Details of Drug Off-Target (DOT)

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

• DOT Name: Lysosomal acid lipase/cholesteryl ester hydrolase (LIPA)
• Synonyms: Acid cholesteryl ester hydrolase; LAL; EC 3.1.1.13; Cholesteryl esterase; Lipase A; Sterol esterase
• Gene Name: LIPA
• Related Disease:
  Obsolete lysosomal acid lipase deficiency
  Cholesteryl ester storage disease
  Wolman disease
• UniProt ID: LICH_HUMAN
• PDB ID: 6V7N
• EC Number: 3.1.1.13
• Pfam ID: PF00561
• Sequence:
  MKMRFLGLVVCLVLWTLHSEGSGGKLTAVDPETNMNVSEIISYWGFPSEEYLVETEDGYI
  LCLNRIPHGRKNHSDKGPKPVVFLQHGLLADSSNWVTNLANSSLGFILADAGFDVWMGNS
  RGNTWSRKHKTLSVSQDEFWAFSYDEMAKYDLPASINFILNKTGQEQVYYVGHSQGTTIG
  FIAFSQIPELAKRIKMFFALGPVASVAFCTSPMAKLGRLPDHLIKDLFGDKEFLPQSAFL
  KWLGTHVCTHVILKELCGNLCFLLCGFNERNLNMSRVDVYTTHSPAGTSVQNMLHWSQAV
  KFQKFQAFDWGSSAKNYFHYNQSYPPTYNVKDMLVPTAVWSGGHDWLADVYDVNILLTQI
  TNLVFHESIPEWEHLDFIWGLDAPWRLYNKIINLMRKYQ
• Function: Catalyzes the deacylation of triacylglyceryl and cholesteryl ester core lipids of endocytosed low density lipoproteins to generate free fatty acids and cholesterol.
• Tissue Specificity: Most abundantly expressed in brain, lung, kidney and mammary gland, a moderate expression seen in placenta and expressed at low levels in the liver and heart.
• KEGG Pathway:
  Steroid biosynthesis (hsa00100)
  Lysosome (hsa04142)
  Efferocytosis (hsa04148)
  Cholesterol metabolism (hsa04979)
• Reactome Pathway: LDL clearance (R-HSA-8964038)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Obsolete lysosomal acid lipase deficiency	DIS7P6M3	Definitive	Autosomal recessive	[1]
Cholesteryl ester storage disease	DISMX85I	Supportive	Autosomal recessive	[2]
Wolman disease	DIS8BKL5	Supportive	Autosomal recessive	[2]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Lysosomal acid lipase/cholesteryl ester hydrolase (LIPA) affects the response to substance of Etoposide.	[21]
Mitoxantrone	DMM39BF	Approved	Lysosomal acid lipase/cholesteryl ester hydrolase (LIPA) affects the response to substance of Mitoxantrone.	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Lysosomal acid lipase/cholesteryl ester hydrolase (LIPA).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Lysosomal acid lipase/cholesteryl ester hydrolase (LIPA).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Lysosomal acid lipase/cholesteryl ester hydrolase (LIPA).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Lysosomal acid lipase/cholesteryl ester hydrolase (LIPA).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Lysosomal acid lipase/cholesteryl ester hydrolase (LIPA).	[7]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Lysosomal acid lipase/cholesteryl ester hydrolase (LIPA).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Lysosomal acid lipase/cholesteryl ester hydrolase (LIPA).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Lysosomal acid lipase/cholesteryl ester hydrolase (LIPA).	[10]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Lysosomal acid lipase/cholesteryl ester hydrolase (LIPA).	[11]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Lysosomal acid lipase/cholesteryl ester hydrolase (LIPA).	[12]
Benzatropine	DMF7EXL	Approved	Benzatropine increases the expression of Lysosomal acid lipase/cholesteryl ester hydrolase (LIPA).	[12]
Haloperidol	DM96SE0	Approved	Haloperidol increases the expression of Lysosomal acid lipase/cholesteryl ester hydrolase (LIPA).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Lysosomal acid lipase/cholesteryl ester hydrolase (LIPA).	[15]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Lysosomal acid lipase/cholesteryl ester hydrolase (LIPA).	[16]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Lysosomal acid lipase/cholesteryl ester hydrolase (LIPA).	[17]
PP-242	DM2348V	Investigative	PP-242 decreases the expression of Lysosomal acid lipase/cholesteryl ester hydrolase (LIPA).	[18]
Linalool	DMGZQ5P	Investigative	Linalool increases the expression of Lysosomal acid lipase/cholesteryl ester hydrolase (LIPA).	[19]
Paraoxon	DMN4ZKC	Investigative	Paraoxon decreases the activity of Lysosomal acid lipase/cholesteryl ester hydrolase (LIPA).	[20]

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 Lysosomal acid lipase/cholesteryl ester hydrolase (LIPA).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Lysosomal acid lipase/cholesteryl ester hydrolase (LIPA).	[14]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Lysosomal lipase deficiency: molecular characterization of eleven patients with Wolman or cholesteryl ester storage disease. Mol Genet Metab. 2012 Mar;105(3):450-6. doi: 10.1016/j.ymgme.2011.12.008. Epub 2011 Dec 17.
• [3] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [8] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [9] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [10] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [11] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [12] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [13] 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.
• [14] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [15] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [16] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [17] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [18] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.
• [19] Linalool is a PPARalpha ligand that reduces plasma TG levels and rewires the hepatic transcriptome and plasma metabolome. J Lipid Res. 2014 Jun;55(6):1098-110.
• [20] Effects of toxicologically relevant xenobiotics and the lipid-derived electrophile 4-hydroxynonenal on macrophage cholesterol efflux: silencing carboxylesterase 1 has paradoxical effects on cholesterol uptake and efflux. Chem Res Toxicol. 2014 Oct 20;27(10):1743-56. doi: 10.1021/tx500221a. Epub 2014 Oct 9.
• [21] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.