Differential mechanisms by which the aryl hydrocarbon receptor attenuates liver regeneration



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Liver regeneration is orchestrated by a series of autocrine and paracrine cues that function to restore hepatic tissue, however the precise cellular and molecular mechanisms that regulate these signaling events are poorly understood. Recent evidence demonstrates that hepatocyte proliferation following partial hepatectomy (PH) can be attenuated by the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that is involved in hepatic organogenesis and cell cycle control. This growth suppression suggests that AhR modulates critical signaling processes of the regenerative program. In particular, the regeneration process is initiated by both cytokines and matrix enzymes and propagated by the potent mitogenic activity of two proteins, the c-Met transmembrane receptor and urokinase plasminogen activator (uPA). However, this growth response is limited by the expression of plasminogen activator inhibitor-1 (PAI-1) and TGF-?, which terminates hepatocyte proliferation. The goal of these studies was to determine the influence of AhR on these moieties in the context of the regenerative program. The hypothesis that AhR modulates these signaling molecules in a mito-inhibitory manner was tested using an in vivo model system of 70% PH in mice pre-treated with 2,3,7,8-tertachlorodibenzo-p-dioxin (TCDD), a potent, prototypical, and persistent AhR agonist. We demonstrate that AhR did not alter cytokine or matrix enzyme expression during the regenerative process, but markedly upregulated PAI-1 and TGF-? protein levels post-PH. As a consequence, both c-Met and uPA activation were greatly suppressed in an AhR-dependent fashion during liver regeneration as well. Conclusion: These observations suggest a novel mechanism of AhR-mediated attenuation of the regenerative response and identify a possible physiologic function of AhR in vivo.



urokinase plasminogen activator, regeneration, PAI-1, liver, aryl hydrocarbon receptor, AhR