ANGL8_HUMAN
ID ANGL8_HUMAN Reviewed; 198 AA.
AC Q6UXH0; Q9NQZ1;
DT 26-FEB-2008, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 113.
DE RecName: Full=Angiopoietin-like protein 8 {ECO:0000312|HGNC:HGNC:24933};
DE AltName: Full=Betatrophin {ECO:0000303|PubMed:25417115};
DE AltName: Full=Lipasin {ECO:0000303|PubMed:22809513};
DE AltName: Full=Refeeding-induced fat and liver protein {ECO:0000303|PubMed:22569073};
DE Flags: Precursor;
GN Name=ANGPTL8 {ECO:0000312|HGNC:HGNC:24933};
GN Synonyms=C19orf80, RIFL {ECO:0000303|PubMed:22569073};
GN ORFNames=UNQ599/PRO1185 {ECO:0000303|PubMed:12975309};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=15352036; DOI=10.1002/ijc.20363;
RA Dong X.Y., Pang X.W., Yu S.T., Su Y.R., Wang H.C., Yin Y.H., Wang Y.D.,
RA Chen W.F.;
RT "Identification of genes differentially expressed in human hepatocellular
RT carcinoma by a modified suppression subtractive hybridization method.";
RL Int. J. Cancer 112:239-248(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT identify novel human secreted and transmembrane proteins: a bioinformatics
RT assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E.,
RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A.,
RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S.,
RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A.,
RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J.,
RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M.,
RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W.,
RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V.,
RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D.,
RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I.,
RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L.,
RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A.,
RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J.,
RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP FUNCTION, TISSUE SPECIFICITY, INDUCTION, AND DEVELOPMENTAL STAGE.
RX PubMed=22569073; DOI=10.1152/ajpendo.00084.2012;
RA Ren G., Kim J.Y., Smas C.M.;
RT "Identification of RIFL, a novel adipocyte-enriched insulin target gene
RT with a role in lipid metabolism.";
RL Am. J. Physiol. 303:E334-E351(2012).
RN [6]
RP TISSUE SPECIFICITY.
RX PubMed=22809513; DOI=10.1016/j.bbrc.2012.07.038;
RA Zhang R.;
RT "Lipasin, a novel nutritionally-regulated liver-enriched factor that
RT regulates serum triglyceride levels.";
RL Biochem. Biophys. Res. Commun. 424:786-792(2012).
RN [7]
RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, INDUCTION, INTERACTION WITH
RP ANGPTL3, VARIANT TRP-59, AND CHARACTERIZATION OF VARIANT TRP-59.
RX PubMed=23150577; DOI=10.1073/pnas.1217552109;
RA Quagliarini F., Wang Y., Kozlitina J., Grishin N.V., Hyde R.,
RA Boerwinkle E., Valenzuela D.M., Murphy A.J., Cohen J.C., Hobbs H.H.;
RT "Atypical angiopoietin-like protein that regulates ANGPTL3.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:19751-19756(2012).
RN [8]
RP RETRACTED PAPER.
RX PubMed=23623304; DOI=10.1016/j.cell.2013.04.008;
RA Yi P., Park J.S., Melton D.A.;
RT "Betatrophin: a hormone that controls pancreatic beta cell proliferation.";
RL Cell 153:747-758(2013).
RN [9]
RP RETRACTION NOTICE OF PUBMED:23623304.
RX PubMed=28038792; DOI=10.1016/j.cell.2016.12.017;
RA Yi P., Park J.S., Melton D.A.;
RL Cell 168:326-326(2017).
RN [10]
RP LACK OF ROLE IN PANCREATIC BETA CELL PROLIFERATION.
RX PubMed=25417115; DOI=10.1016/j.cell.2014.09.027;
RA Gusarova V., Alexa C.A., Na A., Stevis P.E., Xin Y., Bonner-Weir S.,
RA Cohen J.C., Hobbs H.H., Murphy A.J., Yancopoulos G.D., Gromada J.;
RT "ANGPTL8/betatrophin does not control pancreatic beta cell expansion.";
RL Cell 159:691-696(2014).
RN [11]
RP POSSIBLE INVOLVEMENT IN NIDDM.
RX PubMed=25024395; DOI=10.2337/dc14-0602;
RA Hu H., Sun W., Yu S., Hong X., Qian W., Tang B., Wang D., Yang L., Wang J.,
RA Mao C., Zhou L., Yuan G.;
RT "Increased circulating levels of betatrophin in newly diagnosed type 2
RT diabetic patients.";
RL Diabetes Care 37:2718-2722(2014).
RN [12]
RP POSSIBLE INVOLVEMENT IN IDDM.
RX PubMed=24078058; DOI=10.1007/s00125-013-3071-1;
RA Espes D., Lau J., Carlsson P.O.;
RT "Increased circulating levels of betatrophin in individuals with long-
RT standing type 1 diabetes.";
RL Diabetologia 57:50-53(2014).
RN [13]
RP PROTEOLYTIC PROCESSING.
RX PubMed=25099942; DOI=10.1007/s00125-014-3346-1;
RA Fu Z., Abou-Samra A.B., Zhang R.;
RT "An explanation for recent discrepancies in levels of human circulating
RT betatrophin.";
RL Diabetologia 57:2232-2234(2014).
RN [14]
RP POSSIBLE INVOLVEMENT IN NIDDM.
RX PubMed=24963292; DOI=10.1155/2014/323407;
RA Espes D., Martinell M., Carlsson P.O.;
RT "Increased circulating betatrophin concentrations in patients with type 2
RT diabetes.";
RL Int. J. Endocrinol. 2014:323407-323407(2014).
RN [15]
RP POSSIBLE INVOLVEMENT IN NIDDM.
RX PubMed=25050901; DOI=10.1210/jc.2014-1568;
RA Gomez-Ambrosi J., Pascual E., Catalan V., Rodriguez A., Ramirez B.,
RA Silva C., Gil M.J., Salvador J., Fruehbeck G.;
RT "Circulating betatrophin concentrations are decreased in human obesity and
RT type 2 diabetes.";
RL J. Clin. Endocrinol. Metab. 99:E2004-E2004(2014).
RN [16]
RP POSSIBLE INVOLVEMENT IN NIDDM.
RX PubMed=25303484; DOI=10.1210/jc.2014-2300;
RA Chen X., Lu P., He W., Zhang J., Liu L., Yang Y., Liu Z., Xie J., Shao S.,
RA Du T., Su X., Zhou X., Hu S., Yuan G., Zhang M., Zhang H., Liu L., Wang D.,
RA Yu X.;
RT "Circulating betatrophin levels are increased in patients with type 2
RT diabetes and associated with insulin resistance.";
RL J. Clin. Endocrinol. Metab. 100:E96-E100(2015).
RN [17]
RP POSSIBLE INVOLVEMENT IN NIDDM.
RX PubMed=24852694; DOI=10.1038/srep05013;
RA Fu Z., Berhane F., Fite A., Seyoum B., Abou-Samra A.B., Zhang R.;
RT "Elevated circulating lipasin/betatrophin in human type 2 diabetes and
RT obesity.";
RL Sci. Rep. 4:5013-5013(2014).
CC -!- FUNCTION: Hormone that acts as a blood lipid regulator by regulating
CC serum triglyceride levels (PubMed:22569073, PubMed:22809513,
CC PubMed:23150577). May be involved in the metabolic transition between
CC fasting and refeeding: required to direct fatty acids to adipose tissue
CC for storage in the fed state (By similarity).
CC {ECO:0000250|UniProtKB:Q8R1L8, ECO:0000269|PubMed:22569073,
CC ECO:0000269|PubMed:22809513, ECO:0000269|PubMed:23150577}.
CC -!- SUBUNIT: Interacts with ANGPTL3. {ECO:0000269|PubMed:23150577}.
CC -!- INTERACTION:
CC Q6UXH0; Q96PM5: RCHY1; NbExp=2; IntAct=EBI-3943039, EBI-947779;
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:23150577}.
CC -!- TISSUE SPECIFICITY: Predominantly expressed in liver. Also expressed in
CC adipose tissues. {ECO:0000269|PubMed:22569073,
CC ECO:0000269|PubMed:22809513}.
CC -!- DEVELOPMENTAL STAGE: Transcripts are up-regulated by 100 fold during
CC adipogenesis. {ECO:0000269|PubMed:22569073}.
CC -!- INDUCTION: In response to food intake. Stimulated by insulin.
CC {ECO:0000269|PubMed:22569073, ECO:0000269|PubMed:23150577}.
CC -!- PTM: Proteolytically cleaved at the N-terminus.
CC {ECO:0000303|PubMed:25099942}.
CC -!- DISEASE: Diabetes mellitus, insulin-dependent (IDDM) [MIM:222100]: A
CC multifactorial disorder of glucose homeostasis that is characterized by
CC susceptibility to ketoacidosis in the absence of insulin therapy.
CC Clinical features are polydipsia, polyphagia and polyuria which result
CC from hyperglycemia-induced osmotic diuresis and secondary thirst. These
CC derangements result in long-term complications that affect the eyes,
CC kidneys, nerves, and blood vessels. {ECO:0000305|PubMed:24078058}.
CC Note=The gene represented in this entry may be involved in disease
CC pathogenesis. Increased protein levels are observed in the serum of
CC patients. This result should however be reinvestigated in light of
CC recent advances that suggest that this protein is not promoting
CC pancreatic beta cell proliferation. {ECO:0000305|PubMed:24078058}.
CC -!- DISEASE: Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]:
CC A multifactorial disorder of glucose homeostasis caused by a lack of
CC sensitivity to the body's own insulin. Affected individuals usually
CC have an obese body habitus and manifestations of a metabolic syndrome
CC characterized by diabetes, insulin resistance, hypertension and
CC hypertriglyceridemia. The disease results in long-term complications
CC that affect the eyes, kidneys, nerves, and blood vessels.
CC {ECO:0000305|PubMed:24852694, ECO:0000305|PubMed:24963292,
CC ECO:0000305|PubMed:25024395, ECO:0000305|PubMed:25303484}. Note=The
CC gene represented in this entry may be involved in disease pathogenesis.
CC Increased protein levels are observed in the serum of patients and are
CC associated with insulin resistance (PubMed:25024395, PubMed:25303484,
CC PubMed:24963292, PubMed:24852694). According to another report, protein
CC levels are decreased in the serum of patients (PubMed:25050901).
CC Discrepancies between increased and decreased levels of proteins levels
CC in NIDDM patients may be explained by the use of different kits
CC developed on the market that either use antibodies recognizing the N-
CC terminal or the C-terminal part of the protein (PubMed:25099942). These
CC results should however be reinvestigated in light of recent advances
CC that suggest that this protein is not promoting pancreatic beta cell
CC proliferation. {ECO:0000305|PubMed:24852694,
CC ECO:0000305|PubMed:24963292, ECO:0000305|PubMed:25024395,
CC ECO:0000305|PubMed:25050901, ECO:0000305|PubMed:25099942,
CC ECO:0000305|PubMed:25303484}.
CC -!- SIMILARITY: Belongs to the ANGPTL8 family. {ECO:0000305}.
CC -!- CAUTION: Initially reported to specifically promote pancreatic beta
CC cell proliferation without insulin resistance and to promote beta cell
CC mass expansion, thereby improving glucose tolerance (PubMed:23623304).
CC However, this result could not be confirmed by further studies and the
CC original paper was later retracted (PubMed:28038792). The lack of a
CC role in beta cell proliferation was also confirmed in another study
CC (PubMed:25417115). {ECO:0000269|PubMed:25417115,
CC ECO:0000305|PubMed:23623304, ECO:0000305|PubMed:28038792}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAF76204.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=EAW84186.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AF271350; AAF76204.2; ALT_INIT; mRNA.
DR EMBL; AY358356; AAQ88722.1; -; mRNA.
DR EMBL; AC011472; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471106; EAW84186.1; ALT_SEQ; Genomic_DNA.
DR CCDS; CCDS54220.1; -.
DR RefSeq; NP_061157.3; NM_018687.6.
DR AlphaFoldDB; Q6UXH0; -.
DR SMR; Q6UXH0; -.
DR BioGRID; 120994; 90.
DR IntAct; Q6UXH0; 2.
DR STRING; 9606.ENSP00000479969; -.
DR ChEMBL; CHEMBL4523352; -.
DR PhosphoSitePlus; Q6UXH0; -.
DR BioMuta; ANGPTL8; -.
DR DMDM; 74738217; -.
DR MassIVE; Q6UXH0; -.
DR PaxDb; Q6UXH0; -.
DR PeptideAtlas; Q6UXH0; -.
DR PRIDE; Q6UXH0; -.
DR ProteomicsDB; 67615; -.
DR Antibodypedia; 25764; 217 antibodies from 25 providers.
DR DNASU; 55908; -.
DR Ensembl; ENST00000252453.12; ENSP00000252453.7; ENSG00000130173.13.
DR Ensembl; ENST00000616433.4; ENSP00000479969.1; ENSG00000130173.13.
DR GeneID; 55908; -.
DR KEGG; hsa:55908; -.
DR MANE-Select; ENST00000252453.12; ENSP00000252453.7; NM_018687.7; NP_061157.3.
DR UCSC; uc021upf.2; human.
DR CTD; 55908; -.
DR DisGeNET; 55908; -.
DR GeneCards; ANGPTL8; -.
DR HGNC; HGNC:24933; ANGPTL8.
DR HPA; ENSG00000130173; Tissue enriched (liver).
DR MIM; 125853; phenotype.
DR MIM; 222100; phenotype.
DR MIM; 616223; gene.
DR neXtProt; NX_Q6UXH0; -.
DR OpenTargets; ENSG00000130173; -.
DR VEuPathDB; HostDB:ENSG00000130173; -.
DR eggNOG; ENOG502SF52; Eukaryota.
DR GeneTree; ENSGT00440000034383; -.
DR HOGENOM; CLU_097765_0_0_1; -.
DR InParanoid; Q6UXH0; -.
DR OMA; GAWLGHA; -.
DR OrthoDB; 1420384at2759; -.
DR PhylomeDB; Q6UXH0; -.
DR TreeFam; TF337951; -.
DR PathwayCommons; Q6UXH0; -.
DR Reactome; R-HSA-8963889; Assembly of active LPL and LIPC lipase complexes.
DR SignaLink; Q6UXH0; -.
DR BioGRID-ORCS; 55908; 14 hits in 1054 CRISPR screens.
DR GenomeRNAi; 55908; -.
DR Pharos; Q6UXH0; Tbio.
DR PRO; PR:Q6UXH0; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; Q6UXH0; protein.
DR Bgee; ENSG00000130173; Expressed in right lobe of liver and 88 other tissues.
DR ExpressionAtlas; Q6UXH0; baseline and differential.
DR Genevisible; Q6UXH0; HS.
DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB.
DR GO; GO:0005179; F:hormone activity; IEA:UniProtKB-KW.
DR GO; GO:0048469; P:cell maturation; IEA:Ensembl.
DR GO; GO:0044255; P:cellular lipid metabolic process; ISS:UniProtKB.
DR GO; GO:0045444; P:fat cell differentiation; IEA:Ensembl.
DR GO; GO:0010954; P:positive regulation of protein processing; IDA:MGI.
DR GO; GO:0019216; P:regulation of lipid metabolic process; IDA:UniProtKB.
DR GO; GO:0050746; P:regulation of lipoprotein metabolic process; IMP:MGI.
DR GO; GO:0070328; P:triglyceride homeostasis; IDA:UniProtKB.
DR InterPro; IPR026614; ANGPTL8.
DR PANTHER; PTHR21463; PTHR21463; 1.
PE 1: Evidence at protein level;
KW Diabetes mellitus; Hormone; Lipid metabolism; Reference proteome; Secreted;
KW Signal.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT CHAIN 22..198
FT /note="Angiopoietin-like protein 8"
FT /id="PRO_0000319617"
FT VARIANT 59
FT /note="R -> W (lover plasma LDL-cholesterol and HDL-
FT cholesterol levels; dbSNP:rs2278426)"
FT /evidence="ECO:0000269|PubMed:23150577"
FT /id="VAR_039046"
FT VARIANT 147
FT /note="R -> Q (in dbSNP:rs34056604)"
FT /id="VAR_039047"
SQ SEQUENCE 198 AA; 22105 MW; 90A29DCEBC5E992E CRC64;
MPVPALCLLW ALAMVTRPAS AAPMGGPELA QHEELTLLFH GTLQLGQALN GVYRTTEGRL
TKARNSLGLY GRTIELLGQE VSRGRDAAQE LRASLLETQM EEDILQLQAE ATAEVLGEVA
QAQKVLRDSV QRLEVQLRSA WLGPAYREFE VLKAHADKQS HILWALTGHV QRQRREMVAQ
QHRLRQIQER LHTAALPA
