Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE5PDD0)

• DOT Name: Diacylglycerol O-acyltransferase 2 (DGAT2)
• Synonyms: EC 2.3.1.20; Acyl-CoA retinol O-fatty-acyltransferase; ARAT; Retinol O-fatty-acyltransferase; EC 2.3.1.76; Diglyceride acyltransferase 2
• Gene Name: DGAT2
• Related Disease: Charcot marie tooth disease
• UniProt ID: DGAT2_HUMAN
• EC Number: 2.3.1.20; 2.3.1.76
• Pfam ID: PF03982
• Sequence:
  MKTLIAAYSGVLRGERQAEADRSQRSHGGPALSREGSGRWGTGSSILSALQDLFSVTWLN
  RSKVEKQLQVISVLQWVLSFLVLGVACSAILMYIFCTDCWLIAVLYFTWLVFDWNTPKKG
  GRRSQWVRNWAVWRYFRDYFPIQLVKTHNLLTTRNYIFGYHPHGIMGLGAFCNFSTEATE
  VSKKFPGIRPYLATLAGNFRMPVLREYLMSGGICPVSRDTIDYLLSKNGSGNAIIIVVGG
  AAESLSSMPGKNAVTLRNRKGFVKLALRHGADLVPIYSFGENEVYKQVIFEEGSWGRWVQ
  KKFQKYIGFAPCIFHGRGLFSSDTWGLVPYSKPITTVVGEPITIPKLEHPTQQDIDLYHT
  MYMEALVKLFDKHKTKFGLPETEVLEVN
• Function: Essential acyltransferase that catalyzes the terminal and only committed step in triacylglycerol synthesis by using diacylglycerol and fatty acyl CoA as substrates. Required for synthesis and storage of intracellular triglycerides. Probably plays a central role in cytosolic lipid accumulation. In liver, is primarily responsible for incorporating endogenously synthesized fatty acids into triglycerides. Functions also as an acyl-CoA retinol acyltransferase (ARAT). Also able to use 1-monoalkylglycerol (1-MAkG) as an acyl acceptor for the synthesis of monoalkyl-monoacylglycerol (MAMAG).
• Tissue Specificity: Predominantly expressed in liver and white adipose tissue. Expressed at lower level in mammary gland, testis and peripheral blood leukocytes. Expressed in sebaceous glands of normal skin but decreased psoriatic skin.
• KEGG Pathway:
  Glycerolipid metabolism (hsa00561)
  Metabolic pathways (hsa01100)
  Fat digestion and absorption (hsa04975)
• Reactome Pathway:
  Triglyceride biosynthesis (R-HSA-75109)
  Acyl chain remodeling of DAG and TAG (R-HSA-1482883)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Charcot marie tooth disease	DIS3BT2L	Limited	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Diacylglycerol O-acyltransferase 2 (DGAT2).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Diacylglycerol O-acyltransferase 2 (DGAT2).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Diacylglycerol O-acyltransferase 2 (DGAT2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Diacylglycerol O-acyltransferase 2 (DGAT2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Diacylglycerol O-acyltransferase 2 (DGAT2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Diacylglycerol O-acyltransferase 2 (DGAT2).	[3]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Diacylglycerol O-acyltransferase 2 (DGAT2).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Diacylglycerol O-acyltransferase 2 (DGAT2).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Diacylglycerol O-acyltransferase 2 (DGAT2).	[9]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Diacylglycerol O-acyltransferase 2 (DGAT2).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Diacylglycerol O-acyltransferase 2 (DGAT2).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Diacylglycerol O-acyltransferase 2 (DGAT2).	[12]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Diacylglycerol O-acyltransferase 2 (DGAT2).	[13]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Diacylglycerol O-acyltransferase 2 (DGAT2).	[14]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Diacylglycerol O-acyltransferase 2 (DGAT2).	[15]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Diacylglycerol O-acyltransferase 2 (DGAT2).	[16]
Tetracycline	DMZA017	Approved	Tetracycline increases the expression of Diacylglycerol O-acyltransferase 2 (DGAT2).	[17]
Vitamin B3	DMQVRZH	Approved	Vitamin B3 decreases the activity of Diacylglycerol O-acyltransferase 2 (DGAT2).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Diacylglycerol O-acyltransferase 2 (DGAT2).	[19]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone decreases the expression of Diacylglycerol O-acyltransferase 2 (DGAT2).	[20]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Diacylglycerol O-acyltransferase 2 (DGAT2).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Diacylglycerol O-acyltransferase 2 (DGAT2).	[22]
PJ34	DMXO6YH	Preclinical	PJ34 decreases the expression of Diacylglycerol O-acyltransferase 2 (DGAT2).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Diacylglycerol O-acyltransferase 2 (DGAT2).	[24]
U0126	DM31OGF	Investigative	U0126 increases the expression of Diacylglycerol O-acyltransferase 2 (DGAT2).	[17]
GW7647	DM9RD0C	Investigative	GW7647 increases the expression of Diacylglycerol O-acyltransferase 2 (DGAT2).	[25]
T0901317	DMZQVDI	Investigative	T0901317 increases the expression of Diacylglycerol O-acyltransferase 2 (DGAT2).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Diacylglycerol O-acyltransferase 2 (DGAT2).	[23]

References

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• [4] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
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• [10] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [13] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [14] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [15] Deletion of circadian gene Per1 alleviates acute ethanol-induced hepatotoxicity in mice. Toxicology. 2013 Dec 15;314(2-3):193-201. doi: 10.1016/j.tox.2013.09.009. Epub 2013 Oct 18.
• [16] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [17] Increased hepatic Fatty Acid uptake and esterification contribute to tetracycline-induced steatosis in mice. Toxicol Sci. 2015 Jun;145(2):273-82. doi: 10.1093/toxsci/kfv049. Epub 2015 Mar 4.
• [18] Niacin noncompetitively inhibits DGAT2 but not DGAT1 activity in HepG2 cells. J Lipid Res. 2004 Oct;45(10):1835-45. doi: 10.1194/jlr.M300403-JLR200. Epub 2004 Jul 16.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] Effects of dihydrotestosterone on differentiation and proliferation of human mesenchymal stem cells and preadipocytes. Mol Cell Endocrinol. 2008 Dec 16;296(1-2):32-40. doi: 10.1016/j.mce.2008.08.019. Epub 2008 Aug 28.
• [21] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [22] Identification of AhR-regulated genes involved in PAH-induced immunotoxicity using a highly-sensitive DNA chip, 3D-Gene human immunity and metabolic syndrome 9k. Toxicol In Vitro. 2010 Feb;24(1):85-91.
• [23] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [24] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [25] Farnesol induces fatty acid oxidation and decreases triglyceride accumulation in steatotic HepaRG cells. Toxicol Appl Pharmacol. 2019 Feb 15;365:61-70.
• [26] Editor's Highlight: Mechanistic Toxicity Tests Based on an Adverse Outcome Pathway Network for Hepatic Steatosis. Toxicol Sci. 2017 Sep 1;159(1):159-169. doi: 10.1093/toxsci/kfx121.