Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB0DDL0)

• DOT Name: Meteorin-like protein (METRNL)
• Synonyms: Subfatin
• Gene Name: METRNL
• Related Disease:
  Coronary atherosclerosis
  Coronary heart disease
  Non-insulin dependent diabetes
  Obesity
  Bone osteosarcoma
  Osteosarcoma
  Prediabetes syndrome
• UniProt ID: METRL_HUMAN
• Sequence:
  MRGAARAAWGRAGQPWPRPPAPGPPPPPLPLLLLLLAGLLGGAGAQYSSDRCSWKGSGLT
  HEAHRKEVEQVYLRCAAGAVEWMYPTGALIVNLRPNTFSPARHLTVCIRSFTDSSGANIY
  LEKTGELRLLVPDGDGRPGRVQCFGLEQGGLFVEATPQQDIGRRTTGFQYELVRRHRASD
  LHELSAPCRPCSDTEVLLAVCTSDFAVRGSIQQVTHEPERQDSAIHLRVSRLYRQKSRVF
  EPVPEGDGHWQGRVRTLLECGVRPGHGDFLFTGHMHFGEARLGCAPRFKDFQRMYRDAQE
  RGLNPCEVGTD
• Function: Hormone induced following exercise or cold exposure that promotes energy expenditure. Induced either in the skeletal muscle after exercise or in adipose tissue following cold exposure and is present in the circulation. Able to stimulate energy expenditure associated with the browning of the white fat depots and improves glucose tolerance. Does not promote an increase in a thermogenic gene program via direct action on adipocytes, but acts by stimulating several immune cell subtypes to enter the adipose tissue and activate their prothermogenic actions. Stimulates an eosinophil-dependent increase in IL4 expression and promotes alternative activation of adipose tissue macrophages, which are required for the increased expression of the thermogenic and anti-inflammatory gene programs in fat. Required for some cold-induced thermogenic responses, suggesting a role in metabolic adaptations to cold temperatures.
• Tissue Specificity: Highly expressed in the skeletal muscle, in subcutaneous adipose tissue, epididymal white adipose tissue depots and heart. Also expressed in brown adipose tissues and kidney.

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coronary atherosclerosis	DISKNDYU	Strong	Altered Expression	[1]
Coronary heart disease	DIS5OIP1	Strong	Altered Expression	[1]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Altered Expression	[2]
Obesity	DIS47Y1K	Strong	Biomarker	[3]
Bone osteosarcoma	DIST1004	moderate	Altered Expression	[4]
Osteosarcoma	DISLQ7E2	moderate	Altered Expression	[4]
Prediabetes syndrome	DISH2I53	Limited	Biomarker	[5]

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 Meteorin-like protein (METRNL).	[6]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Meteorin-like protein (METRNL).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Meteorin-like protein (METRNL).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Meteorin-like protein (METRNL).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Meteorin-like protein (METRNL).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Meteorin-like protein (METRNL).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Meteorin-like protein (METRNL).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Meteorin-like protein (METRNL).	[11]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Meteorin-like protein (METRNL).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Meteorin-like protein (METRNL).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Meteorin-like protein (METRNL).	[14]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Meteorin-like protein (METRNL).	[15]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Meteorin-like protein (METRNL).	[16]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Meteorin-like protein (METRNL).	[17]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Meteorin-like protein (METRNL).	[19]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Meteorin-like protein (METRNL).	[20]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Meteorin-like protein (METRNL).	[21]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Meteorin-like protein (METRNL).	[22]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Meteorin-like protein (METRNL).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Meteorin-like protein (METRNL).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Meteorin-like protein (METRNL).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Meteorin-like protein (METRNL).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Meteorin-like protein (METRNL).	[26]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Meteorin-like protein (METRNL).	[27]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Meteorin-like protein (METRNL).	[28]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Meteorin-like protein (METRNL).	[29]

References

• [1] Lower serum levels of Meteorin-like/Subfatin in patients with coronary artery disease and type 2 diabetes mellitus are negatively associated with insulin resistance and inflammatory cytokines.PLoS One. 2018 Sep 13;13(9):e0204180. doi: 10.1371/journal.pone.0204180. eCollection 2018.
• [2] Serum Meteorin-like protein levels decreased in patients newly diagnosed with type 2 diabetes.Diabetes Res Clin Pract. 2018 Jan;135:7-10. doi: 10.1016/j.diabres.2017.10.005. Epub 2017 Oct 31.
• [3] Aerobic Exercise Increases Meteorin-Like Protein in Muscle and Adipose Tissue of Chronic High-Fat Diet-Induced Obese Mice.Biomed Res Int. 2018 Apr 30;2018:6283932. doi: 10.1155/2018/6283932. eCollection 2018.
• [4] Meteorin-Like Shows Unique Expression Pattern in Bone and Its Overexpression Inhibits Osteoblast Differentiation.PLoS One. 2016 Oct 7;11(10):e0164446. doi: 10.1371/journal.pone.0164446. eCollection 2016.
• [5] Serum levels of subfatin in patients with type 2 diabetes mellitus and its association with vascular adhesion molecules.Arch Physiol Biochem. 2020 Oct;126(4):335-340. doi: 10.1080/13813455.2018.1538248. Epub 2018 Nov 21.
• [6] 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.
• [7] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [8] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [9] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
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• [11] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [12] 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.
• [13] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [14] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [15] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [16] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [17] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [18] 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.
• [19] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [20] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [21] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [22] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [23] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [24] Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. Int J Cancer. 2015 May 1;136(9):2055-64.
• [25] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [26] 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.
• [27] Identification of formaldehyde-responsive genes by suppression subtractive hybridization. Toxicology. 2008 Jan 14;243(1-2):224-35.
• [28] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [29] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.