Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT54YZ9I)

• DOT Name: Oxysterols receptor LXR-alpha (NR1H3)
• Synonyms: Liver X receptor alpha; Nuclear receptor subfamily 1 group H member 3
• Gene Name: NR1H3
• UniProt ID: NR1H3_HUMAN
• PDB ID: 1UHL; 3IPQ; 3IPS; 3IPU; 5AVI; 5AVL; 5HJS
• Pfam ID: PF00104 ; PF00105
• Sequence:
  MSLWLGAPVPDIPPDSAVELWKPGAQDASSQAQGGSSCILREEARMPHSAGGTAGVGLEA
  AEPTALLTRAEPPSEPTEIRPQKRKKGPAPKMLGNELCSVCGDKASGFHYNVLSCEGCKG
  FFRRSVIKGAHYICHSGGHCPMDTYMRRKCQECRLRKCRQAGMREECVLSEEQIRLKKLK
  RQEEEQAHATSLPPRASSPPQILPQLSPEQLGMIEKLVAAQQQCNRRSFSDRLRVTPWPM
  APDPHSREARQQRFAHFTELAIVSVQEIVDFAKQLPGFLQLSREDQIALLKTSAIEVMLL
  ETSRRYNPGSESITFLKDFSYNREDFAKAGLQVEFINPIFEFSRAMNELQLNDAEFALLI
  AISIFSADRPNVQDQLQVERLQHTYVEALHAYVSIHHPHDRLMFPRMLMKLVSLRTLSSV
  HSEQVFALRLQDKKLPPLLSEIWDVHE
• Function: Nuclear receptor that exhibits a ligand-dependent transcriptional activation activity. Interaction with retinoic acid receptor (RXR) shifts RXR from its role as a silent DNA-binding partner to an active ligand-binding subunit in mediating retinoid responses through target genes defined by LXRES. LXRES are DR4-type response elements characterized by direct repeats of two similar hexanuclotide half-sites spaced by four nucleotides. Plays an important role in the regulation of cholesterol homeostasis, regulating cholesterol uptake through MYLIP-dependent ubiquitination of LDLR, VLDLR and LRP8. Interplays functionally with RORA for the regulation of genes involved in liver metabolism. Induces LPCAT3-dependent phospholipid remodeling in endoplasmic reticulum (ER) membranes of hepatocytes, driving SREBF1 processing and lipogenesis. Via LPCAT3, triggers the incorporation of arachidonate into phosphatidylcholines of ER membranes, increasing membrane dynamics and enabling triacylglycerols transfer to nascent very low-density lipoprotein (VLDL) particles. Via LPCAT3 also counteracts lipid-induced ER stress response and inflammation, likely by modulating SRC kinase membrane compartmentalization and limiting the synthesis of lipid inflammatory mediators.
• Tissue Specificity: Visceral organs specific expression. Strong expression was found in liver, kidney and intestine followed by spleen and to a lesser extent the adrenals.
• KEGG Pathway:
  PPAR sig.ling pathway (hsa03320)
  Efferocytosis (hsa04148)
  Insulin resistance (hsa04931)
  Non-alcoholic fatty liver disease (hsa04932)
  Hepatitis C (hsa05160)
• Reactome Pathway:
  Nuclear Receptor transcription pathway (R-HSA-383280)
  VLDLR internalisation and degradation (R-HSA-8866427)
  NR1H2 & NR1H3 regulate gene expression linked to lipogenesis (R-HSA-9029558)
  NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux (R-HSA-9029569)
  NR1H2 & NR1H3 regulate gene expression to limit cholesterol uptake (R-HSA-9031525)
  NR1H2 & NR1H3 regulate gene expression linked to triglyceride lipolysis in adipose (R-HSA-9031528)
  NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis (R-HSA-9623433)
  NR1H2 & NR1H3 regulate gene expression linked to gluconeogenesis (R-HSA-9632974)
  PPARA activates gene expression (R-HSA-1989781)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Oxysterols receptor LXR-alpha (NR1H3).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Oxysterols receptor LXR-alpha (NR1H3).	[6]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[9]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[10]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[11]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[12]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[13]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[14]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[15]
Pioglitazone	DMKJ485	Approved	Pioglitazone increases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[16]
Bexarotene	DMOBIKY	Approved	Bexarotene decreases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[17]
Bosentan	DMIOGBU	Approved	Bosentan decreases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[18]
Bezafibrate	DMZDCS0	Approved	Bezafibrate increases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[15]
Vitamin B3	DMQVRZH	Approved	Vitamin B3 increases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[19]
Lansoprazole	DMXYLQ3	Approved	Lansoprazole increases the activity of Oxysterols receptor LXR-alpha (NR1H3).	[20]
Gemfibrozil	DMD8Q3J	Approved	Gemfibrozil increases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[15]
Teniposide	DMLW57T	Approved	Teniposide increases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[13]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[21]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[22]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[23]
LY-518674	DMBM2I9	Phase 2	LY-518674 increases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[15]
GW-501516	DMPL2KM	Discontinued in Phase 4	GW-501516 increases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[15]
Tetramethylpyrazine	DMC0WNB	Discontinued in Phase 2	Tetramethylpyrazine increases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[26]
EMODIN	DMAEDQG	Terminated	EMODIN increases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[27]
SB 203580	DMAET6F	Terminated	SB 203580 increases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[29]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[30]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug affects the expression of Oxysterols receptor LXR-alpha (NR1H3).	[31]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl increases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[32]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide increases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[33]
U0126	DM31OGF	Investigative	U0126 increases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[28]
T0901317	DMZQVDI	Investigative	T0901317 increases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[34]
2,6-Dihydroanthra/1,9-Cd/Pyrazol-6-One	DMDN12L	Investigative	2,6-Dihydroanthra/1,9-Cd/Pyrazol-6-One increases the expression of Oxysterols receptor LXR-alpha (NR1H3).	[28]
Chlorphrifos oxon	DMGBT68	Investigative	Chlorphrifos oxon affects the expression of Oxysterols receptor LXR-alpha (NR1H3).	[35]
25-hydroxycholesterol	DMCHAQ7	Investigative	25-hydroxycholesterol increases the activity of Oxysterols receptor LXR-alpha (NR1H3).	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Oxysterols receptor LXR-alpha (NR1H3).	[24]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Oxysterols receptor LXR-alpha (NR1H3).	[25]

References

• [1] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [2] 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.
• [3] Retinoic acid-induced downmodulation of telomerase activity in human cancer cells. Exp Mol Pathol. 2005 Oct;79(2):108-17.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [7] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] Dexamethasone controls aryl hydrocarbon receptor (AhR)-mediated CYP1A1 and CYP1A2 expression and activity in primary cultures of human hepatocytes. Chem Biol Interact. 2009 May 15;179(2-3):288-96.
• [10] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [11] Rosiglitazone upregulates caveolin-1 expression in THP-1 cells through a PPAR-dependent mechanism. J Lipid Res. 2004 Nov;45(11):2015-24. doi: 10.1194/jlr.M400049-JLR200. Epub 2004 Aug 16.
• [12] The potential effects of HECTD4 variants on fasting glucose and triglyceride levels in relation to prevalence of type 2 diabetes based on alcohol intake. Arch Toxicol. 2022 Sep;96(9):2487-2499. doi: 10.1007/s00204-022-03325-y. Epub 2022 Jun 17.
• [13] Regulation of Hepatic Cholesteryl Ester Transfer Protein Expression and Reverse Cholesterol Transport by Inhibition of DNA Topoisomerase II. J Biol Chem. 2015 Jun 5;290(23):14418-29. doi: 10.1074/jbc.M115.643015. Epub 2015 Apr 25.
• [14] Placental mechanism of prenatal nicotine exposure-reduced blood cholesterol levels in female fetal rats. Toxicol Lett. 2018 Oct 15;296:31-38. doi: 10.1016/j.toxlet.2018.07.022. Epub 2018 Jul 20.
• [15] On the mechanism for PPAR agonists to enhance ABCA1 gene expression. Atherosclerosis. 2009 Aug;205(2):413-9. doi: 10.1016/j.atherosclerosis.2009.01.008. Epub 2009 Jan 19.
• [16] Comparison of the effects of pioglitazone and rosiglitazone on macrophage foam cell formation. Biochem Biophys Res Commun. 2004 Oct 22;323(3):782-8.
• [17] Combinations of LXR and RXR agonists induce triglyceride accumulation in human HepaRG cells in a synergistic manner. Arch Toxicol. 2020 Apr;94(4):1303-1320. doi: 10.1007/s00204-020-02685-7. Epub 2020 Mar 2.
• [18] Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
• [19] Stimulation of CD36 and the key effector of reverse cholesterol transport ATP-binding cassette A1 in monocytoid cells by niacin. Biochem Pharmacol. 2004 Feb 1;67(3):411-9. doi: 10.1016/j.bcp.2003.09.014.
• [20] Proton pump inhibitor lansoprazole is a nuclear liver X receptor agonist. Biochem Pharmacol. 2010 May 1;79(9):1310-6. doi: 10.1016/j.bcp.2009.12.018. Epub 2010 Jan 8.
• [21] Resveratrol regulates the expression of LXR-alpha in human macrophages. Biochem Biophys Res Commun. 2006 Sep 29;348(3):1047-54. doi: 10.1016/j.bbrc.2006.07.155. Epub 2006 Aug 1.
• [22] Curcumin induces changes in expression of genes involved in cholesterol homeostasis. J Nutr Biochem. 2007 Feb;18(2):113-9.
• [23] The environmental obesogen bisphenol A increases macrophage self-renewal. Cell Tissue Res. 2019 Oct;378(1):81-96. doi: 10.1007/s00441-019-03019-5. Epub 2019 Apr 22.
• [24] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [25] 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.
• [26] Effects of tetramethylpyrazine from Chinese black vinegar on antioxidant and hypolipidemia activities in HepG2 cells. Food Chem Toxicol. 2017 Nov;109(Pt 2):930-940.
• [27] Emodin isolated from Polygoni Multiflori Ramulus inhibits melanogenesis through the liver X receptor-mediated pathway. Chem Biol Interact. 2016 Apr 25;250:78-84. doi: 10.1016/j.cbi.2016.03.014. Epub 2016 Mar 10.
• [28] Role of the nuclear receptors HNF4 alpha, PPAR alpha, and LXRs in the TNF alpha-mediated inhibition of human apolipoprotein A-I gene expression in HepG2 cells. Biochemistry. 2009 Dec 22;48(50):11950-60. doi: 10.1021/bi9015742.
• [29] In vitro evaluation of the hepatic lipid accumulation of bisphenol analogs: A high-content screening assay. Toxicol In Vitro. 2020 Oct;68:104959. doi: 10.1016/j.tiv.2020.104959. Epub 2020 Aug 5.
• [30] Quercetin and allopurinol reduce liver thioredoxin-interacting protein to alleviate inflammation and lipid accumulation in diabetic rats. Br J Pharmacol. 2013 Jul;169(6):1352-71. doi: 10.1111/bph.12226.
• [31] The pharmacodynamic effects of sirolimus and sirolimus-calcineurin inhibitor combinations on macrophage scavenger and nuclear hormone receptors. J Pharm Sci. 2007 Jan;96(1):209-22. doi: 10.1002/jps.20751.
• [32] Persistent organic pollutants alter DNA methylation during human adipocyte differentiation. Toxicol In Vitro. 2017 Apr;40:79-87. doi: 10.1016/j.tiv.2016.12.011. Epub 2016 Dec 20.
• [33] Comparative analysis of AhR-mediated TCDD-elicited gene expression in human liver adult stem cells. Toxicol Sci. 2009 Nov;112(1):229-44.
• [34] Inhibition of progesterone production in human luteinized granulosa cells treated with LXR agonists. Mol Hum Reprod. 2007 Jun;13(6):373-9.
• [35] Concentration-dependent effects of chlorpyrifos oxon on peroxisome proliferator-activated receptor signaling in MCF-7 cells. Toxicol In Vitro. 2022 Feb;78:105268. doi: 10.1016/j.tiv.2021.105268. Epub 2021 Oct 29.
• [36] Upregulation of hydroxysteroid sulfotransferase 2B1b promotes hepatic oval cell proliferation by modulating oxysterol-induced LXR activation in a mouse model of liver injury. Arch Toxicol. 2017 Jan;91(1):271-287. doi: 10.1007/s00204-016-1693-z. Epub 2016 Apr 6.