ANGPTL8

Last updated
ANGPTL8
Identifiers
Aliases ANGPTL8 , PRO1185, PVPA599, RIFL, TD26, C19orf80, Betatrophin, angiopoietin like 8
External IDs OMIM: 616223; MGI: 3643534; HomoloGene: 83285; GeneCards: ANGPTL8; OMA:ANGPTL8 - orthologs
Orthologs
SpeciesHumanMouse
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: 21.75 – 21.75 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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

Contents

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 [9] In fact, in December 2016 the original paper by Melton and Yi was retracted, putting the link between ANGPTL8 and islets cells to rest.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]

Related Research Articles

<span class="mw-page-title-main">Lipolysis</span> Metabolism involving breakdown of lipids

Lipolysis is the metabolic pathway through which lipid triglycerides are hydrolyzed into a glycerol and free fatty acids. It is used to mobilize stored energy during fasting or exercise, and usually occurs in fat adipocytes. The most important regulatory hormone in lipolysis is insulin; lipolysis can only occur when insulin action falls to low levels, as occurs during fasting. Other hormones that affect lipolysis include leptin, glucagon, epinephrine, norepinephrine, growth hormone, atrial natriuretic peptide, brain natriuretic peptide, and cortisol.

<span class="mw-page-title-main">Chylomicron</span> One of the five major groups of lipoprotein

Chylomicrons, also known as ultra low-density lipoproteins (ULDL), are lipoprotein particles that consist of triglycerides (85–92%), phospholipids (6–12%), cholesterol (1–3%), and proteins (1–2%). They transport dietary lipids, such as fats and cholesterol, from the intestines to other locations in the body, within the water-based solution of the bloodstream. ULDLs are one of the five major groups lipoproteins are divided into based on their density. A protein specific to chylomicrons is ApoB48.

<span class="mw-page-title-main">Lipoprotein lipase</span> Mammalian protein found in Homo sapiens

Lipoprotein lipase (LPL) (EC 3.1.1.34, systematic name triacylglycerol acylhydrolase (lipoprotein-dependent)) is a member of the lipase gene family, which includes pancreatic lipase, hepatic lipase, and endothelial lipase. It is a water-soluble enzyme that hydrolyzes triglycerides in lipoproteins, such as those found in chylomicrons and very low-density lipoproteins (VLDL), into two free fatty acids and one monoacylglycerol molecule:

<span class="mw-page-title-main">Colipase</span> Mammalian protein found in humans

Colipase, abbreviated CLPS, is a protein co-enzyme required for optimal enzyme activity of pancreatic lipase. It is secreted by the pancreas in an inactive form, procolipase, which is activated in the intestinal lumen by trypsin. Its function is to prevent the inhibitory effect of bile salts on the lipase-catalyzed intraduodenal hydrolysis of dietary long-chain triglycerides.

Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown and storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In animals, these fats are obtained from food and are synthesized by the liver. Lipogenesis is the process of synthesizing these fats. The majority of lipids found in the human body from ingesting food are triglycerides and cholesterol. Other types of lipids found in the body are fatty acids and membrane lipids. Lipid metabolism is often considered the digestion and absorption process of dietary fat; however, there are two sources of fats that organisms can use to obtain energy: from consumed dietary fats and from stored fat. Vertebrates use both sources of fat to produce energy for organs such as the heart to function. Since lipids are hydrophobic molecules, they need to be solubilized before their metabolism can begin. Lipid metabolism often begins with hydrolysis, which occurs with the help of various enzymes in the digestive system. Lipid metabolism also occurs in plants, though the processes differ in some ways when compared to animals. The second step after the hydrolysis is the absorption of the fatty acids into the epithelial cells of the intestinal wall. In the epithelial cells, fatty acids are packaged and transported to the rest of the body.

<span class="mw-page-title-main">Monoacylglycerol lipase</span> Class of enzymes

Monoacylglycerol lipase is an enzyme that, in humans, is encoded by the MGLL gene. MAGL is a 33-kDa, membrane-associated member of the serine hydrolase superfamily and contains the classical GXSXG consensus sequence common to most serine hydrolases. The catalytic triad has been identified as Ser122, His269, and Asp239.

<span class="mw-page-title-main">Hormone-sensitive lipase</span> Enzyme

Hormone-sensitive lipase (EC 3.1.1.79, HSL), also previously known as cholesteryl ester hydrolase (CEH), sometimes referred to as triacylglycerol lipase, is an enzyme that, in humans, is encoded by the LIPE gene, and catalyzes the following reaction:

<span class="mw-page-title-main">Lipoprotein lipase deficiency</span> Genetic disorder in fat handling

Lipoprotein lipase deficiency is a genetic disorder in which a person has a defective gene for lipoprotein lipase, which leads to very high triglycerides, which in turn causes stomach pain and deposits of fat under the skin, and which can lead to problems with the pancreas and liver, which in turn can lead to diabetes. The disorder only occurs if a child acquires the defective gene from both parents. It is managed by restricting fat in diet to less than 20 g/day.

<span class="mw-page-title-main">Hepatic lipase</span> Mammalian protein found in Homo sapiens

Hepatic lipase (HL), also called hepatic triglyceride lipase (HTGL) or LIPC (for "lipase, hepatic"), is a form of lipase, catalyzing the hydrolysis of triacylglyceride. Hepatic lipase is coded by chromosome 15 and its gene is also often referred to as HTGL or LIPC. Hepatic lipase is expressed mainly in liver cells, known as hepatocytes, and endothelial cells of the liver. The hepatic lipase can either remain attached to the liver or can unbind from the liver endothelial cells and is free to enter the body's circulation system. When bound on the endothelial cells of the liver, it is often found bound to heparan sulfate proteoglycans (HSPG), keeping HL inactive and unable to bind to HDL (high-density lipoprotein) or IDL (intermediate-density lipoprotein). When it is free in the bloodstream, however, it is found associated with HDL to maintain it inactive. This is because the triacylglycerides in HDL serve as a substrate, but the lipoprotein contains proteins around the triacylglycerides that can prevent the triacylglycerides from being broken down by HL.

Endothelial lipase (LIPG) is a form of lipase secreted by vascular endothelial cells in tissues with high metabolic rates and vascularization, such as the liver, lung, kidney, and thyroid gland. The LIPG enzyme is a vital component to many biological processes. These processes include lipoprotein metabolism, cytokine expression, and lipid composition in cells. Unlike the lipases that hydrolyze Triglycerides, endothelial lipase primarily hydrolyzes phospholipids. Due to the hydrolysis specificity, endothelial lipase contributes to multiple vital systems within the body. On the contrary to the beneficial roles that LIPG plays within the body, endothelial lipase is thought to play a potential role in cancer and inflammation. Knowledge obtained in vitro and in vivo suggest the relations to these conditions, but human interaction knowledge lacks due to the recent discovery of endothelial lipase. Endothelial lipase was first characterized in 1999. The two independent research groups which are notable for this discovery cloned the endothelial lipase gene and identified the novel lipase secreted from endothelial cells. The anti-Atherosclerosis opportunity through alleviating plaque blockage and prospective ability to raise High-density lipoprotein (HDL) have gained endothelial lipase recognition.

<span class="mw-page-title-main">Gastric lipase</span> Class of enzymes

Gastric lipase, also known as LIPF, is an enzymatic protein that, in humans, is encoded by the LIPF gene.

<span class="mw-page-title-main">ANGPTL4</span> Protein-coding gene in the species Homo sapiens

Angiopoietin-like 4 is a protein that in humans is encoded by the ANGPTL4 gene. Alternatively spliced transcript variants encoded with different isoforms have been described. This gene was previously referred to as ANGPTL2, HFARP, PGAR, or FIAF but has been renamed ANGPTL4.

<span class="mw-page-title-main">Adipose triglyceride lipase</span> Mammalian protein found in Homo sapiens

Adipose triglyceride lipase, also known as patatin-like phospholipase domain-containing protein 2 and ATGL, is an enzyme that in humans is encoded by the PNPLA2 gene. ATGL catalyses the first reaction of lipolysis, where triacylglycerols are hydrolysed to diacylglycerols.

<span class="mw-page-title-main">Pancreatic lipase family</span> Mammalian protein found in Homo sapiens

Triglyceride lipases are a family of lipolytic enzymes that hydrolyse ester linkages of triglycerides. Lipases are widely distributed in animals, plants and prokaryotes.

<span class="mw-page-title-main">ANGPTL3</span> Protein-coding gene in the species Homo sapiens

Angiopoietin-like 3, also known as ANGPTL3, is a protein that in humans is encoded by the ANGPTL3 gene.

<span class="mw-page-title-main">Lipase</span> Class of enzymes which cleave fats via hydrolysis

In biochemistry, lipase refers to a class of enzymes that catalyzes the hydrolysis of fats. Some lipases display broad substrate scope including esters of cholesterol, phospholipids, and of lipid-soluble vitamins and sphingomyelinases; however, these are usually treated separately from "conventional" lipases. Unlike esterases, which function in water, lipases "are activated only when adsorbed to an oil–water interface". Lipases perform essential roles in digestion, transport and processing of dietary lipids in most, if not all, organisms.

<span class="mw-page-title-main">Familial hypertriglyceridemia</span> Medical condition

Familial hypertriglyceridemia is a genetic disorder characterized by the liver overproducing very-low-density lipoproteins (VLDL). As a result, an affected individual will have an excessive number of VLDL and triglycerides on a lipid profile. This genetic disorder usually follows an autosomal dominant inheritance pattern. The disorder presents clinically in patients with mild to moderate elevations in triglyceride levels. Familial hypertriglyceridemia is typically associated with other co-morbid conditions such as hypertension, obesity, and hyperglycemia. Individuals with the disorder are mostly heterozygous in an inactivating mutation of the gene encoding for lipoprotein lipase (LPL). This sole mutation can markedly elevate serum triglyceride levels. However, when combined with other medications or pathologies it can further elevate serum triglyceride levels to pathologic levels. Substantial increases in serum triglyceride levels can lead to certain clinical signs and the development of acute pancreatitis.

<span class="mw-page-title-main">Pirinixic acid</span> Chemical compound

Pirinixic acid is a peroxisome proliferator-activated receptor alpha (PPARα) agonist that is under experimental investigation for prevention of severe cardiac dysfunction, cardiomyopathy and heart failure as a result of lipid accumulation within cardiac myocytes. Treatment is primarily aimed at individuals with an adipose triglyceride lipase (ATGL) enzyme deficiency or mutation because of the essential PPAR protein interactions with free fatty acid monomers derived from the ATGL catalyzed lipid oxidation reaction. It was discovered as WY-14,643 in 1974.

<span class="mw-page-title-main">GPIHBP1</span> Protein-coding gene in the species Homo sapiens

Glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1 (GPI-HBP1) also known as high density lipoprotein-binding protein 1 is a protein that in humans is encoded by the GPIHBP1 gene.

The Angiopoietin-like proteins are proteins structurally like the angiopoietins but which do not bind to the angiopoietin receptors.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000130173 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000047822 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 Zhang R (August 2012). "Lipasin, a novel nutritionally-regulated liver-enriched factor that regulates serum triglyceride levels". Biochemical and Biophysical Research Communications. 424 (4): 786–792. doi:10.1016/j.bbrc.2012.07.038. PMID   22809513.
  6. 1 2 Ren G, Kim JY, Smas CM (August 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–E351. doi:10.1152/ajpendo.00084.2012. PMC   3423120 . PMID   22569073.
  7. ↑ Quagliarini F, Wang Y, Kozlitina J, Grishin NV, Hyde R, Boerwinkle E, et al. (November 2012). "Atypical angiopoietin-like protein that regulates ANGPTL3". Proceedings of the National Academy of Sciences of the United States of America. 109 (48): 19751–19756. Bibcode:2012PNAS..10919751Q. doi: 10.1073/pnas.1217552109 . PMC   3511699 . PMID   23150577.
  8. 1 2 Yi P, Park JS, Melton DA (May 2013). "Betatrophin: a hormone that controls pancreatic β cell proliferation". Cell. 153 (4): 747–758. doi:10.1016/j.cell.2013.04.008. PMC   3756510 . PMID   23623304. (Retracted, see doi:10.1016/j.cell.2016.12.017, PMID   28038792,  Retraction Watch . If this is an intentional citation to a retracted paper, please replace {{ retracted |...}} with {{ retracted |...|intentional=yes}}.)
  9. ↑ Gusarova V, Alexa CA, Na E, Stevis PE, Xin Y, Bonner-Weir S, et al. (October 2014). "ANGPTL8/betatrophin does not control pancreatic beta cell expansion". Cell. 159 (3): 691–696. doi:10.1016/j.cell.2014.09.027. PMC   4243040 . PMID   25417115.
  10. ↑ 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. PMID   23415864.
  11. ↑ 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. PMID   23261442.
  12. ↑ Chen YQ, Pottanat TG, Siegel RW, Ehsani M, Qian YW, Zhen EY, et al. (August 2020). "Angiopoietin-like protein 8 differentially regulates ANGPTL3 and ANGPTL4 during postprandial partitioning of fatty acids". Journal of Lipid Research. 61 (8): 1203–1220. doi: 10.1194/jlr.ra120000781 . PMC   7397750 . PMID   32487544.
  13. 1 2 3 Chi X, Britt EC, Shows HW, Hjelmaas AJ, Shetty SK, Cushing EM, et al. (October 2017). "ANGPTL8 promotes the ability of ANGPTL3 to bind and inhibit lipoprotein lipase". Molecular Metabolism. 6 (10): 1137–1149. doi:10.1016/j.molmet.2017.06.014. PMC   5641604 . PMID   29031715.
  14. ↑ Haller JF, Mintah IJ, Shihanian LM, Stevis P, Buckler D, Alexa-Braun CA, et al. (June 2017). "ANGPTL8 requires ANGPTL3 to inhibit lipoprotein lipase and plasma triglyceride clearance". Journal of Lipid Research. 58 (6): 1166–1173. doi: 10.1194/jlr.M075689 . PMC   5454515 . PMID   28413163.
  15. 1 2 Wang Y, Quagliarini F, Gusarova V, Gromada J, Valenzuela DM, Cohen JC, et al. (October 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): 16109–16114. Bibcode:2013PNAS..11016109W. doi: 10.1073/pnas.1315292110 . PMC   3791734 . PMID   24043787.
  16. 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. Bibcode:2015NatSR...518502F. doi:10.1038/srep18502. PMC   4685196 . PMID   26687026.
  17. ↑ Zhang R (April 2016). "The ANGPTL3-4-8 model, a molecular mechanism for triglyceride trafficking". Open Biology. 6 (4): 150272. doi:10.1098/rsob.150272. PMC   4852456 . PMID   27053679.
  18. 1 2 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): 1283–1288. doi:10.2337/db13-1435. PMC   3964501 . PMID   24353178.
  19. 1 2 Gusarova V, Alexa CA, Na E, Stevis PE, Xin Y, Bonner-Weir S, et al. (October 2014). "ANGPTL8/betatrophin does not control pancreatic beta cell expansion". Cell. 159 (3): 691–696. doi:10.1016/j.cell.2014.09.027. PMC   4243040 . PMID   25417115.
  20. ↑ 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): 1198–1199. doi:10.2337/DB14-0009. PMC   3964499 . PMID   24651805.
  21. ↑ 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. PMID   26908254.
  22. ↑ Siddiqa A, Cirillo E, Tareen SH, Ali A, Kutmon M, Eijssen LM, et al. (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 . PMID   28684091.
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