|Chromosome 19 open reading frame 80|
|Symbols||; ANGPTL8; PRO1185; PVPA599; RIFL; TD26|
The gene for betatrophin lies on mouse chromosome 9 (gene symbol: Gm6484) and on human chromosome 19 (gene symbol: C19orf80).
The link between betatrophin and mouse islet cell proliferation was made by Douglas Melton and Peng Yi from Harvard in 2013. Before that time, betatrophin was and actually still is known under various names: TD26, RIFL, Lipasin, and Angptl8. Since betatrophin is a member of the angiopoietin-like gene family and shares extensive homology with Angptl4 and Angptl3, the name Angptl8 is preferred.
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. 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. Based on these studies, it is fairly safe to say that the notion that betatrophin promotes beta cell expansion is dead.
The encoded 22kDa protein contains an N-terminal secretion signal and two coiled-coil domains and is a member of the angiopoietin-like gene family. However, in contrast to other angiopoietin-like proteins, betatrophin lacks the C-terminal fibrinogen-like domain. It shares with Angptl4 and Angptl3 the ability to inhibit the enzyme Lipoprotein lipase, causing elevation of circulating Triglyceride levels in mice. Despite having elevated post-heparin plasma Lipoprotein lipase activity, mice lacking betatrophin/Angptl8 exhibit markedly decreased uptake of Very low-density lipoprotein-derived fatty acids into adipose tissue. Deletion of betatrophin/Angptl8 does not seem to impact glucose and insulin tolerance in mice.
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. Unfortunately, since new data have greatly called into question the ability of betatrophin to increase beta-cell replication, its potential use a therapy for type 2 diabetes is limited. Inhibition of Angptl8 represents a possible therapeutic strategy for hypertriglyceridemia.
- Jiao Y, Le Lay J, Yu M, Naji A, Kaestner KH (April 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.
- Gusarova V, Alexa CA, Na E, Stevis PE, Xin Y, Bonner-Weir S, Cohen JC, Hobbs HH, Murphy AJ, Yancopoulos GD, Gromada J (October 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.
- Wang Y, Quagliarini F, Gusarova V, Gromada J, Valenzuela DM, Cohen JC, Hobbs HH (October 2013). "Mice lacking ANGPTL8 (Betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis.". Proc Natl Acad Sci U S A 110 (10): 16109–14. doi:10.1073/pnas.1315292110. PMID 24043787.
- Ren G, Kim JY, Smas CM. (August 2012). "Identification of RIFL, a novel adipocyte-enriched insulin target gene with a role in lipid metabolism.". Am J Physiol Endocrinol Metab 303 (3): E334. doi:10.1152/ajpendo.00084.2012. PMID 22569073.
- Zhang R (August 2012). "Lipasin, a novel nutritionally-regulated liver-enriched factor that regulates serum triglyceride levels.". Biochem Biophys Res Commun. 424 (4): 786–92. doi:10.1016/j.bbrc.2012.07.038. PMID 22809513.
- Yi P, Park JS, Melton DA (April 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.
- Stewart AF (April 2014). "Betatrophin versus bitter-trophin and the elephant in the room: time for a new normal in β-cell regeneration research". Diabetes 63 (4): 1198–99. doi:10.2337/db14-0000. PMID 24353178.
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