Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3RXVRD)

• DOT Name: Fibroblast growth factor 21 (FGF21)
• Synonyms: FGF-21
• Gene Name: FGF21
• UniProt ID: FGF21_HUMAN
• PDB ID: 5VAQ; 6M6E; 6M6F
• Pfam ID: PF00167
• Sequence:
  MDSDETGFEHSGLWVSVLAGLLLGACQAHPIPDSSPLLQFGGQVRQRYLYTDDAQQTEAH
  LEIREDGTVGGAADQSPESLLQLKALKPGVIQILGVKTSRFLCQRPDGALYGSLHFDPEA
  CSFRELLLEDGYNVYQSEAHGLPLHLPGNKSPHRDPAPRGPARFLPLPGLPPALPEPPGI
  LAPQPPDVGSSDPLSMVGPSQGRSPSYAS
• Function: Stimulates glucose uptake in differentiated adipocytes via the induction of glucose transporter SLC2A1/GLUT1 expression (but not SLC2A4/GLUT4 expression). Activity requires the presence of KLB. Regulates systemic glucose homeostasis and insulin sensitivity.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  Calcium sig.ling pathway (hsa04020)
  PI3K-Akt sig.ling pathway (hsa04151)
  Thermogenesis (hsa04714)
  Regulation of actin cytoskeleton (hsa04810)
  Pathways in cancer (hsa05200)
  Melanoma (hsa05218)
  Breast cancer (hsa05224)
  Gastric cancer (hsa05226)
• Reactome Pathway:
  Assembly of active LPL and LIPC lipase complexes (R-HSA-8963889)
  Cellular hexose transport (R-HSA-189200)

Molecular Interaction Atlas (MIA) of This DOT

1 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 Fibroblast growth factor 21 (FGF21).	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Fibroblast growth factor 21 (FGF21).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Fibroblast growth factor 21 (FGF21).	[3]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Fibroblast growth factor 21 (FGF21).	[4]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Fibroblast growth factor 21 (FGF21).	[5]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Fibroblast growth factor 21 (FGF21).	[6]
Pioglitazone	DMKJ485	Approved	Pioglitazone increases the expression of Fibroblast growth factor 21 (FGF21).	[5]
Bezafibrate	DMZDCS0	Approved	Bezafibrate increases the expression of Fibroblast growth factor 21 (FGF21).	[6]
Lansoprazole	DMXYLQ3	Approved	Lansoprazole increases the expression of Fibroblast growth factor 21 (FGF21).	[7]
Famotidine	DMRL3AB	Approved	Famotidine increases the expression of Fibroblast growth factor 21 (FGF21).	[7]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Fibroblast growth factor 21 (FGF21).	[8]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Fibroblast growth factor 21 (FGF21).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Fibroblast growth factor 21 (FGF21).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Fibroblast growth factor 21 (FGF21).	[6]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Fibroblast growth factor 21 (FGF21).	[11]
GW7647	DM9RD0C	Investigative	GW7647 increases the expression of Fibroblast growth factor 21 (FGF21).	[11]
1,4-Dithiothreitol	DMIFOXE	Investigative	1,4-Dithiothreitol increases the expression of Fibroblast growth factor 21 (FGF21).	[9]
ACEA	DMWX3HT	Investigative	ACEA increases the expression of Fibroblast growth factor 21 (FGF21).	[12]

References

• [1] 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.
• [2] 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.
• [3] 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.
• [4] Activation of GR but not PXR by dexamethasone attenuated acetaminophen hepatotoxicities via Fgf21 induction. Toxicology. 2017 Mar 1;378:95-106. doi: 10.1016/j.tox.2017.01.009. Epub 2017 Jan 11.
• [5] Thiazolidinediones are potent inducers of fibroblast growth factor 21 expression in the liver. Biol Pharm Bull. 2011;34(7):1120-1. doi: 10.1248/bpb.34.1120.
• [6] Sodium butyrate stimulates expression of fibroblast growth factor 21 in liver by inhibition of histone deacetylase 3. Diabetes. 2012 Apr;61(4):797-806. doi: 10.2337/db11-0846. Epub 2012 Feb 14.
• [7] Increased immunoreactivity and concentration of basic fibroblast growth factor in lansoprazole-treated gastric mucosa. J Clin Gastroenterol. 1995;21 Suppl 1:S24-9.
• [8] Hepatic SIRT1 attenuates hepatic steatosis and controls energy balance in mice by inducing fibroblast growth factor 21. Gastroenterology. 2014 Feb;146(2):539-49.e7. doi: 10.1053/j.gastro.2013.10.059. Epub 2013 Nov 1.
• [9] Fibroblast growth factor 21 is induced by endoplasmic reticulum stress. Biochimie. 2013 Apr;95(4):692-9. doi: 10.1016/j.biochi.2012.10.019. Epub 2012 Nov 2.
• [10] The genomic response of Ishikawa cells to bisphenol A exposure is dose- and time-dependent. Toxicology. 2010 Apr 11;270(2-3):137-49. doi: 10.1016/j.tox.2010.02.008. Epub 2010 Feb 17.
• [11] Hepatic Aryl Hydrocarbon Receptor Attenuates Fibroblast Growth Factor 21 Expression. J Biol Chem. 2016 Jul 15;291(29):15378-87. doi: 10.1074/jbc.M116.715151. Epub 2016 May 25.
• [12] The Orphan Nuclear Receptor ERR Regulates Hepatic CB1 Receptor-Mediated Fibroblast Growth Factor 21 Gene Expression. PLoS One. 2016 Jul 25;11(7):e0159425. doi: 10.1371/journal.pone.0159425. eCollection 2016.