Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCD5Z9W)

• DOT Name: Angiopoietin-related protein 3 (ANGPTL3)
• Synonyms: Angiopoietin-5; ANG-5; Angiopoietin-like protein 3
• Gene Name: ANGPTL3
• Related Disease: Familial hypobetalipoproteinemia 2
• UniProt ID: ANGL3_HUMAN
• PDB ID: 6EUA
• Pfam ID: PF00147
• Sequence:
  MFTIKLLLFIVPLVISSRIDQDNSSFDSLSPEPKSRFAMLDDVKILANGLLQLGHGLKDF
  VHKTKGQINDIFQKLNIFDQSFYDLSLQTSEIKEEEKELRRTTYKLQVKNEEVKNMSLEL
  NSKLESLLEEKILLQQKVKYLEEQLTNLIQNQPETPEHPEVTSLKTFVEKQDNSIKDLLQ
  TVEDQYKQLNQQHSQIKEIENQLRRTSIQEPTEISLSSKPRAPRTTPFLQLNEIRNVKHD
  GIPAECTTIYNRGEHTSGMYAIRPSNSQVFHVYCDVISGSPWTLIQHRIDGSQNFNETWE
  NYKYGFGRLDGEFWLGLEKIYSIVKQSNYVLRIELEDWKDNKHYIEYSFYLGNHETNYTL
  HLVAITGNVPNAIPENKDLVFSTWDHKAKGHFNCPEGYSGGWWWHDECGENNLNGKYNKP
  RAKSKPERRRGLSWKSQNGRLYSIKSTKMLIHPTDSESFE
• Function: Acts in part as a hepatokine that is involved in regulation of lipid and glucose metabolism. Proposed to play a role in the trafficking of energy substrates to either storage or oxidative tissues in response to food intake. Has a stimulatory effect on plasma triglycerides (TG), which is achieved by suppressing plasma TG clearance via inhibition of LPL activity. The inhibition of LPL activity appears to be an indirect mechanism involving recruitment of proprotein convertases PCSK6 and FURIN to LPL leading to cleavage and dissociation of LPL from the cell surface; the function does not require ANGPTL3 proteolytic cleavage but seems to be mediated by the N-terminal domain, and is not inhibited by GPIHBP1. Can inhibit endothelial lipase, causing increased plasma levels of high density lipoprotein (HDL) cholesterol and phospholipids. Can bind to adipocytes to activate lipolysis, releasing free fatty acids and glycerol. Suppresses LPL specifically in oxidative tissues which is required to route very low density lipoprotein (VLDL)-TG to white adipose tissue (WAT) for storage in response to food; the function may involve cooperation with circulating, liver-derived ANGPTL8 and ANGPTL4 expression in WAT. Contributes to lower plasma levels of low density lipoprotein (LDL)-cholesterol by a mechanism that is independent of the canonical pathway implicating APOE and LDLR. May stimulate hypothalamic LPL activity; [ANGPTL3(17-221)]: In vitro inhibits LPL activity; not effective on GPIHBP1-stabilized LPL; Involved in angiogenesis. Binds to endothelial cells via integrin alpha-V/beta-3 (ITGAV:ITGB3), activates FAK, MAPK and Akt signaling pathways and induces cell adhesion and cell migration. Secreted from podocytes, may modulate properties of glomerular endothelial cells involving integrin alpha-V/beta-3 and Akt signaling. May increase the motility of podocytes. May induce actin filament rearrangements in podocytes implicating integrin alpha-V/beta-3 and Rac1 activation. Binds to hematopoietic stem cells (HSC) and is involved in the regulation of HSC activity probably implicating down-regulation of IKZF1/IKAROS.
• Tissue Specificity: Expressed principally in liver. Weakly expressed in kidney. Binds to adipocytes. Increased expression and colocalization with activated ITGB3 in glomeruli of patients with nephrotic syndrome showing effaced podocyte foot processes (at protein level).
• KEGG Pathway: Cholesterol metabolism (hsa04979)
• Reactome Pathway:
  NR1H2 & NR1H3 regulate gene expression linked to lipogenesis (R-HSA-9029558)
  Assembly of active LPL and LIPC lipase complexes (R-HSA-8963889)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial hypobetalipoproteinemia 2	DISNSAA7	Definitive	Autosomal recessive	[1]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Angiopoietin-related protein 3 (ANGPTL3).	[2]

18 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Angiopoietin-related protein 3 (ANGPTL3).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Angiopoietin-related protein 3 (ANGPTL3).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Angiopoietin-related protein 3 (ANGPTL3).	[3]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Angiopoietin-related protein 3 (ANGPTL3).	[5]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Angiopoietin-related protein 3 (ANGPTL3).	[6]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Angiopoietin-related protein 3 (ANGPTL3).	[6]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Angiopoietin-related protein 3 (ANGPTL3).	[7]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Angiopoietin-related protein 3 (ANGPTL3).	[6]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Angiopoietin-related protein 3 (ANGPTL3).	[6]
Sulindac	DM2QHZU	Approved	Sulindac decreases the expression of Angiopoietin-related protein 3 (ANGPTL3).	[6]
Chenodiol	DMQ8JIK	Approved	Chenodiol decreases the expression of Angiopoietin-related protein 3 (ANGPTL3).	[8]
Allopurinol	DMLPAOB	Approved	Allopurinol decreases the expression of Angiopoietin-related protein 3 (ANGPTL3).	[6]
Tianeptine	DMYN8MA	Approved	Tianeptine decreases the expression of Angiopoietin-related protein 3 (ANGPTL3).	[7]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone decreases the expression of Angiopoietin-related protein 3 (ANGPTL3).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Angiopoietin-related protein 3 (ANGPTL3).	[9]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Angiopoietin-related protein 3 (ANGPTL3).	[6]
Citrate	DM37NYK	Preclinical	Citrate increases the expression of Angiopoietin-related protein 3 (ANGPTL3).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Angiopoietin-related protein 3 (ANGPTL3).	[10]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [6] Drug-induced hepatic steatosis in absence of severe mitochondrial dysfunction in HepaRG cells: proof of multiple mechanism-based toxicity. Cell Biol Toxicol. 2021 Apr;37(2):151-175. doi: 10.1007/s10565-020-09537-1. Epub 2020 Jun 14.
• [7] Advantageous use of HepaRG cells for the screening and mechanistic study of drug-induced steatosis. Toxicol Appl Pharmacol. 2016 Jul 1;302:1-9. doi: 10.1016/j.taap.2016.04.007. Epub 2016 Apr 16.
• [8] Chenodeoxycholic acid significantly impacts the expression of miRNAs and genes involved in lipid, bile acid and drug metabolism in human hepatocytes. Life Sci. 2016 Jul 1;156:47-56.
• [9] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [10] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.