Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFOWL2H)

• DOT Name: Apolipoprotein E (APOE)
• Synonyms: Apo-E
• Gene Name: APOE
• Related Disease:
  Alzheimer disease 2
  Dysbetalipoproteinemia
  Lipoprotein glomerulopathy
  Sea-blue histiocyte syndrome
• UniProt ID: APOE_HUMAN
• PDB ID: 1B68; 1BZ4; 1EA8; 1GS9; 1H7I; 1LE2; 1LE4; 1LPE; 1NFN; 1NFO; 1OEF; 1OEG; 1OR2; 1OR3; 2KC3; 2KNY; 2L7B; 6IWB; 6NCN; 6NCO; 7FCR; 7FCS; 7UVJ; 8AX8; 8AX9; 8CDY; 8CE0; 8GRX
• Pfam ID: PF01442
• Sequence:
  MKVLWAALLVTFLAGCQAKVEQAVETEPEPELRQQTEWQSGQRWELALGRFWDYLRWVQT
  LSEQVQEELLSSQVTQELRALMDETMKELKAYKSELEEQLTPVAEETRARLSKELQAAQA
  RLGADMEDVCGRLVQYRGEVQAMLGQSTEELRVRLASHLRKLRKRLLRDADDLQKRLAVY
  QAGAREGAERGLSAIRERLGPLVEQGRVRAATVGSLAGQPLQERAQAWGERLRARMEEMG
  SRTRDRLDEVKEQVAEVRAKLEEQAQQIRLQAEAFQARLKSWFEPLVEDMQRQWAGLVEK
  VQAAVGTSAAPVPSDNH
• Function: APOE is an apolipoprotein, a protein associating with lipid particles, that mainly functions in lipoprotein-mediated lipid transport between organs via the plasma and interstitial fluids. APOE is a core component of plasma lipoproteins and is involved in their production, conversion and clearance. Apolipoproteins are amphipathic molecules that interact both with lipids of the lipoprotein particle core and the aqueous environment of the plasma. As such, APOE associates with chylomicrons, chylomicron remnants, very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL) but shows a preferential binding to high-density lipoproteins (HDL). It also binds a wide range of cellular receptors including the LDL receptor/LDLR, the LDL receptor-related proteins LRP1, LRP2 and LRP8 and the very low-density lipoprotein receptor/VLDLR that mediate the cellular uptake of the APOE-containing lipoprotein particles. Finally, APOE has also a heparin-binding activity and binds heparan-sulfate proteoglycans on the surface of cells, a property that supports the capture and the receptor-mediated uptake of APOE-containing lipoproteins by cells. A main function of APOE is to mediate lipoprotein clearance through the uptake of chylomicrons, VLDLs, and HDLs by hepatocytes. APOE is also involved in the biosynthesis by the liver of VLDLs as well as their uptake by peripheral tissues ensuring the delivery of triglycerides and energy storage in muscle, heart and adipose tissues. By participating in the lipoprotein-mediated distribution of lipids among tissues, APOE plays a critical role in plasma and tissues lipid homeostasis. APOE is also involved in two steps of reverse cholesterol transport, the HDLs-mediated transport of cholesterol from peripheral tissues to the liver, and thereby plays an important role in cholesterol homeostasis. First, it is functionally associated with ABCA1 in the biogenesis of HDLs in tissues. Second, it is enriched in circulating HDLs and mediates their uptake by hepatocytes. APOE also plays an important role in lipid transport in the central nervous system, regulating neuron survival and sprouting. APOE is also involved in innate and adaptive immune responses, controlling for instance the survival of myeloid-derived suppressor cells. Binds to the immune cell receptor LILRB4. APOE may also play a role in transcription regulation through a receptor-dependent and cholesterol-independent mechanism, that activates MAP3K12 and a non-canonical MAPK signal transduction pathway that results in enhanced AP-1-mediated transcription of APP ; (Microbial infection) Through its interaction with HCV envelope glycoprotein E2, participates in the attachment of HCV to HSPGs and other receptors (LDLr, VLDLr, and SR-B1) on the cell surface and to the assembly, maturation and infectivity of HCV viral particles. This interaction is probably promoted via the up-regulation of cellular autophagy by the virus.
• Tissue Specificity: Produced by several tissues and cell types and mainly found associated with lipid particles in the plasma, the interstitial fluid and lymph . Mainly synthesized by liver hepatocytes . Significant quantities are also produced in brain, mainly by astrocytes and glial cells in the cerebral cortex, but also by neurons in frontal cortex and hippocampus . It is also expressed by cells of the peripheral nervous system . Also expressed by adrenal gland, testis, ovary, skin, kidney, spleen and adipose tissue and macrophages in various tissues .
• KEGG Pathway:
  Cholesterol metabolism (hsa04979)
  Alzheimer disease (hsa05010)
• Reactome Pathway:
  Scavenging by Class A Receptors (R-HSA-3000480)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors (R-HSA-8864260)
  Post-translational protein phosphorylation (R-HSA-8957275)
  Chylomicron assembly (R-HSA-8963888)
  Chylomicron remodeling (R-HSA-8963901)
  Chylomicron clearance (R-HSA-8964026)
  HDL remodeling (R-HSA-8964058)
  NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux (R-HSA-9029569)
  Retinoid metabolism and transport (R-HSA-975634)
  Amyloid fiber formation (R-HSA-977225)
  Nuclear signaling by ERBB4 (R-HSA-1251985)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease 2	DISJ6Y23	Definitive	Autosomal dominant	[1]
Dysbetalipoproteinemia	DISNRSNM	Strong	Autosomal dominant	[2]
Lipoprotein glomerulopathy	DISQYQQT	Strong	Autosomal dominant	[2]
Sea-blue histiocyte syndrome	DISHFROI	Supportive	Autosomal dominant	[3]

This DOT Affected the Drug Response of 15 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Apolipoprotein E (APOE) increases the response to substance of Arsenic.	[36]
Isotretinoin	DM4QTBN	Approved	Apolipoprotein E (APOE) affects the response to substance of Isotretinoin.	[37]
Aspirin	DM672AH	Approved	Apolipoprotein E (APOE) affects the response to substance of Aspirin.	[38]
Simvastatin	DM30SGU	Approved	Apolipoprotein E (APOE) increases the response to substance of Simvastatin.	[39]
Warfarin	DMJYCVW	Approved	Apolipoprotein E (APOE) affects the response to substance of Warfarin.	[40]
Ketamine	DMT5HA4	Approved	Apolipoprotein E (APOE) decreases the response to substance of Ketamine.	[41]
Trihexyphenidyl	DMB19L8	Approved	Apolipoprotein E (APOE) increases the response to substance of Trihexyphenidyl.	[42]
Tacrine	DM51FY6	Approved	Apolipoprotein E (APOE) increases the Dementia ADR of Tacrine.	[43]
Acenocoumarol	DMH75KV	Approved	Apolipoprotein E (APOE) affects the response to substance of Acenocoumarol.	[44]
Pravastatin	DM6A0X7	Approved	Apolipoprotein E (APOE) increases the Myocardial ischaemia ADR of Pravastatin.	[43]
Fluvastatin	DM4MDJY	Approved	Apolipoprotein E (APOE) increases the Myocardial ischaemia ADR of Fluvastatin.	[43]
Clobazam	DMW1OQ0	Approved	Apolipoprotein E (APOE) increases the Parapsoriasis ADR of Clobazam.	[45]
Tropicamide	DM1D90W	Approved	Apolipoprotein E (APOE) increases the response to substance of Tropicamide.	[46]
Dihydrotestosterone	DM3S8XC	Phase 4	Apolipoprotein E (APOE) affects the response to substance of Dihydrotestosterone.	[47]
Chlorpyrifos	DMKPUI6	Investigative	Apolipoprotein E (APOE) affects the response to substance of Chlorpyrifos.	[48]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Vitamin K	DMN6EZY	Investigative	Apolipoprotein E (APOE) affects the abundance of Vitamin K.	[49]

32 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 Apolipoprotein E (APOE).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Apolipoprotein E (APOE).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Apolipoprotein E (APOE).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Apolipoprotein E (APOE).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Apolipoprotein E (APOE).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Apolipoprotein E (APOE).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Apolipoprotein E (APOE).	[10]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Apolipoprotein E (APOE).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Apolipoprotein E (APOE).	[12]
Selenium	DM25CGV	Approved	Selenium increases the expression of Apolipoprotein E (APOE).	[13]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Apolipoprotein E (APOE).	[14]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Apolipoprotein E (APOE).	[15]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Apolipoprotein E (APOE).	[16]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Apolipoprotein E (APOE).	[17]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Apolipoprotein E (APOE).	[18]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Apolipoprotein E (APOE).	[19]
Palbociclib	DMD7L94	Approved	Palbociclib increases the expression of Apolipoprotein E (APOE).	[20]
Bezafibrate	DMZDCS0	Approved	Bezafibrate increases the expression of Apolipoprotein E (APOE).	[21]
LY2835219	DM93VBZ	Approved	LY2835219 increases the expression of Apolipoprotein E (APOE).	[20]
Lansoprazole	DMXYLQ3	Approved	Lansoprazole increases the expression of Apolipoprotein E (APOE).	[22]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Apolipoprotein E (APOE).	[23]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Apolipoprotein E (APOE).	[24]
Atorvastatin	DMF28YC	Phase 3 Trial	Atorvastatin decreases the expression of Apolipoprotein E (APOE).	[18]
GSK2816126	DMJDVW4	Phase 1	GSK2816126 increases the expression of Apolipoprotein E (APOE).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Apolipoprotein E (APOE).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Apolipoprotein E (APOE).	[29]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Apolipoprotein E (APOE).	[30]
acrolein	DMAMCSR	Investigative	acrolein decreases the activity of Apolipoprotein E (APOE).	[32]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone increases the expression of Apolipoprotein E (APOE).	[33]
GW-3965	DMG60ET	Investigative	GW-3965 increases the expression of Apolipoprotein E (APOE).	[34]
T0901317	DMZQVDI	Investigative	T0901317 increases the expression of Apolipoprotein E (APOE).	[34]
Ganoderic acid A	DM42EVG	Investigative	Ganoderic acid A decreases the expression of Apolipoprotein E (APOE).	[35]

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 decreases the methylation of Apolipoprotein E (APOE).	[25]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Apolipoprotein E (APOE).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
D-glucose	DMMG2TO	Investigative	D-glucose affects the secretion of Apolipoprotein E (APOE).	[31]

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