Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4APA60)

• DOT Name: Oxysterols receptor LXR-beta (NR1H2)
• Synonyms: Liver X receptor beta; Nuclear receptor NER; Nuclear receptor subfamily 1 group H member 2; Ubiquitously-expressed nuclear receptor
• Gene Name: NR1H2
• UniProt ID: NR1H2_HUMAN
• PDB ID: 1P8D; 1PQ6; 1PQ9; 1PQC; 1UPV; 1UPW; 3KFC; 3L0E; 4DK7; 4DK8; 4NQA; 4RAK; 5HJP; 5I4V; 5JY3; 5KYA; 5KYJ; 6JIO; 6K9G; 6K9H; 6K9M; 6S4N; 6S4T; 6S4U; 6S5K
• Pfam ID: PF00104 ; PF00105
• Sequence:
  MSSPTTSSLDTPLPGNGPPQPGAPSSSPTVKEEGPEPWPGGPDPDVPGTDEASSACSTDW
  VIPDPEEEPERKRKKGPAPKMLGHELCRVCGDKASGFHYNVLSCEGCKGFFRRSVVRGGA
  RRYACRGGGTCQMDAFMRRKCQQCRLRKCKEAGMREQCVLSEEQIRKKKIRKQQQESQSQ
  SQSPVGPQGSSSSASGPGASPGGSEAGSQGSGEGEGVQLTAAQELMIQQLVAAQLQCNKR
  SFSDQPKVTPWPLGADPQSRDARQQRFAHFTELAIISVQEIVDFAKQVPGFLQLGREDQI
  ALLKASTIEIMLLETARRYNHETECITFLKDFTYSKDDFHRAGLQVEFINPIFEFSRAMR
  RLGLDDAEYALLIAINIFSADRPNVQEPGRVEALQQPYVEALLSYTRIKRPQDQLRFPRM
  LMKLVSLRTLSSVHSEQVFALRLQDKKLPPLLSEIWDVHE
• Function: Nuclear receptor that exhibits a ligand-dependent transcriptional activation activity. Binds preferentially to double-stranded oligonucleotide direct repeats having the consensus half-site sequence 5'-AGGTCA-3' and 4-nt spacing (DR-4). Regulates cholesterol uptake through MYLIP-dependent ubiquitination of LDLR, VLDLR and LRP8; DLDLR 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. Plays an anti-inflammatory role during the hepatic acute phase response by acting as a corepressor: inhibits the hepatic acute phase response by preventing dissociation of the N-Cor corepressor complex.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Efferocytosis (hsa04148)
  Insulin resistance (hsa04931)
• Reactome Pathway:
  Nuclear Receptor transcription pathway (R-HSA-383280)
  SUMOylation of intracellular receptors (R-HSA-4090294)
  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)
  PPARA activates gene expression (R-HSA-1989781)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Teniposide	DMLW57T	Approved	Oxysterols receptor LXR-beta (NR1H2) affects the response to substance of Teniposide.	[7]

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 Oxysterols receptor LXR-beta (NR1H2).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Oxysterols receptor LXR-beta (NR1H2).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Oxysterols receptor LXR-beta (NR1H2).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Oxysterols receptor LXR-beta (NR1H2).	[2]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Oxysterols receptor LXR-beta (NR1H2).	[3]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Oxysterols receptor LXR-beta (NR1H2).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Oxysterols receptor LXR-beta (NR1H2).	[6]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Oxysterols receptor LXR-beta (NR1H2).	[8]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Oxysterols receptor LXR-beta (NR1H2).	[9]
Pioglitazone	DMKJ485	Approved	Pioglitazone increases the expression of Oxysterols receptor LXR-beta (NR1H2).	[9]
Bosentan	DMIOGBU	Approved	Bosentan decreases the expression of Oxysterols receptor LXR-beta (NR1H2).	[10]
Bezafibrate	DMZDCS0	Approved	Bezafibrate increases the expression of Oxysterols receptor LXR-beta (NR1H2).	[9]
Lansoprazole	DMXYLQ3	Approved	Lansoprazole increases the activity of Oxysterols receptor LXR-beta (NR1H2).	[11]
Gemfibrozil	DMD8Q3J	Approved	Gemfibrozil increases the expression of Oxysterols receptor LXR-beta (NR1H2).	[9]
Ezetimibe	DM7A8TW	Approved	Ezetimibe decreases the expression of Oxysterols receptor LXR-beta (NR1H2).	[12]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Oxysterols receptor LXR-beta (NR1H2).	[13]
ANW-32821	DMMJOZD	Phase 2	ANW-32821 increases the activity of Oxysterols receptor LXR-beta (NR1H2).	[14]
LY-518674	DMBM2I9	Phase 2	LY-518674 increases the expression of Oxysterols receptor LXR-beta (NR1H2).	[9]
GW-501516	DMPL2KM	Discontinued in Phase 4	GW-501516 increases the expression of Oxysterols receptor LXR-beta (NR1H2).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Oxysterols receptor LXR-beta (NR1H2).	[3]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Oxysterols receptor LXR-beta (NR1H2).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Oxysterols receptor LXR-beta (NR1H2).	[17]
T0901317	DMZQVDI	Investigative	T0901317 increases the activity of Oxysterols receptor LXR-beta (NR1H2).	[18]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Etoposide affects the localization of Oxysterols receptor LXR-beta (NR1H2).	[7]

References

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• [10] Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
• [11] 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.
• [12] Carotenoid transport is decreased and expression of the lipid transporters SR-BI, NPC1L1, and ABCA1 is downregulated in Caco-2 cells treated with ezetimibe. J Nutr. 2005 Oct;135(10):2305-12. doi: 10.1093/jn/135.10.2305.
• [13] 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.
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• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [18] Inhibition of drug metabolism by blocking the activation of nuclear receptors by ketoconazole. Oncogene. 2007 Jan 11;26(2):258-68.