Liver steatosis adverse outcome pathway (Homo sapiens)

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Cytoplasm displacementFatty liver cellsSterol Regulatory Element-Binding Proteins (SREBP) signallingKE232: Decreased, PPAR-beta activationKE479: Activation, NR1H4Constitutive Androstane Receptor PathwayKE116: Activation, FASPPAR Alpha PathwayKE345: Liver steatosisKE474: Down Regulation, HMGCS2Pregnane X Receptor pathwayKE89: Synthesis, De Novo FALipid Metabolism PathwayAMP-activated Protein Kinase (AMPK) SignalingKE66: Activation, ChREBPFatty acid transportersKE472: Down Regulation, CPT1AKE258: Activation, SCD-1KE115: Increase, FA InfluxFarnesoid X Receptor PathwayMetabolic pathway of LDLKE245: Activation, PXR/SXRAryl Hydrocarbon Receptor NetpathKE227: Activation, PPARαBranched-chain amino acid catabolismKE466: Up Regulation, LDLR (low density lipoprotein receptor)KE860: Decreased, Mitochondrial Fatty Acid Beta OxidationKE471: Inhibition, FoxA2KE167: Activation, LXRAngiopoietin Like Protein 8 Regulatory PathwayCholesterol metabolismNRF2 pathwayLiver X Receptor PathwayKE291: Accumulation, TriglycerideKE1214: Altered gene expression specific to CAR activation, HepatocytesKE228: demethylation, PPARg promoterKE18: Activation, AhRKE10106: Fatty Acid LysisMitochondrial LC-Fatty Acid Beta-OxidationKE478: Activation, NRF2KE54 Up Regulation, CD36KE264: Activation, SREBP-1cKE140: Decreased, HSD17B10 expressionFatty Acid BiosynthesisPPAR Gamma PathwayPPAR Beta/Delta pathwayEndoplasmic reticulum stressNucleus distortionMitochondrial distruptionFoxa2 Pathway


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. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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
  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. 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
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  19. 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

History

View all...
CompareRevisionActionTimeUserComment
129354view09:32, 27 March 2024MkutmonOntology Term : 'disease pathway' added !
128765view13:41, 21 February 2024Marvin M2Reverted to version '11:25, 23 June 2021' by Marvin M2
128764view13:41, 21 February 2024MysticArchers
128763view13:39, 21 February 2024Marvin M2Reverted to version '11:25, 23 June 2021' by Marvin M2
128762view13:38, 21 February 2024Marvin M2
119296view11:25, 23 June 2021FinterlyAdded ISBN for book citation
118491view08:46, 28 May 2021FinterlyReplace DataNode Type "Key Event" with "Event"
116509view10:44, 7 May 2021EweitzModified title
115813view20:37, 14 March 2021ChesdeWindtFixed incorrect reference on KE 860
115727view08:51, 9 March 2021Marvin M2Updated PPARa and b/d KE pathways, and cleaned the AOP
115692view17:12, 4 March 2021Jkearns445Fixed interactions
115688view10:40, 4 March 2021ChesdeWindtModified description
115648view14:35, 3 March 2021Jkearns445
115644view14:28, 3 March 2021Jkearns445
115643view14:27, 3 March 2021Jkearns445
115642view14:10, 3 March 2021Jkearns445
115627view18:32, 2 March 2021ChesdeWindt
115626view17:12, 2 March 2021ChesdeWindtAdded KE479 to KE227
115578view22:58, 27 February 2021ChesdeWindtModified description
115545view15:10, 26 February 2021Jkearns445
115544view15:08, 26 February 2021Jkearns445
115543view15:06, 26 February 2021Jkearns445Cleaned up the patway, added a new pathway
115542view14:59, 26 February 2021Jkearns445
115540view14:19, 26 February 2021Jkearns445
115539view14:14, 26 February 2021Jkearns445
115526view13:24, 25 February 2021Jkearns445
115525view13:13, 25 February 2021Jkearns445
115524view12:54, 25 February 2021Marvin M2Ontology Term : 'hepatocyte' added !
115523view12:52, 25 February 2021Marvin M2Ontology Term : 'fatty liver disease' added !
115522view22:17, 24 February 2021ChesdeWindtModified description
115495view07:22, 24 February 2021Jkearns445
115494view07:20, 24 February 2021Jkearns445
115346view09:56, 15 February 2021Jkearns445
115332view18:56, 13 February 2021Jkearns445
115331view18:54, 13 February 2021Jkearns445
115330view18:53, 13 February 2021Jkearns445
115327view11:17, 13 February 2021Jkearns445
115326view11:03, 13 February 2021Jkearns445Cleaned up the pathway and added pathways to KE nodes
115314view07:28, 12 February 2021Jkearns445
115313view07:18, 12 February 2021Jkearns445
115310view17:13, 11 February 2021Marvin M2updated KE title of KE66
115309view17:11, 11 February 2021Marvin M2Added Key Event type to KE66
115304view13:11, 11 February 2021Jkearns445
115303view12:43, 11 February 2021Jkearns445Added database IDs for more Key Events
115302view12:24, 11 February 2021Jkearns445Added database IDs for Key Events and changed the shape of the pathway nodes
115301view10:49, 11 February 2021Marvin M2
115300view10:48, 11 February 2021Marvin M2
95148view03:34, 17 November 2017AlexanderPicofixed interactions
93179view11:11, 2 August 2017JJvdHeijdenMaking the AOP network (biological) more compact
93178view11:10, 2 August 2017JJvdHeijdenDeleted a error

External references

DataNodes

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NameTypeDatabase referenceComment
AMP-activated Protein Kinase (AMPK) SignalingPathwayWP1403 (WikiPathways)
Angiopoietin Like Protein 8 Regulatory PathwayPathwayWP3915 (WikiPathways)
Aryl Hydrocarbon Receptor NetpathPathwayWP2586 (WikiPathways)
Branched-chain amino acid catabolismPathwayWP3556 (WikiPathways)
Cholesterol metabolismPathwayWP4718 (WikiPathways)
Constitutive Androstane Receptor PathwayPathwayWP2875 (WikiPathways)
Farnesoid X Receptor PathwayPathwayWP2879 (WikiPathways)
Fatty Acid BiosynthesisPathwayWP357 (WikiPathways)
Fatty acid transportersPathwayWP5061 (WikiPathways)
Foxa2 PathwayPathwayWP5066 (WikiPathways)
KE10106: Fatty Acid LysisEvent10106 (AOP-Wiki KE)
KE115: Increase, FA InfluxEvent115 (AOP-Wiki KE)
KE116: Activation, FASEvent116 (AOP-Wiki KE)
KE1214: Altered gene expression specific to CAR activation, HepatocytesEvent1214 (AOP-Wiki KE)
KE140: Decreased, HSD17B10 expressionEvent140 (AOP-Wiki KE)
KE167: Activation, LXREvent167 (AOP-Wiki KE)
KE18: Activation, AhREvent18 (AOP-Wiki KE)
KE227: Activation, PPARαEvent227 (AOP-Wiki KE)
KE228: demethylation, PPARg promoterEvent228 (AOP-Wiki KE)
KE232: Decreased, PPAR-beta activationEvent232 (AOP-Wiki KE)
KE245: Activation, PXR/SXREvent245 (AOP-Wiki KE)
KE258: Activation, SCD-1Event258 (AOP-Wiki KE)
KE264: Activation, SREBP-1cEvent264 (AOP-Wiki KE)
KE291: Accumulation, TriglycerideEvent291 (AOP-Wiki KE)
KE345: Liver steatosisEvent345 (AOP-Wiki KE)
KE466: Up Regulation, LDLR (low density lipoprotein receptor)Event466 (AOP-Wiki KE)
KE471: Inhibition, FoxA2Event471 (AOP-Wiki KE)
KE472: Down Regulation, CPT1AEvent472 (AOP-Wiki KE)
KE474: Down Regulation, HMGCS2Event474 (AOP-Wiki KE)
KE478: Activation, NRF2Event478 (AOP-Wiki KE)
KE479: Activation, NR1H4Event479 (AOP-Wiki KE)
KE54 Up Regulation, CD36Event54 (AOP-Wiki KE)
KE66: Activation, ChREBPEvent66 (AOP-Wiki KE)
KE860: Decreased, Mitochondrial Fatty Acid Beta OxidationEvent860 (AOP-Wiki KE)
KE89: Synthesis, De Novo FAEvent89 (AOP-Wiki KE)
Lipid Metabolism PathwayPathwayWP3965 (WikiPathways)
Liver X Receptor PathwayPathwayWP2874 (WikiPathways)
Metabolic pathway of LDLPathwayWP4522 (WikiPathways)
Mitochondrial LC-Fatty Acid Beta-OxidationPathwayWP368 (WikiPathways)
NRF2 pathwayPathwayWP2884 (WikiPathways)
PPAR Alpha PathwayPathwayWP2878 (WikiPathways)
PPAR Beta/Delta pathwayPathwayWP5073 (WikiPathways)
PPAR Gamma PathwayPathwayWP5071 (WikiPathways)
Pregnane X Receptor pathwayPathwayWP2876 (WikiPathways)
Sterol Regulatory Element-Binding Proteins (SREBP) signallingPathwayWP1982 (WikiPathways)

Annotated Interactions

No annotated interactions

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