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Increase, Phenotypic enzyme activity leads to Increase, cell proliferation (hepatocytes)
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|PPARα activation leading to hepatocellular adenomas and carcinomas in rodents||adjacent||High||Moderate||Chris Corton (send email)||Under development: Not open for comment. Do not cite||Under Development|
Life Stage Applicability
Key Event Relationship Description
Growth factors and other cytokines secreted from Kupffer cells following PPARα activation include tumor necrosis factor α (TNFα), interleukin-1α (IL-1α), and interleukin-1β (IL-1β). Although TNFα levels increase following PPARα activation, proliferation was observed in wild type, TNFα-null, and TNFα receptor-null mice, suggesting that multiple cytokines stimulate cell proliferation (Maeda et al. 2005). PPARα activation reduces the level of miRNA let-7c in liver. In turn, let-7c normally down-regulates c-Myc expression and thus, PPARα activation increases c-Myc expression that increase cell proliferation (Shah et al. 2007). PPARα activation increases levels of other cell cycle proteins including Cdk-1, Cdk-4, Cyclin D1 and Pcna (Currie et al. 2005; Woods et al. 2007).
Evidence Collection Strategy
Evidence Supporting this KER
Whilst knowledge of the molecular pathways underlying cell proliferation remains incomplete, the consistent observation of increases in both cell proliferation, liver weight and cytokine levels are consistent with biological knowledge.
Alteration of genes/proteins involved in cell growth by PPARα activators was not observed in PPARα-null mice
Uncertainties and Inconsistencies
The precise mechanism for activation of growth control genes is not known.
Known modulating factors
Quantitative Understanding of the Linkage
Cell proliferation measured by BrdU labeling index was plotted against the enzyme response of the three PPARα activators. The enzyme measured was acyl CoA oxidase, a lipid-metabolizing enzyme and was considered a surrogate for the cytokines and other growth-related cytokines stimulated by PPARα activation. These data were well fit by a Michaelis-Menten equation, suggesting that receptor mechanisms are likely involved in the growth response.
The maximal proliferation level was 30.88% and the half-maximal enzyme response was 3.37.
Levels of cytokines and other cellular proteins involved in cell cycle control are increased concomitant with increased enzyme activity and stimulate cell proliferation.
Both responses considered above occured 1 week after commencing PPARα activation.
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The domain of applicability is the same as for AOP 37.