.301698. PMID 23640487. 
  26. ↑ "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. doi:10.1161/CIRCRESAHA.110.217380. PMID 20378851. 
  27. ↑ "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. doi:10.1073/pnas.1400889111. PMID 24591600. 
  28. ↑ "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. doi:10.1002/path.4145. PMID 23180419. 
  29. ↑ "Angiopoietin-like 4 Increases Pulmonary Tissue Leakiness and Damage during Influenza Pneumonia". Cell Reports 10 (5): 654–663. February 2015. doi:10.1016/j.celrep.2015.01.011. PMID 25660016. 
  30. ↑ "Antibody Treatment against Angiopoietin-Like 4 Reduces Pulmonary Edema and Injury in Secondary Pneumococcal Pneumonia". mBio 10 (3). June 2019. doi:10.1128/mBio.02469-18. PMID 31164474. 

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