Biology:ANGPTL8

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Short description: Mammalian protein found in Homo sapiens


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

ANGPTL8 (also known as lipasin, previously betatrophin) is a protein that in humans is encoded by the C19orf80 gene.

Gene

The ANGPTL8 gene lies on mouse chromosome 9 (gene symbol: Gm6484) and on human chromosome 19 (gene symbol: C19orf80).

Discovery

The ANGPTL8 gene was discovered in 2012 as RIFL, Lipasin, and ANGPTL8.[1][2] [3] In 2013 it was suggested by Melton and Yi from Harvard that ANGPTL8 promotes mouse pancreatic islet cell proliferation. These results led the authors to propose an alternative name for ANGPTL8, betatrophin.[4] However, the link between ANGPTL8 and islet proliferation was quickly proven false by other researchers.[5] In fact, in December 2016 the original paper by Melton and Yi was retracted, putting the link between ANGPTL8 and islets cells to rest. Nevertheless, the name betatrophin continues to be used. Given the homology of ANGPTL8 with ANGPTL4 and ANGPTL3, and considering that ANGPTL8 does not promote beta cell proliferation, the name betatrophin should be abandoned in favor of ANGPTL8.[6]

Function

The encoded 22 kDa protein contains an N-terminal secretion signal and two coiled-coil domains and is a member of the angiopoietin-like (ANGPTL) protein family. However, in contrast to other ANGPTL proteins, ANGPTL8 lacks the C-terminal fibrinogen-like domain, and therefore it is an atypical member of the ANGPTL family.[7] It shares with ANGPTL4 and ANGPTL8 the ability to inhibit the enzyme Lipoprotein lipase (LPL), and its hepatic overexpression causes elevation of circulating Triglyceride levels in mice.[1] In mice ANGPTL8 is secreted by the liver and by adipose tissue.[1][2]

Despite having elevated post-heparin plasma LPL activity, mice lacking ANGPTL8 exhibit markedly decreased uptake of Very low-density lipoprotein-derived fatty acids into white adipose tissue (WAT).[8] The defect in fatty acids uptake by WAT in ANGPTL8-null mice is likely due to the enhanced fatty acid uptake by the heart and skeletal muscle, because of the elevated LPL activity in these two tissues,[9] as suggested by the ANGPTL3-4-8 model.[10]

ANGPTL8 was proposed to increase the rate at which beta-cells undergo cell division. Injection of mice with ANGPTL8 cDNA lowered blood sugar (i.e. hypoglycemia), presumably due to action at the pancreas. However, treatment of human islets with ANGPTL8 is unable to increase beta-cell division.[11] Furthermore, studies in ANGPTL8 knock-out mice do not support a role of ANGPTL8 in controlling beta cell growth, yet point to a clear role in regulating plasma triglyceride levels.[12] Based on these studies, it is fairly safe to say that the notion that ANGPTL8 promotes beta cell expansion is dead, which was made official by the retraction of the original paper.[11][13] Deletion of ANGPTL8 does not seem to impact glucose and insulin tolerance in mice.[8]

Structure

Three dimensional structure of none of the members of Angiopoietin like proteins (ANGPTLs) is available up until now.[when?] However, the structure of ANGPTL8 was predicted by homology modeling and is also reported in literature.[14] It consists of alpha helices and its sequence show high similarity with the coiled-coil domains of ANGPTL3 and ANGPTL4.

Pathway

The ANGPTL8 regulatory pathway has been constructed recently by integrating the information of its know transcription factors which is available at WikiPathways data repository with the pathway id WP3915.[15]

Clinical significance

It was hoped that ANGPTL8 or its homolog in humans may provide an effective treatment for type 2 diabetes and perhaps even type I diabetes.[4] Unfortunately, since new data have greatly called into question the ability of ANGPTL8 to increase beta-cell replication, its potential use as a therapy for type 2 diabetes is limited.[12] Inhibition of ANGPTL8 represents a possible therapeutic strategy for hypertriglyceridemia.[9]

References

  1. ↑ 1.0 1.1 1.2 "Lipasin, a novel nutritionally-regulated liver-enriched factor that regulates serum triglyceride levels". Biochemical and Biophysical Research Communications 424 (4): 786–92. Aug 2012. doi:10.1016/j.bbrc.2012.07.038. PMID 22809513. 
  2. ↑ 2.0 2.1 "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. Aug 2012. doi:10.1152/ajpendo.00084.2012. PMID 22569073. 
  3. ↑ "Atypical angiopoietin-like protein that regulates ANGPTL3". Proceedings of the National Academy of Sciences of the United States of America 109 (48): 19751–6. Nov 2012. doi:10.1073/pnas.1217552109. PMID 23150577. Bibcode: 2012PNAS..10919751Q. 
  4. ↑ 4.0 4.1 "Betatrophin: a hormone that controls pancreatic β cell proliferation". Cell 153 (4): 747–58. May 2013. doi:10.1016/j.cell.2013.04.008. PMID 23623304. 
  5. ↑ Gusarova, Viktoria; Alexa, Corey A.; Na, Erqian; Stevis, Panayiotis E.; Xin, Yurong; Bonner-Weir, Susan; Cohen, Jonathan C.; Hobbs, Helen H. et al. (2014). "ANGPTL8/Betatrophin Does Not Control Pancreatic Beta Cell Expansion". Cell 159 (3): 691–696. doi:10.1016/j.cell.2014.09.027. PMID 25417115. 
  6. ↑ "Emerging roles of Lipasin as a critical lipid regulator". Biochemical and Biophysical Research Communications 432 (3): 401–5. Mar 2013. doi:10.1016/j.bbrc.2013.01.129. PMID 23415864. 
  7. ↑ "Lipasin, thermoregulated in brown fat, is a novel but atypical member of the angiopoietin-like protein family". Biochemical and Biophysical Research Communications 430 (3): 1126–31. Jan 2013. doi:10.1016/j.bbrc.2012.12.025. PMID 23261442. 
  8. ↑ 8.0 8.1 "Mice lacking ANGPTL8 (Betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis". Proceedings of the National Academy of Sciences of the United States of America 110 (40): 16109–14. Oct 2013. doi:10.1073/pnas.1315292110. PMID 24043787. Bibcode: 2013PNAS..11016109W. 
  9. ↑ 9.0 9.1 "A lipasin/Angptl8 monoclonal antibody lowers mouse serum triglycerides involving increased postprandial activity of the cardiac lipoprotein lipase". Scientific Reports 5: 18502. December 2015. doi:10.1038/srep18502. PMID 26687026. Bibcode: 2015NatSR...518502F. 
  10. ↑ "The ANGPTL3-4-8 model, a molecular mechanism for triglyceride trafficking.". Open Biology 6 (4): 150272. April 2016. doi:10.1098/rsob.150272. PMID 27053679. 
  11. ↑ 11.0 11.1 "Elevated mouse hepatic betatrophin expression does not increase human β-cell replication in the transplant setting". Diabetes 63 (4): 1283–8. Apr 2014. doi:10.2337/db13-1435. PMID 24353178. 
  12. ↑ 12.0 12.1 "ANGPTL8/betatrophin does not control pancreatic beta cell expansion". Cell 159 (3): 691–6. Oct 2014. doi:10.1016/j.cell.2014.09.027. PMID 25417115. 
  13. ↑ "Betatrophin versus bitter-trophin and the elephant in the room: time for a new normal in β-cell regeneration research". Diabetes 63 (4): 1198–9. Apr 2014. doi:10.2337/DB14-0009. PMID 24651805. 
  14. ↑ "Structural characterization of ANGPTL8 (betatrophin) with its interacting partner lipoprotein lipase". Computational Biology and Chemistry 61: 210–20. April 2016. doi:10.1016/j.compbiolchem.2016.01.009. PMID 26908254. 
  15. ↑ "Visualizing the regulatory role of Angiopoietin-like protein 8 (ANGPTL8) in glucose and lipid metabolic pathways". Genomics 109 (5–6): 408–418. October 2017. doi:10.1016/j.ygeno.2017.06.006. PMID 28684091. 

External links



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