ANGPTL8 (also known as lipasin, previously betatrophin) is a
protein that in humans is encoded by the C19orf80gene.
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.[5][6][7] 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.[8] However, the link between ANGPTL8 and islet proliferation was quickly proven false by other researchers.[9] In fact, in December 2016 the original paper by Melton and Yi was retracted, putting the link between ANGPTL8 and islets cells to rest.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.[10]
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.[11] ANGPTL8 has been shown to form complexes with ANGPTL3 with an apparent stoichiometry of 3:1 of ANGPTL3 to ANGPTL8 respectively.[12] Formation of these complexes appears to require intracellular co-folding as mixing of ANGPTL8 and ANGPTL3 extracellularly does not result in complex formation.[13] ANGPTL8 is expressed in the hepatic tissue and secreted into circulation, in order for the efficient secretion of ANGPTL8 it must form a complex with ANGPTL3.[13] ANGPTL8 alone shows little inhibitory capacity and must form a complex with
ANGPTL3 to inhibit the enzyme
Lipoprotein lipase (LPL) and has been shown to greatly promote the ability of
ANGPTL3 to inhibit
LPL.[13][14] In mice ANGPTL8 is secreted by the liver and by adipose tissue, hepatic overexpression of ANGPTL8 causes elevation of circulating
Triglyceride levels.[5][6]
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).[15] 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,[16] as suggested by the ANGPTL3-4-8 model.[17]
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.[18] 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.[19] 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.[18][20] Deletion of ANGPTL8 does not seem to impact glucose and insulin tolerance in mice.[15]
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.[21] 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.[22]
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.[8] 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.[19] Inhibition of ANGPTL8 represents a possible therapeutic strategy for
hypertriglyceridemia.[16]
^Zhang R, Abou-Samra AB (March 2013). "Emerging roles of Lipasin as a critical lipid regulator". Biochemical and Biophysical Research Communications. 432 (3): 401–405.
doi:
10.1016/j.bbrc.2013.01.129.
PMID23415864.
^Fu Z, Yao F, Abou-Samra AB, Zhang R (January 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): 1126–1131.
doi:
10.1016/j.bbrc.2012.12.025.
PMID23261442.
^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: 210–220.
doi:
10.1016/j.compbiolchem.2016.01.009.
PMID26908254.