Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPY4WQR)

• DOT Name: CD5 antigen-like (CD5L)
• Synonyms: Apoptosis inhibitor expressed by macrophages; hAIM; CT-2; IgM-associated peptide; SP-alpha
• Gene Name: CD5L
• Related Disease:
  Nephropathy
  Type-1/2 diabetes
  Advanced cancer
  Alzheimer disease
  Anemia
  Arteriosclerosis
  Ataxia-telangiectasia
  Atherosclerosis
  Autism
  Autism spectrum disorder
  Autoimmune disease
  Breast cancer
  Breast carcinoma
  Cardiovascular disease
  Chronic idiopathic urticaria
  Deafness
  Diabetic kidney disease
  Enthesopathy
  Hepatitis
  Hepatitis A virus infection
  Hepatocellular carcinoma
  High blood pressure
  Inflammation
  Kidney failure
  Liver cirrhosis
  Lymphoproliferative syndrome
  Major depressive disorder
  Myocardial infarction
  Nasopharyngeal carcinoma
  Neoplasm
  Non-alcoholic fatty liver disease
  Obesity
  Pneumonitis
  Seckel syndrome
  Spondyloarthropathy
  Systemic lupus erythematosus
  Triple negative breast cancer
  Age-related macular degeneration
  Chronic obstructive pulmonary disease
  Methicillin-resistant staphylococci infection
  Non-insulin dependent diabetes
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Dental caries
  Fatty liver disease
  Membranous glomerulonephritis
  Pneumonia
• UniProt ID: CD5L_HUMAN
• Pfam ID: PF00530
• Sequence:
  MALLFSLILAICTRPGFLASPSGVRLVGGLHRCEGRVEVEQKGQWGTVCDDGWDIKDVAV
  LCRELGCGAASGTPSGILYEPPAEKEQKVLIQSVSCTGTEDTLAQCEQEEVYDCSHDEDA
  GASCENPESSFSPVPEGVRLADGPGHCKGRVEVKHQNQWYTVCQTGWSLRAAKVVCRQLG
  CGRAVLTQKRCNKHAYGRKPIWLSQMSCSGREATLQDCPSGPWGKNTCNHDEDTWVECED
  PFDLRLVGGDNLCSGRLEVLHKGVWGSVCDDNWGEKEDQVVCKQLGCGKSLSPSFRDRKC
  YGPGVGRIWLDNVRCSGEEQSLEQCQHRFWGFHDCTHQEDVAVICSG
• Function: Secreted protein that acts as a key regulator of lipid synthesis: mainly expressed by macrophages in lymphoid and inflamed tissues and regulates mechanisms in inflammatory responses, such as infection or atherosclerosis. Able to inhibit lipid droplet size in adipocytes. Following incorporation into mature adipocytes via CD36-mediated endocytosis, associates with cytosolic FASN, inhibiting fatty acid synthase activity and leading to lipolysis, the degradation of triacylglycerols into glycerol and free fatty acids (FFA). CD5L-induced lipolysis occurs with progression of obesity: participates in obesity-associated inflammation following recruitment of inflammatory macrophages into adipose tissues, a cause of insulin resistance and obesity-related metabolic disease. Regulation of intracellular lipids mediated by CD5L has a direct effect on transcription regulation mediated by nuclear receptors ROR-gamma (RORC). Acts as a key regulator of metabolic switch in T-helper Th17 cells. Regulates the expression of pro-inflammatory genes in Th17 cells by altering the lipid content and limiting synthesis of cholesterol ligand of RORC, the master transcription factor of Th17-cell differentiation. CD5L is mainly present in non-pathogenic Th17 cells, where it decreases the content of polyunsaturated fatty acyls (PUFA), affecting two metabolic proteins MSMO1 and CYP51A1, which synthesize ligands of RORC, limiting RORC activity and expression of pro-inflammatory genes. Participates in obesity-associated autoimmunity via its association with IgM, interfering with the binding of IgM to Fcalpha/mu receptor and enhancing the development of long-lived plasma cells that produce high-affinity IgG autoantibodies. Also acts as an inhibitor of apoptosis in macrophages: promotes macrophage survival from the apoptotic effects of oxidized lipids in case of atherosclerosis. Involved in early response to microbial infection against various pathogens by acting as a pattern recognition receptor and by promoting autophagy.
• Tissue Specificity: Expressed in spleen, lymph node, thymus, bone marrow, and fetal liver, but not in non-lymphoid tissues.

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nephropathy	DISXWP4P	Definitive	Altered Expression	[1]
Type-1/2 diabetes	DISIUHAP	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[4]
Anemia	DISTVL0C	Strong	Genetic Variation	[5]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[6]
Ataxia-telangiectasia	DISP3EVR	Strong	Altered Expression	[7]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[6]
Autism	DISV4V1Z	Strong	Biomarker	[8]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[9]
Autoimmune disease	DISORMTM	Strong	Biomarker	[10]
Breast cancer	DIS7DPX1	Strong	Biomarker	[11]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[11]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[12]
Chronic idiopathic urticaria	DISZA5CE	Strong	Altered Expression	[13]
Deafness	DISKCLH4	Strong	Biomarker	[14]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[15]
Enthesopathy	DIS2724M	Strong	Biomarker	[16]
Hepatitis	DISXXX35	Strong	Biomarker	[17]
Hepatitis A virus infection	DISUMFQV	Strong	Biomarker	[17]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[18]
High blood pressure	DISY2OHH	Strong	Biomarker	[19]
Inflammation	DISJUQ5T	Strong	Biomarker	[20]
Kidney failure	DISOVQ9P	Strong	Biomarker	[21]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[20]
Lymphoproliferative syndrome	DISMVL8O	Strong	Biomarker	[22]
Major depressive disorder	DIS4CL3X	Strong	Altered Expression	[23]
Myocardial infarction	DIS655KI	Strong	Biomarker	[24]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Genetic Variation	[22]
Neoplasm	DISZKGEW	Strong	Biomarker	[25]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[26]
Obesity	DIS47Y1K	Strong	Biomarker	[27]
Pneumonitis	DIS88E0K	Strong	Altered Expression	[28]
Seckel syndrome	DISEVUBA	Strong	Biomarker	[29]
Spondyloarthropathy	DISBPYCZ	Strong	Biomarker	[16]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[30]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[31]
Age-related macular degeneration	DIS0XS2C	moderate	Biomarker	[32]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Altered Expression	[33]
Methicillin-resistant staphylococci infection	DIS6DRDZ	moderate	Biomarker	[34]
Non-insulin dependent diabetes	DISK1O5Z	moderate	Biomarker	[15]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Disputed	Altered Expression	[25]
Liver cancer	DISDE4BI	Disputed	Altered Expression	[25]
Dental caries	DISRBCMD	Limited	Biomarker	[35]
Fatty liver disease	DIS485QZ	Limited	Biomarker	[27]
Membranous glomerulonephritis	DISFSUKQ	Limited	Biomarker	[36]
Pneumonia	DIS8EF3M	Limited	Biomarker	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of CD5 antigen-like (CD5L).	[37]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of CD5 antigen-like (CD5L).	[38]

References

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• [2] Antidiabetic activity of root tubers of Asparagus gonoclados Baker in streptozotocin induced diabetic rats.J Ethnopharmacol. 2019 Oct 5;242:112027. doi: 10.1016/j.jep.2019.112027. Epub 2019 Jun 19.
• [3] CD5L Promotes M2 Macrophage Polarization through Autophagy-Mediated Upregulation of ID3.Front Immunol. 2018 Mar 12;9:480. doi: 10.3389/fimmu.2018.00480. eCollection 2018.
• [4] Estrogen receptor variants modify risk for Alzheimer's disease in a multiethnic female cohort.J Alzheimers Dis. 2014;40(1):83-93. doi: 10.3233/JAD-130551.
• [5] Association of Anemia and Iron Parameters With Mortality Among Patients Undergoing Prevalent Hemodialysis in Taiwan: The AIM - HD Study.J Am Heart Assoc. 2018 Aug 7;7(15):e009206. doi: 10.1161/JAHA.118.009206.
• [6] MT4-MMP deficiency increases patrolling monocyte recruitment to early lesions and accelerates atherosclerosis.Nat Commun. 2018 Mar 2;9(1):910. doi: 10.1038/s41467-018-03351-4.
• [7] What has the cloning of the ATM gene told us about ataxia telangiectasia?.Int J Radiat Biol. 1998 Apr;73(4):365-71. doi: 10.1080/095530098142185.
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• [9] Effectiveness of Training Therapists to Deliver An Individualized Mental Health Intervention for Children With ASD in Publicly Funded Mental Health Services: A Cluster Randomized Clinical Trial.JAMA Psychiatry. 2019 Jun 1;76(6):574-583. doi: 10.1001/jamapsychiatry.2019.0011.
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• [11] A pilot randomized controlled trial of cognitive bias modification to reduce fear of breast cancer recurrence.Cancer. 2017 Apr 15;123(8):1424-1433. doi: 10.1002/cncr.30478. Epub 2017 Jan 5.
• [12] Effects of Extended-Release Niacin on Quartile Lp-PLA(2) Levels and Clinical Outcomes in Statin-treated Patients with Established Cardiovascular Disease and Low Baseline Levels of HDL-Cholesterol: Post Hoc Analysis of the AIM HIGH Trial.J Cardiovasc Pharmacol Ther. 2019 Nov;24(6):534-541. doi: 10.1177/1074248419852955. Epub 2019 May 26.
• [13] Validity and responsiveness of the Urticaria Activity and Impact Measure: A new patient-reported tool.Ann Allergy Asthma Immunol. 2018 Jun;120(6):641-647. doi: 10.1016/j.anai.2018.03.012. Epub 2018 Mar 19.
• [14] Evidence for an Association Between Hearing Impairment and Disrupted Sleep: Scoping Review.Am J Audiol. 2019 Dec 16;28(4):1015-1024. doi: 10.1044/2019_AJA-19-0026. Epub 2019 Oct 17.
• [15] Validation of a protein biomarker test for predicting renal decline in type 2 diabetes: The Fremantle Diabetes Study Phase II.J Diabetes Complications. 2019 Dec;33(12):107406. doi: 10.1016/j.jdiacomp.2019.07.003. Epub 2019 Aug 27.
• [16] Foot functions in ankylosing spondylitis.Clin Rheumatol. 2019 Apr;38(4):1083-1088. doi: 10.1007/s10067-018-4386-6. Epub 2018 Dec 3.
• [17] CD5L is a pleiotropic player in liver fibrosis controlling damage, fibrosis and immune cell content.EBioMedicine. 2019 May;43:513-524. doi: 10.1016/j.ebiom.2019.04.052. Epub 2019 May 8.
• [18] Identification of special key genes for alcohol-related hepatocellular carcinoma through bioinformatic analysis.PeerJ. 2019 Feb 6;7:e6375. doi: 10.7717/peerj.6375. eCollection 2019.
• [19] Sample size re-estimation in crossover trials: application to the AIM HY-INFORM study.Trials. 2019 Dec 2;20(1):665. doi: 10.1186/s13063-019-3724-6.
• [20] AIM/CD5L: a key protein in the control of immune homeostasis and inflammatory disease.J Leukoc Biol. 2015 Aug;98(2):173-84. doi: 10.1189/jlb.3RU0215-074R. Epub 2015 Jun 5.
• [21] AIM associated with the IgM pentamer: attackers on stand-by at aircraft carrier.Cell Mol Immunol. 2018 Jun;15(6):563-574. doi: 10.1038/cmi.2017.141. Epub 2018 Jan 29.
• [22] Anti-interleukin-10 antibodies in patients with chronic active Epstein-Barr virus infection.J Infect Dis. 1997 Dec;176(6):1454-61. doi: 10.1086/514141.
• [23] Increased serum levels of leptin and insulin in both schizophrenia and major depressive disorder: A cross-disorder proteomics analysis.Eur Neuropsychopharmacol. 2019 Jul;29(7):835-846. doi: 10.1016/j.euroneuro.2019.05.010. Epub 2019 Jun 21.
• [24] Apoptosis inhibitor of macrophage depletion decreased M1 macrophage accumulation and the incidence of cardiac rupture after myocardial infarction in mice.PLoS One. 2017 Nov 9;12(11):e0187894. doi: 10.1371/journal.pone.0187894. eCollection 2017.
• [25] CD5L is upregulated in hepatocellular carcinoma and promotes liver cancer cell proliferation and antiapoptotic responses by binding to HSPA5 (GRP78).FASEB J. 2018 Jul;32(7):3878-3891. doi: 10.1096/fj.201700941RR. Epub 2018 Feb 20.
• [26] AIM-deficient mouse fed a high-trans fat, high-cholesterol diet: a new animal model for nonalcoholic fatty liver disease.Exp Anim. 2019 May 8;68(2):147-158. doi: 10.1538/expanim.18-0108. Epub 2018 Nov 28.
• [27] Independent modes of disease repair by AIM protein distinguished in AIM-felinized mice.Sci Rep. 2018 Sep 3;8(1):13157. doi: 10.1038/s41598-018-31580-6.
• [28] The effect of exposure time and concentration of airborne PM(2.5) on lung injury in mice: A transcriptome analysis.Redox Biol. 2019 Sep;26:101264. doi: 10.1016/j.redox.2019.101264. Epub 2019 Jul 2.
• [29] Novel CENPJ mutation causes Seckel syndrome. J Med Genet. 2010 Jun;47(6):411-4. doi: 10.1136/jmg.2009.076646.
• [30] Elevation of serum CD5L concentration is correlated with disease activity in patients with systemic lupus erythematosus.Int Immunopharmacol. 2018 Oct;63:311-316. doi: 10.1016/j.intimp.2018.07.022. Epub 2018 Aug 30.
• [31] Brain-metastatic triple-negative breast cancer cells regain growth ability by altering gene expression patterns.Cancer Genomics Proteomics. 2013 Nov-Dec;10(6):265-75.
• [32] Retinal pigment epithelium and microglia express the CD5 antigen-like protein, a novel autoantigen in age-related macular degeneration.Exp Eye Res. 2017 Feb;155:64-74. doi: 10.1016/j.exer.2016.12.006. Epub 2016 Dec 15.
• [33] Apoptosis inhibitor of macrophage (AIM) expression in alveolar macrophages in COPD.Respir Res. 2013 Mar 5;14(1):30. doi: 10.1186/1465-9921-14-30.
• [34] CD5L contributes to the pathogenesis of methicillin-resistant Staphylococcus aureus-induced pneumonia.Int Immunopharmacol. 2019 Jul;72:40-47. doi: 10.1016/j.intimp.2019.03.057. Epub 2019 Apr 5.
• [35] Genotypic diversity of Streptococcus mutans and Streptococcus sobrinus in 3-4-year-old children with severe caries or without caries.Int J Paediatr Dent. 2011 Nov;21(6):422-31. doi: 10.1111/j.1365-263X.2011.01145.x. Epub 2011 Jun 20.
• [36] Predicting risk of pulmonary infection in patients with primary membranous nephropathy on immunosuppressive therapy: The AIM-7C score.Nephrology (Carlton). 2019 Oct;24(10):1009-1016. doi: 10.1111/nep.13544. Epub 2019 Apr 29.
• [37] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [38] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.