Regulation of in vitro and in vivo Hepatic Stellate Cell Activation by the Ayrl Hydrocarbon Receptor
Publication Date
12-2020
Date of Final Oral Examination (Defense)
10-8-2020
Type of Culminating Activity
Dissertation
Degree Title
Doctor of Philosophy in Biomolecular Sciences
Department
Biology
Major Advisor
Kristen A. Mitchell, Ph.D.
Advisor
Kenneth A. Cornell, Ph.D.
Advisor
Allan R. Albig, Ph.D.
Advisor
Eric J. Hayden, Ph.D.
Advisor
Matthew L. Ferguson, Ph.D.
Abstract
Liver fibrosis is a pathological condition characterized by the excessive deposition of extracellular matrix material by activated hepatic stellate cells (HSCs). We recently reported that activation of the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases HSC activation in vitro and in mouse models of experimental liver fibrosis. The goal of this project was to determine the mechanism by which AhR activation impacts HSC activation and the subsequent development of liver fibrosis. It is possible that HSCs are direct cellular targets for TCDD. Alternatively, TCDD could increase HSC activation indirectly by exacerbating hepatocyte damage and inflammation. To investigate this, we generated mice in which the AhR was selectively removed from either hepatocytes or HSCs to determine the ramifications on liver injury, inflammation, and HSC activation in an experimental model of liver fibrosis elicited by chronic administration of TCDD. Results from these studies indicate that TCDD does not directly activate HSCs in the mouse liver to produce fibrosis. Instead, it appears that TCDD-induced changes in hepatocytes, such as the development of steatosis, are what ultimately stimulate HSC activation and produce fibrosis. A second focus of this project was to investigate an endogenous role for AhR signaling in the regulation of HSC activation in the absence of liver injury and inflammation. To this end, I used CRISPR/Cas9 technology to knock down the AhR in the human HSC cell line, LX-2. I discovered that a functional AhR is required for optimal proliferation of activated HSCs. However, other endpoints of HSC activation, such as the production of collagen type I, were not impacted by the removal of AhR signaling. These findings are important because the AhR has been shown to be a druggable target, and there is growing interest in therapeutically modulating AhR activity to prevent or reverse HSC activation. Collectively, results from this project indicate that therapeutically targeting AhR signaling in hepatocytes, instead of AhR signaling in HSCs, might be a preferred approach for limiting HSC activation and preventing or diminishing liver fibrosis.
DOI
10.18122/td/1750/boisestate
Recommended Citation
Rayavara Veerabhadraiah, Shivakumar, "Regulation of in vitro and in vivo Hepatic Stellate Cell Activation by the Ayrl Hydrocarbon Receptor" (2020). Boise State University Theses and Dissertations. 1750.
10.18122/td/1750/boisestate
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