Details of Drug Off-Target (DOT)

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

• DOT Name: Cholesteryl ester transfer protein (CETP)
• Synonyms: Lipid transfer protein I
• Gene Name: CETP
• Related Disease: Cholesterol-ester transfer protein deficiency
• UniProt ID: CETP_HUMAN
• PDB ID: 2OBD; 4EWS; 4F2A
• Pfam ID: PF01273 ; PF02886
• Sequence:
  MLAATVLTLALLGNAHACSKGTSHEAGIVCRITKPALLVLNHETAKVIQTAFQRASYPDI
  TGEKAMMLLGQVKYGLHNIQISHLSIASSQVELVEAKSIDVSIQNVSVVFKGTLKYGYTT
  AWWLGIDQSIDFEIDSAIDLQINTQLTCDSGRVRTDAPDCYLSFHKLLLHLQGEREPGWI
  KQLFTNFISFTLKLVLKGQICKEINVISNIMADFVQTRAASILSDGDIGVDISLTGDPVI
  TASYLESHHKGHFIYKNVSEDLPLPTFSPTLLGDSRMLYFWFSERVFHSLAKVAFQDGRL
  MLSLMGDEFKAVLETWGFNTNQEIFQEVVGGFPSQAQVTVHCLKMPKISCQNKGVVVNSS
  VMVKFLFPRPDQQHSVAYTFEEDIVTTVQASYSKKKLFLSLLDFQITPKTVSNLTESSSE
  SVQSFLQSMITAVGIPEVMSRLEVVFTALMNSKGVSLFDIINPEIITRDGFLLLQMDFGF
  PEHLLVDFLQSLS
• Function: Involved in the transfer of neutral lipids, including cholesteryl ester and triglyceride, among lipoprotein particles. Allows the net movement of cholesteryl ester from high density lipoproteins/HDL to triglyceride-rich very low density lipoproteins/VLDL, and the equimolar transport of triglyceride from VLDL to HDL. Regulates the reverse cholesterol transport, by which excess cholesterol is removed from peripheral tissues and returned to the liver for elimination.
• Tissue Specificity: Expressed by the liver and secreted in plasma.
• KEGG Pathway: Cholesterol metabolism (hsa04979)
• Reactome Pathway:
  HDL remodeling (R-HSA-8964058)
  NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux (R-HSA-9029569)
  LDL remodeling (R-HSA-8964041)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cholesterol-ester transfer protein deficiency	DISP9UAV	Strong	Autosomal dominant	[1]

2 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 Cholesteryl ester transfer protein (CETP).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cholesteryl ester transfer protein (CETP).	[9]

11 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 Cholesteryl ester transfer protein (CETP).	[3]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Cholesteryl ester transfer protein (CETP).	[4]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Cholesteryl ester transfer protein (CETP).	[3]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the expression of Cholesteryl ester transfer protein (CETP).	[5]
Alitretinoin	DMME8LH	Approved	Alitretinoin increases the expression of Cholesteryl ester transfer protein (CETP).	[6]
Bezafibrate	DMZDCS0	Approved	Bezafibrate decreases the activity of Cholesteryl ester transfer protein (CETP).	[7]
Nevirapine	DM6HX9B	Approved	Nevirapine increases the expression of Cholesteryl ester transfer protein (CETP).	[8]
Teniposide	DMLW57T	Approved	Teniposide increases the expression of Cholesteryl ester transfer protein (CETP).	[3]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Cholesteryl ester transfer protein (CETP).	[10]
GW-3965	DMG60ET	Investigative	GW-3965 increases the expression of Cholesteryl ester transfer protein (CETP).	[11]
T0901317	DMZQVDI	Investigative	T0901317 increases the expression of Cholesteryl ester transfer protein (CETP).	[6]

References

• [1] Letter: Jimson weed seeds. Ann Intern Med. 1975 Dec;83(6):905. doi: 10.7326/0003-4819-83-6-905_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] 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.
• [4] Arsenic trioxide suppresses liver X receptor and enhances cholesteryl ester transfer protein expression without affecting the liver X receptor in HepG2 cells. Chem Biol Interact. 2016 Oct 25;258:288-96. doi: 10.1016/j.cbi.2016.09.009. Epub 2016 Sep 10.
• [5] Comparative effects of simvastatin and cholestyramine on plasma lipoproteins and CETP in humans. Can J Clin Pharmacol. 1999 Summer;6(2):85-90.
• [6] Liver X receptor and retinoic X receptor agonists modulate the expression of genes involved in lipid metabolism in human endothelial cells. Int J Mol Med. 2005 Oct;16(4):717-22.
• [7] Decreased PLTP mass but elevated PLTP activity linked to insulin resistance in HTG: effects of bezafibrate therapy. J Lipid Res. 2003 Aug;44(8):1462-9. doi: 10.1194/jlr.M300008-JLR200. Epub 2003 May 16.
• [8] Nevirapine increases high-density lipoprotein cholesterol concentration by stimulation of apolipoprotein A-I production. Arterioscler Thromb Vasc Biol. 2009 Sep;29(9):1336-41. doi: 10.1161/ATVBAHA.109.192088. Epub 2009 Aug 10.
• [9] 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.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [11] LXR-activating oxysterols induce the expression of inflammatory markers in endothelial cells through LXR-independent mechanisms. Atherosclerosis. 2009 Nov;207(1):38-44.