Differential mechanisms by which the aryl hydrocarbon receptor attenuates liver regeneration

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Title: Differential mechanisms by which the aryl hydrocarbon receptor attenuates liver regeneration
Author: Courtney Alicia Lockhart
Abstract: 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 .
URI: http : / /hdl .handle .net /2152 .3 /239
Date: 2007-10-11

Citation

Differential mechanisms by which the aryl hydrocarbon receptor attenuates liver regeneration. Doctoral dissertation, The University of Texas Medical Branch. Available electronically from http : / /hdl .handle .net /2152 .3 /239 .

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