Betatrophin

Chromosome 19 open reading frame 80
Identifiers
Symbols C19orf80 ; ANGPTL8; PRO1185; PVPA599; RIFL; TD26
External IDs OMIM: 616223 HomoloGene: 83285 GeneCards: C19orf80 Gene
Orthologs
Species Human Mouse
Entrez 55908 624219
Ensembl ENSG00000130173 ENSMUSG00000047822
UniProt Q6UXH0 Q8R1L8
RefSeq (mRNA) NM_018687 NM_001080940
RefSeq (protein) NP_061157 NP_001074409
Location (UCSC) Chr 19:
11.24 – 11.24 Mb		 Chr 9:
21.84 – 21.84 Mb
PubMed search

Betatrophin is a protein that in humans is encoded by the C19orf80 gene.

Gene

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

Discovery

The link between betatrophin and mouse islet cell proliferation was made by Douglas Melton and Peng Yi from Harvard in 2013.[1] Before that time, betatrophin was and actually still is known under various names: TD26, RIFL, Lipasin, and Angptl8.[2] Since betatrophin is a member of the angiopoietin-like gene family and shares extensive homology with Angptl4 and Angptl3, the name Angptl8 is preferred.

Function

Betatrophin is a putative peptide hormone found in mice that was proposed to increase the rate at which beta-cells undergo cell division. Injection of mice with betatrophin cDNA lowered blood sugar (i.e. hypoglycemia), presumably due to action at the pancreas. However, treatment of human islets with betatrophin is unable to increase beta-cell division.[3] Furthermore, studies in betatrophin/Angptl8 knock-out mice do not support a role of betatrophin in controlling beta cell growth, yet point to a clear role in regulating plasma triglyceride levels.[4] Based on these studies, it is fairly safe to say that the notion that betatrophin promotes beta cell expansion is dead.[3][5] Deletion of betatrophin/Angptl8 does not seem to impact glucose and insulin tolerance in mice.[6]

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, betatrophin lacks the C-terminal fibrinogen-like domain, and therefore it is an atypical member of the ANGPTL family.[7] It shares with Angptl4 and Angptl3 the ability to inhibit the enzyme Lipoprotein lipase (LPL), and its hepatic overexpression causes elevation of circulating Triglyceride levels in mice.[8] In mice betatrophin is secreted by the liver.[8][9]

Despite having elevated post-heparin plasma LPL activity, mice lacking betatrophin/Angptl8 exhibit markedly decreased uptake of Very low-density lipoprotein-derived fatty acids into white adipose tissue (WAT).[6] The defect in fatty acids uptake by WAT in Angptl8-null mice is likely due to the enhanced fatty acids uptake by the heart and skeletal muscle, because of the elevated LPL activity in these two tissues,[10] as suggested by the ANGPTL3-4-8 model.[11]

Clinical significance

It was hoped that betatrophin or its homolog in humans may provide an effective treatment for type 2 diabetes and perhaps even type I diabetes.[1] Unfortunately, since new data have greatly called into question the ability of betatrophin to increase beta-cell replication, its potential use as a therapy for type 2 diabetes is limited.[4] Inhibition of Angptl8 represents a possible therapeutic strategy for hypertriglyceridemia.[10]

References

  1. 1 2 Yi P, Park JS, Melton DA (May 2013). "Betatrophin: a hormone that controls pancreatic β cell proliferation". Cell 153 (4): 747–58. doi:10.1016/j.cell.2013.04.008. PMC: 3756510. PMID 23623304.
  2. ↑ Zhang R, Abou-Samra AB (Mar 2013). "Emerging roles of Lipasin as a critical lipid regulator". Biochemical and Biophysical Research Communications 432 (3): 401–5. doi:10.1016/j.bbrc.2013.01.129. PMC: 3756510. PMID 23415864.
  3. 1 2 Jiao Y, Le Lay J, Yu M, Naji A, Kaestner KH (Apr 2014). "Elevated mouse hepatic betatrophin expression does not increase human β-cell replication in the transplant setting". Diabetes 63 (4): 1283–8. doi:10.2337/db13-1435. PMID 24353178.
  4. 1 2 Gusarova V, Alexa CA, Na E, Stevis PE, Xin Y, Bonner-Weir S, Cohen JC, Hobbs HH, Murphy AJ, Yancopoulos GD, Gromada J (Oct 2014). "ANGPTL8/betatrophin does not control pancreatic beta cell expansion". Cell 159 (3): 691–6. doi:10.1016/j.cell.2014.09.027. PMID 25417115.
  5. ↑ Stewart AF (Apr 2014). "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. doi:10.2337/db14-0000. PMID 24651805.
  6. 1 2 Wang Y, Quagliarini F, Gusarova V, Gromada J, Valenzuela DM, Cohen JC, Hobbs HH (Oct 2013). "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. doi:10.1073/pnas.1315292110. PMID 24043787.
  7. ↑ Fu Z, Yao F, Abou-Samra AB, Zhang R (Jan 2013). "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. doi:10.1016/j.bbrc.2012.12.025. PMID 23261442.
  8. 1 2 Zhang R (Aug 2012). "Lipasin, a novel nutritionally-regulated liver-enriched factor that regulates serum triglyceride levels". Biochemical and Biophysical Research Communications 424 (4): 786–92. doi:10.1016/j.bbrc.2012.07.038. PMID 22809513.
  9. ↑ Ren G, Kim JY, Smas CM (Aug 2012). "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. doi:10.1152/ajpendo.00084.2012. PMID 22569073.
  10. 1 2 Fu Z, Abou-Samra AB, Zhang R (December 2015). "A lipasin/Angptl8 monoclonal antibody lowers mouse serum triglycerides involving increased postprandial activity of the cardiac lipoprotein lipase". Scientific Reports 5: 18502. doi:10.1038/srep18502. PMID 26687026.
  11. ↑ Zhang R (April 2016). "The ANGPTL3-4-8 model, a molecular mechanism for triglyceride trafficking.". Open Biology 6: 150272. doi:10.1098/rsob.150272. PMID 27053679.
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