| Structural highlights
Disease
[ANGL3_HUMAN] Familial hypobetalipoproteinemia. The disease is caused by mutations affecting the gene represented in this entry. May be involved in atherosclerosis. Plasma levels are closely associated with arterial wall thickness.[1] May be involved in nephrotic syndrome.[2]
Function
[ANGL3_HUMAN] Acts in part as a hepatokine that is involved in regulation of lipid and glucose metabolism (PubMed:11788823, PubMed:12909640, PubMed:23661675, PubMed:25495645). Proposed to play a role in the trafficking of energy substrates to either storage or oxidative tissues in response to food intake (By similarity). Has a stimulatory effect on plasma triglycerides (TG), which is achieved by suppressing plasma TG clearance via inhibition of LPL activity. The inhibition of LPL activity appears to be an indirect mechanism involving recruitment of proprotein convertases PCSK6 and FURIN to LPL leading to cleavage and dissociation of LPL from the cell surface; the function does not require ANGPTL3 proteolytic cleavage but seems to be mediated by the N-terminal domain, and is not inhibited by GPIHBP1 (PubMed:12097324, PubMed:19318355, PubMed:20581395). Can inhibit endothelial lipase, causing increased plasma levels of high density lipoprotein (HDL) cholesterol and phospholipids (PubMed:17110602, PubMed:19028676). Can bind to adipocytes to activate lipolysis, releasing free fatty acids and glycerol (PubMed:12565906). Suppresses LPL specifically in oxidative tissues which is required to route very low density lipoprotein (VLDL)-TG to white adipose tissue (WAT) for storage in response to food; the function may involve cooperation with circulating, liver-derived ANGPTL8 and ANGPTL4 expression in WAT (By similarity). Contributes to lower plasma levels of low density lipoprotein (LDL)-cholesterol by a mechanism that is independent of the canonical pathway implicating APOE and LDLR. May stimulate hypothalamic LPL activity (By similarity).[UniProtKB:Q9R182][3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] ANGPTL3(17-221): In vitro inhibits LPL activity; not effective on GPIHBP1-stabilized LPL.[14] Involved in angiogenesis. Binds to endothelial cells via integrin alpha-V/beta-3 (ITGAV:ITGB3), activates FAK, MAPK and Akt signaling pathways and induces cell adhesion and cell migration (PubMed:11877390). Secreted from podocytes, may modulate properties of glomerular endothelial cells involving integrin alpha-V/beta-3 and Akt signaling (PubMed:18535744). May increase the motility of podocytes. May induce actin filament rearrangements in podocytes implicating integrin alpha-V/beta-3 and Rac1 activation. Binds to hematopoietic stem cells (HSC) and is involved in the regulation of HSC activity probably implicating down-regulation of IKZF1/IKAROS (By similarity).[UniProtKB:Q9R182][15] [16]
Publication Abstract from PubMed
Coronary artery disease is the most common cause of death globally and is linked to a number of risk factors including serum low density lipoprotein, high density lipoprotein, triglycerides and lipoprotein(a). Recently two proteins, angiopoietin-like protein 3 and 4, have emerged from genetic studies as being factors that significantly modulate plasma triglyceride levels and coronary artery disease. The exact function and mechanism of action of both proteins remains to be elucidated, however, mutations in these proteins results in up to 34% reduction in coronary artery disease and inhibition of function results in reduced plasma triglyceride levels. Here we report the crystal structures of the fibrinogen-like domains of both proteins. These structures offer new insights into the reported loss of function mutations, the mechanisms of action of the proteins and open up the possibility for the rational design of low molecular weight inhibitors for intervention in coronary artery disease.
Structures of Angptl3 and Angptl4, modulators of triglyceride levels and coronary artery disease.,Biterova E, Esmaeeli M, Alanen HI, Saaranen M, Ruddock LW Sci Rep. 2018 Apr 30;8(1):6752. doi: 10.1038/s41598-018-25237-7. PMID:29713054[17]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Hatsuda S, Shoji T, Shinohara K, Kimoto E, Mori K, Fukumoto S, Koyama H, Emoto M, Nishizawa Y. Association between plasma angiopoietin-like protein 3 and arterial wall thickness in healthy subjects. J Vasc Res. 2007;44(1):61-6. doi: 10.1159/000098153. Epub 2006 Dec 21. PMID:17191020 doi:http://dx.doi.org/10.1159/000098153
- ↑ Liu J, Gao X, Zhai Y, Shen Q, Sun L, Feng C, Rao J, Liu H, Zha X, Guo M, Ma D, Zhang Z, Li R, Xu H. A novel role of angiopoietin-like-3 associated with podocyte injury. Pediatr Res. 2015 Jun;77(6):732-9. doi: 10.1038/pr.2015.38. Epub 2015 Feb 24. PMID:25710887 doi:http://dx.doi.org/10.1038/pr.2015.38
- ↑ Koishi R, Ando Y, Ono M, Shimamura M, Yasumo H, Fujiwara T, Horikoshi H, Furukawa H. Angptl3 regulates lipid metabolism in mice. Nat Genet. 2002 Feb;30(2):151-7. doi: 10.1038/ng814. Epub 2002 Jan 14. PMID:11788823 doi:http://dx.doi.org/10.1038/ng814
- ↑ Shimizugawa T, Ono M, Shimamura M, Yoshida K, Ando Y, Koishi R, Ueda K, Inaba T, Minekura H, Kohama T, Furukawa H. ANGPTL3 decreases very low density lipoprotein triglyceride clearance by inhibition of lipoprotein lipase. J Biol Chem. 2002 Sep 13;277(37):33742-8. doi: 10.1074/jbc.M203215200. Epub 2002 , Jul 3. PMID:12097324 doi:http://dx.doi.org/10.1074/jbc.M203215200
- ↑ Shimamura M, Matsuda M, Kobayashi S, Ando Y, Ono M, Koishi R, Furukawa H, Makishima M, Shimomura I. Angiopoietin-like protein 3, a hepatic secretory factor, activates lipolysis in adipocytes. Biochem Biophys Res Commun. 2003 Feb 7;301(2):604-9. PMID:12565906
- ↑ Ono M, Shimizugawa T, Shimamura M, Yoshida K, Noji-Sakikawa C, Ando Y, Koishi R, Furukawa H. Protein region important for regulation of lipid metabolism in angiopoietin-like 3 (ANGPTL3): ANGPTL3 is cleaved and activated in vivo. J Biol Chem. 2003 Oct 24;278(43):41804-9. doi: 10.1074/jbc.M302861200. Epub 2003 , Aug 8. PMID:12909640 doi:http://dx.doi.org/10.1074/jbc.M302861200
- ↑ Shimamura M, Matsuda M, Yasumo H, Okazaki M, Fujimoto K, Kono K, Shimizugawa T, Ando Y, Koishi R, Kohama T, Sakai N, Kotani K, Komuro R, Ishida T, Hirata K, Yamashita S, Furukawa H, Shimomura I. Angiopoietin-like protein3 regulates plasma HDL cholesterol through suppression of endothelial lipase. Arterioscler Thromb Vasc Biol. 2007 Feb;27(2):366-72. doi:, 10.1161/01.ATV.0000252827.51626.89. Epub 2006 Nov 16. PMID:17110602 doi:http://dx.doi.org/10.1161/01.ATV.0000252827.51626.89
- ↑ Shan L, Yu XC, Liu Z, Hu Y, Sturgis LT, Miranda ML, Liu Q. The angiopoietin-like proteins ANGPTL3 and ANGPTL4 inhibit lipoprotein lipase activity through distinct mechanisms. J Biol Chem. 2009 Jan 16;284(3):1419-24. doi: 10.1074/jbc.M808477200. Epub 2008, Nov 21. PMID:19028676 doi:http://dx.doi.org/10.1074/jbc.M808477200
- ↑ Lee EC, Desai U, Gololobov G, Hong S, Feng X, Yu XC, Gay J, Wilganowski N, Gao C, Du LL, Chen J, Hu Y, Zhao S, Kirkpatrick L, Schneider M, Zambrowicz BP, Landes G, Powell DR, Sonnenburg WK. Identification of a new functional domain in angiopoietin-like 3 (ANGPTL3) and angiopoietin-like 4 (ANGPTL4) involved in binding and inhibition of lipoprotein lipase (LPL). J Biol Chem. 2009 May 15;284(20):13735-45. doi: 10.1074/jbc.M807899200. Epub 2009, Mar 23. PMID:19318355 doi:http://dx.doi.org/10.1074/jbc.M807899200
- ↑ Liu J, Afroza H, Rader DJ, Jin W. Angiopoietin-like protein 3 inhibits lipoprotein lipase activity through enhancing its cleavage by proprotein convertases. J Biol Chem. 2010 Sep 3;285(36):27561-70. doi: 10.1074/jbc.M110.144279. Epub 2010, Jun 26. PMID:20581395 doi:http://dx.doi.org/10.1074/jbc.M110.144279
- ↑ Robciuc MR, Maranghi M, Lahikainen A, Rader D, Bensadoun A, Oorni K, Metso J, Minicocci I, Ciociola E, Ceci F, Montali A, Arca M, Ehnholm C, Jauhiainen M. Angptl3 deficiency is associated with increased insulin sensitivity, lipoprotein lipase activity, and decreased serum free fatty acids. Arterioscler Thromb Vasc Biol. 2013 Jul;33(7):1706-13. doi:, 10.1161/ATVBAHA.113.301397. Epub 2013 May 9. PMID:23661675 doi:http://dx.doi.org/10.1161/ATVBAHA.113.301397
- ↑ Tikka A, Soronen J, Laurila PP, Metso J, Ehnholm C, Jauhiainen M. Silencing of ANGPTL 3 (angiopoietin-like protein 3) in human hepatocytes results in decreased expression of gluconeogenic genes and reduced triacylglycerol-rich VLDL secretion upon insulin stimulation. Biosci Rep. 2014 Dec 12;34(6):e00160. doi: 10.1042/BSR20140115. PMID:25495645 doi:http://dx.doi.org/10.1042/BSR20140115
- ↑ Liu J, Afroza H, Rader DJ, Jin W. Angiopoietin-like protein 3 inhibits lipoprotein lipase activity through enhancing its cleavage by proprotein convertases. J Biol Chem. 2010 Sep 3;285(36):27561-70. doi: 10.1074/jbc.M110.144279. Epub 2010, Jun 26. PMID:20581395 doi:http://dx.doi.org/10.1074/jbc.M110.144279
- ↑ Sonnenburg WK, Yu D, Lee EC, Xiong W, Gololobov G, Key B, Gay J, Wilganowski N, Hu Y, Zhao S, Schneider M, Ding ZM, Zambrowicz BP, Landes G, Powell DR, Desai U. GPIHBP1 stabilizes lipoprotein lipase and prevents its inhibition by angiopoietin-like 3 and angiopoietin-like 4. J Lipid Res. 2009 Dec;50(12):2421-9. doi: 10.1194/jlr.M900145-JLR200. Epub 2009, Jun 21. PMID:19542565 doi:http://dx.doi.org/10.1194/jlr.M900145-JLR200
- ↑ Camenisch G, Pisabarro MT, Sherman D, Kowalski J, Nagel M, Hass P, Xie MH, Gurney A, Bodary S, Liang XH, Clark K, Beresini M, Ferrara N, Gerber HP. ANGPTL3 stimulates endothelial cell adhesion and migration via integrin alpha vbeta 3 and induces blood vessel formation in vivo. J Biol Chem. 2002 May 10;277(19):17281-90. doi: 10.1074/jbc.M109768200. Epub 2002, Feb 27. PMID:11877390 doi:http://dx.doi.org/10.1074/jbc.M109768200
- ↑ Li Y, Sun L, Xu H, Fang Z, Yao W, Guo W, Rao J, Zha X. Angiopoietin-like protein 3 modulates barrier properties of human glomerular endothelial cells through a possible signaling pathway involving phosphatidylinositol-3 kinase/protein kinase B and integrin alphaVbeta3. Acta Biochim Biophys Sin (Shanghai). 2008 Jun;40(6):459-65. PMID:18535744
- ↑ Biterova E, Esmaeeli M, Alanen HI, Saaranen M, Ruddock LW. Structures of Angptl3 and Angptl4, modulators of triglyceride levels and coronary artery disease. Sci Rep. 2018 Apr 30;8(1):6752. doi: 10.1038/s41598-018-25237-7. PMID:29713054 doi:http://dx.doi.org/10.1038/s41598-018-25237-7
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