AhR activation to steatosis AOP (Homo sapiens)

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Increase in Fatty Acid influxFatty liver cellsFatty Acid SynthesisActivation AhRActivation of SCD-1Up Regulation LDLRAccumulation of TriglycerideLiver steatosisMetabolic pathway of LDLFatty acid transportersAryl Hydrocarbon Receptor NetpathFatty Acid BiosynthesisCytoplasm displacementEndoplasmic reticulum stressNucleus distortionMitochondrial distruption


Description

This liver steatosis AOP starts from the top with different molecular initiating events going down towards liver steatosis. The black nodes are Key Events and green nodes are molecular pathways. Adverse outcome pathway liver steatosis; the accumulation of lipids in hepatocytes, caused either by over-nutrition, visceral obesity, metabolic syndrome, or environmental toxins. Liver steatosis can be divided into three main categories: alcoholic liver disease (ALD), non-alcoholic liver disease (NAFLD), and toxicant-associated liver disease (TAFLD).Review on liver steatosis

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Bibliography

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  1. Dentin R, Benhamed F, Hainault I, Fauveau V, Foufelle F, Dyck JR, Girard J, Postic C; ''Liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in ob/ob mice.''; Diabetes, 2006 PubMed Europe PMC Scholia
  2. Bock KW; ''From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans.''; Biochem Pharmacol, 2011 PubMed Europe PMC Scholia
  3. Kodama S; ''Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic enzymes''; Mol Cell Biol, 2004 PubMed Europe PMC Scholia
  4. Mellor CL, Steinmetz FP, Cronin MT; ''The identification of nuclear receptors associated with hepatic steatosis to develop and extend adverse outcome pathways.''; Crit Rev Toxicol, 2016 PubMed Europe PMC Scholia
  5. Brigitte Landesmann, Marina Goumenou, Sharon Munn, Maurice Whelan; ''Description of Prototype Modes-of-Action Related to Repeated Dose Toxicity ''; http://publications.jrc.ec.europa.eu/repository/bitstream/JRC75689/lb-na-25631-en-n.pdf, 2012
  6. Maglich JM, Parks DJ, Moore LB, Collins JL, Goodwin B, Billin AN, Stoltz CA, Kliewer SA, Lambert MH, Willson TM, Moore JT; ''Identification of a novel human constitutive androstane receptor (CAR) agonist and its use in the identification of CAR target genes.''; J Biol Chem, 2003 PubMed Europe PMC Scholia
  7. Hariparsad N, Chu X, Yabut J, Labhart P, Hartley DP, Dai X, Evers R; ''Identification of pregnane-X receptor target genes and coactivator and corepressor binding to promoter elements in human hepatocytes.''; Nucleic Acids Res, 2009 PubMed Europe PMC Scholia
  8. Pavek P, Dvorak Z; ''Xenobiotic-induced transcriptional regulation of xenobiotic metabolizing enzymes of the cytochrome P450 superfamily in human extrahepatic tissues.''; Curr Drug Metab, 2008 PubMed Europe PMC Scholia
  9. Handschin C, Meyer UA; ''Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR.''; Arch Biochem Biophys, 2005 PubMed Europe PMC Scholia
  10. Quattrochi LC, Vu T, Tukey RH; ''The human CYP1A2 gene and induction by 3-methylcholanthrene. A region of DNA that supports AH-receptor binding and promoter-specific induction.''; J Biol Chem, 1994 PubMed Europe PMC Scholia
  11. Tang YM, Wo YY, Stewart J, Hawkins AL, Griffin CA, Sutter TR, Greenlee WF; ''Isolation and characterization of the human cytochrome P450 CYP1B1 gene.''; J Biol Chem, 1996 PubMed Europe PMC Scholia
  12. Hashimoto K, Mori M; ''Crosstalk of thyroid hormone receptor and liver X receptor in lipid metabolism and beyond [Review].''; Endocr J, 2011 PubMed Europe PMC Scholia
  13. Shimada T, Oda Y, Gillam EM, Guengerich FP, Inoue K; ''Metabolic activation of polycyclic aromatic hydrocarbons and other procarcinogens by cytochromes P450 1A1 and P450 1B1 allelic variants and other human cytochromes P450 in Salmonella typhimurium NM2009.''; Drug Metab Dispos, 2001 PubMed Europe PMC Scholia
  14. Nebert DW, Petersen DD, Puga A; ''Human AH locus polymorphism and cancer: inducibility of CYP1A1 and other genes by combustion products and dioxin.''; Pharmacogenetics, 1991 PubMed Europe PMC Scholia
  15. Handschin C, Meyer UA; ''Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR.''; Arch Biochem Biophys, 2005 PubMed Europe PMC Scholia
  16. Maglich JM, Watson J, McMillen PJ, Goodwin B, Willson TM, Moore JT; ''The nuclear receptor CAR is a regulator of thyroid hormone metabolism during caloric restriction.''; J Biol Chem, 2004 PubMed Europe PMC Scholia
  17. Sugatani J, Kojima H, Ueda A, Kakizaki S, Yoshinari K, Gong QH, Owens IS, Negishi M, Sueyoshi T; ''The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR.''; Hepatology, 2001 PubMed Europe PMC Scholia
  18. Kolluri SK, Weiss C, Koff A, Göttlicher M; ''p27(Kip1) induction and inhibition of proliferation by the intracellular Ah receptor in developing thymus and hepatoma cells.''; Genes Dev, 1999 PubMed Europe PMC Scholia
  19. Echchgadda I, Song CS, Oh T, Ahmed M, De La Cruz IJ, Chatterjee B; ''The xenobiotic-sensing nuclear receptors pregnane X receptor, constitutive androstane receptor, and orphan nuclear receptor hepatocyte nuclear factor 4alpha in the regulation of human steroid-/bile acid-sulfotransferase.''; Mol Endocrinol, 2007 PubMed Europe PMC Scholia

History

CompareRevisionActionTimeUserComment
129379view10:20, 28 March 2024MysticArchersModified title
129378view10:16, 28 March 2024MysticArchersNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
Accumulation of TriglycerideKE291 (AOP-Wiki KE)
Activation AhRKE18 (AOP-Wiki KE)
Activation of SCD-1KE258 (AOP-Wiki KE)
Aryl Hydrocarbon Receptor NetpathPathwayWP2586 (WikiPathways)
Fatty Acid BiosynthesisPathwayWP357 (WikiPathways)
Fatty Acid SynthesisKE89 (AOP-Wiki KE)
Fatty acid transportersPathwayWP5061 (WikiPathways)
Fatty liver cells
Increase in Fatty Acid influxKE115 (AOP-Wiki KE)
Liver steatosisKE345 (AOP-Wiki KE)
Metabolic pathway of LDLPathwayWP4522 (WikiPathways)
Up Regulation LDLRKE466 (AOP-Wiki KE)

Annotated Interactions

No annotated interactions

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