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] However, this link has been quickly proven false by other researchers.[2] In fact, in December 2016 the original paper by Melton and Yi was retracted, putting the link between betatrophin and islets cells to rest. Given the status of betatrophin and taking into account that betatrophin is a member of the angiopoietin-like gene family and shares extensive homology with Angptl4 and Angptl3, the name betatrophin should be abandoned in favor of Angptl8. Other names for betatrophin include TD26, RIFL, and Lipasin.[3]
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.[4] 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.[5] Based on these studies, it is fairly safe to say that the notion that betatrophin promotes beta cell expansion is dead, which was made official by the retraction of the original paper.[4][6] Deletion of betatrophin/Angptl8 does not seem to impact glucose and insulin tolerance in mice.[7]
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.[8] 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.[9] In mice betatrophin is secreted by the liver.[9][10]
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).[7] 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,[11] as suggested by the ANGPTL3-4-8 model.[12]
Structure
Three dimensional structure of none of the members of Angiopoietin like proteins (ANGPTLs) is available up till now. However, the structure of ANGPTL8 was predicted by homology modeling and is also reported in literature.[13] 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.[14]
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.[5] Inhibition of Angptl8 represents a possible therapeutic strategy for hypertriglyceridemia.[11]
↑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. PMID23415864.
↑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. PMID23261442.
↑ 9.09.1Zhang 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. PMID22809513.
↑Siddiqa A, Ahmad J, Ali A, Paracha RZ, Bibi Z, Aslam B (April 2016). "Structural characterization of ANGPTL8 (betatrophin) with its interacting partner lipoprotein lipase". Computational Biology and Chemistry. 61: 210–20. doi:10.1016/j.compbiolchem.2016.01.009. PMID26908254.
↑Siddiqa A, Cirillo E, Tareen SH, Ali A, Kutmon M, Eijssen LM, Ahmad J, Evelo CT, Coort SL (October 2017). "Visualizing the regulatory role of Angiopoietin-like protein 8 (ANGPTL8) in glucose and lipid metabolic pathways". Genomics. 109 (5–6): 408–418. doi:10.1016/j.ygeno.2017.06.006. PMID28684091.