Angiopoietin-like 4 is a protein that in human is encoded by the ANGPTL4gene.[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.
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
File:Overview ANGPTL4.pngPicture 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]
↑ 6.06.1Zhu 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. PMID21397862.
↑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. 33 (7): 1529–37. doi:10.1161/ATVBAHA.113.301698. PMID23640487.
↑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 (11): 1712–1721. doi:10.1161/CIRCRESAHA.110.217380. PMID20378851.
Alex S, Lichtenstein L, Dijk W, Mensink RP, Tan NS, Kersten S (2014). "ANGPTL4 is produced by entero-endocrine cells in the human intestinal tract". Histochem. Cell Biol. 141 (4): 383–91. doi:10.1007/s00418-013-1157-y. PMID24141811.
Grootaert C, Van de Wiele T, Verstraete W, Bracke M, Vanhoecke B (2012). "Angiopoietin-like protein 4: health effects, modulating agents and structure-function relationships". Expert Rev Proteomics. 9 (3): 181–199. doi:10.1586/epr.12.12. PMID22462789.
Terada LS, Nwariaku FE (2011). "Escaping Anoikis through ROS: ANGPTL4 controls integrin signaling through Nox1". Cancer Cell. 19 (3): 297–299. doi:10.1016/j.ccr.2011.02.019. PMID21397852.
Mandard S, Zandbergen F, Tan NS, Escher P, Patsouris D, Koenig W, Kleemann R, Bakker A, Veenman F, Wahli W, Müller M, Kersten S (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". J. Biol. Chem. 279 (33): 34411–34420. doi:10.1074/jbc.M403058200. PMID15190076.
Hermann LM, Pinkerton M, Jennings K, Yang L, Grom A, Sowders D, Kersten S, Witte DP, Hirsch R, Thornton S (2005). "Angiopoietin-like-4 is a potential angiogenic mediator in arthritis". Clin. Immunol. 115 (1): 93–101. doi:10.1016/j.clim.2004.12.002. PMID15870027.
