ANGPTL3 explained

Angiopoietin-like 3, also known as ANGPTL3, is a protein that in humans is encoded by the ANGPTL3 gene.^{[1] [2]}

Function

The protein encoded by this gene is a member of the angiopoietin-like family of secreted factors. It is expressed predominantly in the liver, and has the characteristic structure of angiopoietins, consisting of a signal peptide, N-terminal coiled-coil domain, and the C-terminal fibrinogen (FBN)-like domain. The FBN-like domain in angiopoietin-like 3 protein was shown to bind alpha-5/beta-3 integrins, and this binding induced endothelial cell adhesion and migration. This protein may also play a role in the regulation of angiogenesis.^[1]

Angptl3 also acts as dual inhibitor of lipoprotein lipase (LPL) and endothelial lipase (EL),^[3] thereby increasing plasma triglyceride, LDL cholesterol and HDL cholesterol in mice and humans.

ANGPTL3 inhibits endothelial lipase hydrolysis of HDL-phospholipid (PL), thereby increasing HDL-PL levels. Circulating PL-rich HDL particles have high cholesterol efflux abilities.

Angptl3 plays a major role in promoting uptake of circulating triglycerides into white adipose tissue in the fed state,^[4] likely through activation by Angptl8, a feeding-induced hepatokine,^{[5] [6]} to inhibit postprandial LPL activity in cardiac and skeletal muscles,^[7] as suggested by the ANGPTL3-4-8 model.^[8]

Clinical significance

In human, ANGPTL3 is a determinant factor of HDL level and positively correlates with plasma HDL cholesterol.

In humans with genetic loss-of-function variants in one copy of ANGPTL3, the serum LDL-C levels are reduced. In those with loss-of-function variants in both copies of ANGPTL3, low LDL-C, low HDL-C, and low triglycerides are seen ("familial combined hypolipidemia").^[9]

Further reading

• Miida T, Seino U, Miyazaki O, Hanyu O, Hirayama S, Saito T, Ishikawa Y, Akamatsu S, Nakano T, Nakajima K, Okazaki M, Okada M . 6 . Probucol markedly reduces HDL phospholipids and elevated prebeta1-HDL without delayed conversion into alpha-migrating HDL: putative role of angiopoietin-like protein 3 in probucol-induced HDL remodeling . Atherosclerosis . 200 . 2 . 329–35 . October 2008 . 18279878 . 10.1016/j.atherosclerosis.2007.12.031 .
• Moon HD, Nakajima K, Kamiyama K, Takanashi K, Sakurabayashi I, Nagamine T . Higher frequency of abnormal serum angiopoietin-like protein 3 than abnormal cholesteryl ester transfer protein in Japanese hyperalphalipoproteinemic subjects . Clinica Chimica Acta; International Journal of Clinical Chemistry . 398 . 1–2 . 99–104 . December 2008 . 18804459 . 10.1016/j.cca.2008.08.021 .
• Li C . Genetics and regulation of angiopoietin-like proteins 3 and 4 . Current Opinion in Lipidology . 17 . 2 . 152–6 . April 2006 . 16531751 . 10.1097/01.mol.0000217896.67444.05 . 37001655 .
• 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 . 6 . ANGPTL3 stimulates endothelial cell adhesion and migration via integrin alpha vbeta 3 and induces blood vessel formation in vivo . The Journal of Biological Chemistry . 277 . 19 . 17281–90 . May 2002 . 11877390 . 10.1074/jbc.M109768200 . free .
• Kaplan R, Zhang T, Hernandez M, Gan FX, Wright SD, Waters MG, Cai TQ . Regulation of the angiopoietin-like protein 3 gene by LXR . Journal of Lipid Research . 44 . 1 . 136–43 . January 2003 . 12518032 . 10.1194/jlr.M200367-JLR200 . free .
• Shimamura M, Matsuda M, Kobayashi S, Ando Y, Ono M, Koishi R, Furukawa H, Makishima M, Shimomura I . 6 . Angiopoietin-like protein 3, a hepatic secretory factor, activates lipolysis in adipocytes . Biochemical and Biophysical Research Communications . 301 . 2 . 604–9 . February 2003 . 12565906 . 10.1016/S0006-291X(02)03058-9 .
• Zeng L, Dai J, Ying K, Zhao E, Jin W, Ye Y, Dai J, Xu J, Xie Y, Mao Y . 6 . Identification of a novel human angiopoietin-like gene expressed mainly in heart . Journal of Human Genetics . 48 . 3 . 159–62 . 2003 . 12624729 . 10.1007/s100380300025 . free .
• Ono M, Shimizugawa T, Shimamura M, Yoshida K, Noji-Sakikawa C, Ando Y, Koishi R, Furukawa H . 6 . Protein region important for regulation of lipid metabolism in angiopoietin-like 3 (ANGPTL3): ANGPTL3 is cleaved and activated in vivo . The Journal of Biological Chemistry . 278 . 43 . 41804–9 . October 2003 . 12909640 . 10.1074/jbc.M302861200 . free .
• Zhang Z, Henzel WJ . Signal peptide prediction based on analysis of experimentally verified cleavage sites . Protein Science . 13 . 10 . 2819–24 . October 2004 . 15340161 . 2286551 . 10.1110/ps.04682504 .
• Liu T, Qian WJ, Gritsenko MA, Camp DG, Monroe ME, Moore RJ, Smith RD . Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry . Journal of Proteome Research . 4 . 6 . 2070–80 . 2006 . 16335952 . 1850943 . 10.1021/pr0502065 .
• 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 . 6 . Angiopoietin-like protein3 regulates plasma HDL cholesterol through suppression of endothelial lipase . Arteriosclerosis, Thrombosis, and Vascular Biology . 27 . 2 . 366–72 . February 2007 . 17110602 . 10.1161/01.ATV.0000252827.51626.89 . free .

Notes and References

1. Web site: Entrez Gene: ANGPTL3 angiopoietin-like 3.
2. Conklin D, Gilbertson D, Taft DW, Maurer MF, Whitmore TE, Smith DL, Walker KM, Chen LH, Wattler S, Nehls M, Lewis KB . 16567474 . 6 . Identification of a mammalian angiopoietin-related protein expressed specifically in liver . Genomics . 62 . 3 . 477–82 . December 1999 . 10644446 . 10.1006/geno.1999.6041 .
3. Tikka A, Jauhiainen M . The role of ANGPTL3 in controlling lipoprotein metabolism . Endocrine . 52 . 2 . 187–93 . May 2016 . 26754661 . 4824806 . 10.1007/s12020-015-0838-9 .
4. Wang Y, McNutt MC, Banfi S, Levin MG, Holland WL, Gusarova V, Gromada J, Cohen JC, Hobbs HH . 6 . Hepatic ANGPTL3 regulates adipose tissue energy homeostasis . Proceedings of the National Academy of Sciences of the United States of America . 112 . 37 . 11630–5 . September 2015 . 26305978 . 4577179 . 10.1073/pnas.1515374112 . 2015PNAS..11211630W . free .
5. Zhang R . Lipasin, a novel nutritionally-regulated liver-enriched factor that regulates serum triglyceride levels . Biochemical and Biophysical Research Communications . 424 . 4 . 786–92 . August 2012 . 22809513 . 10.1016/j.bbrc.2012.07.038 .
6. Ren G, Kim JY, Smas CM . Identification of RIFL, a novel adipocyte-enriched insulin target gene with a role in lipid metabolism . American Journal of Physiology. Endocrinology and Metabolism . 303 . 3 . E334-51 . August 2012 . 22569073 . 3423120 . 10.1152/ajpendo.00084.2012 .
7. Fu Z, Abou-Samra AB, Zhang R . A lipasin/Angptl8 monoclonal antibody lowers mouse serum triglycerides involving increased postprandial activity of the cardiac lipoprotein lipase . Scientific Reports . 5 . 18502 . December 2015 . 26687026 . 4685196 . 10.1038/srep18502 . 2015NatSR...518502F .
8. Zhang R . The ANGPTL3-4-8 model, a molecular mechanism for triglyceride trafficking . Open Biology . 6 . 4 . 150272 . April 2016 . 27053679 . 4852456 . 10.1098/rsob.150272 . 2016-04-15 . dead . https://web.archive.org/web/20180804201514/http://rsob.royalsocietypublishing.org/content/6/4/150272.long . 2018-08-04 .
9. Musunuru K, Pirruccello JP, Do R, Peloso GM, Guiducci C, Sougnez C, Garimella KV, Fisher S, Abreu J, Barry AJ, Fennell T, Banks E, Ambrogio L, Cibulskis K, Kernytsky A, Gonzalez E, Rudzicz N, Engert JC, DePristo MA, Daly MJ, Cohen JC, Hobbs HH, Altshuler D, Schonfeld G, Gabriel SB, Yue P, Kathiresan S . 6 . Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia . The New England Journal of Medicine . 363 . 23 . 2220–7 . December 2010 . 20942659 . 3008575 . 10.1056/NEJMoa1002926 .