Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL104WL)

• DOT Name: Diacylglycerol O-acyltransferase 1 (DGAT1)
• Synonyms: EC 2.3.1.20; ACAT-related gene product 1; Acyl-CoA retinol O-fatty-acyltransferase; ARAT; Retinol O-fatty-acyltransferase; EC 2.3.1.76; Diglyceride acyltransferase
• Gene Name: DGAT1
• Related Disease: Congenital diarrhea 7 with exudative enteropathy
• UniProt ID: DGAT1_HUMAN
• PDB ID: 6VP0; 6VYI; 6VZ1; 8ESM; 8ETM
• EC Number: 2.3.1.20; 2.3.1.76
• Pfam ID: PF03062
• Sequence:
  MGDRGSSRRRRTGSRPSSHGGGGPAAAEEEVRDAAAGPDVGAAGDAPAPAPNKDGDAGVG
  SGHWELRCHRLQDSLFSSDSGFSNYRGILNWCVVMLILSNARLFLENLIKYGILVDPIQV
  VSLFLKDPYSWPAPCLVIAANVFAVAAFQVEKRLAVGALTEQAGLLLHVANLATILCFPA
  AVVLLVESITPVGSLLALMAHTILFLKLFSYRDVNSWCRRARAKAASAGKKASSAAAPHT
  VSYPDNLTYRDLYYFLFAPTLCYELNFPRSPRIRKRFLLRRILEMLFFTQLQVGLIQQWM
  VPTIQNSMKPFKDMDYSRIIERLLKLAVPNHLIWLIFFYWLFHSCLNAVAELMQFGDREF
  YRDWWNSESVTYFWQNWNIPVHKWCIRHFYKPMLRRGSSKWMARTGVFLASAFFHEYLVS
  VPLRMFRLWAFTGMMAQIPLAWFVGRFFQGNYGNAAVWLSLIIGQPIAVLMYVHDYYVLN
  YEAPAAEA
• Function: Catalyzes the terminal and only committed step in triacylglycerol synthesis by using diacylglycerol and fatty acyl CoA as substrates. Highly expressed in epithelial cells of the small intestine and its activity is essential for the absorption of dietary fats. In liver, plays a role in esterifying exogenous fatty acids to glycerol, and is required to synthesize fat for storage. Also present in female mammary glands, where it produces fat in the milk. May be involved in VLDL (very low density lipoprotein) assembly. In contrast to DGAT2 it is not essential for survival. Functions as the major acyl-CoA retinol acyltransferase (ARAT) in the skin, where it acts to maintain retinoid homeostasis and prevent retinoid toxicity leading to skin and hair disorders. Exhibits additional acyltransferase activities, includin acyl CoA:monoacylglycerol acyltransferase (MGAT), wax monoester and wax diester synthases. Also able to use 1-monoalkylglycerol (1-MAkG) as an acyl acceptor for the synthesis of monoalkyl-monoacylglycerol (MAMAG).
• KEGG Pathway:
  Glycerolipid metabolism (hsa00561)
  Retinol metabolism (hsa00830)
  Metabolic pathways (hsa01100)
  Fat digestion and absorption (hsa04975)
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  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
Congenital diarrhea 7 with exudative enteropathy	DISNANDK	Strong	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Diacylglycerol O-acyltransferase 1 (DGAT1).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Diacylglycerol O-acyltransferase 1 (DGAT1).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Diacylglycerol O-acyltransferase 1 (DGAT1).	[18]

19 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 Diacylglycerol O-acyltransferase 1 (DGAT1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Diacylglycerol O-acyltransferase 1 (DGAT1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Diacylglycerol O-acyltransferase 1 (DGAT1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Diacylglycerol O-acyltransferase 1 (DGAT1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Diacylglycerol O-acyltransferase 1 (DGAT1).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Diacylglycerol O-acyltransferase 1 (DGAT1).	[9]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Diacylglycerol O-acyltransferase 1 (DGAT1).	[10]
Triclosan	DMZUR4N	Approved	Triclosan affects the expression of Diacylglycerol O-acyltransferase 1 (DGAT1).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Diacylglycerol O-acyltransferase 1 (DGAT1).	[12]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Diacylglycerol O-acyltransferase 1 (DGAT1).	[13]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Diacylglycerol O-acyltransferase 1 (DGAT1).	[14]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Diacylglycerol O-acyltransferase 1 (DGAT1).	[15]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Diacylglycerol O-acyltransferase 1 (DGAT1).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Diacylglycerol O-acyltransferase 1 (DGAT1).	[3]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Diacylglycerol O-acyltransferase 1 (DGAT1).	[17]
PJ34	DMXO6YH	Preclinical	PJ34 decreases the expression of Diacylglycerol O-acyltransferase 1 (DGAT1).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Diacylglycerol O-acyltransferase 1 (DGAT1).	[19]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the expression of Diacylglycerol O-acyltransferase 1 (DGAT1).	[20]
Farnesol	DMV2X1B	Investigative	Farnesol decreases the expression of Diacylglycerol O-acyltransferase 1 (DGAT1).	[21]

References

• [1] DGAT1 mutations leading to delayed chronic diarrhoea: a case report. BMC Med Genet. 2020 Dec 1;21(1):239. doi: 10.1186/s12881-020-01164-1.
• [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] 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.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [9] Poly(ADP-Ribose) Polymerase Inhibitor PJ34 Attenuated Hepatic Triglyceride Accumulation in Alcoholic Fatty Liver Disease in Mice. J Pharmacol Exp Ther. 2018 Mar;364(3):452-461. doi: 10.1124/jpet.117.243105. Epub 2018 Jan 9.
• [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] The modulatory effect of triclosan on the reversion of the activated phenotype of LX-2 hepatic stellate cells. J Biochem Mol Toxicol. 2020 Jan;34(1):e22413. doi: 10.1002/jbt.22413. Epub 2019 Nov 12.
• [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] Autophagy alleviates amiodarone-induced hepatotoxicity. Arch Toxicol. 2020 Oct;94(10):3527-3539. doi: 10.1007/s00204-020-02837-9. Epub 2020 Jul 10.
• [17] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [18] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [19] Sulforaphane ameliorates bisphenol A-induced hepatic lipid accumulation by inhibiting endoplasmic reticulum stress. Sci Rep. 2023 Jan 20;13(1):1147. doi: 10.1038/s41598-023-28395-5.
• [20] Exendin-4, a glucagon-like peptide-1 receptor agonist, reduces hepatic steatosis and endoplasmic reticulum stress by inducing nuclear factor erythroid-derived 2-related factor 2 nuclear translocation. Toxicol Appl Pharmacol. 2018 Dec 1;360:18-29.
• [21] Farnesol induces fatty acid oxidation and decreases triglyceride accumulation in steatotic HepaRG cells. Toxicol Appl Pharmacol. 2019 Feb 15;365:61-70.