Systems-Level Analysis of Regulatory Networks Involved in Alcoholic Liver Disease
The ability of the liver to repair and regenerate itself following injury is a complex and tightly regulated process, the disruption of which can lead to severe loss of function across multiple organ systems. Initiation of liver regeneration in response to injury is controlled through multiple signaling pathways involving cytokines, growth factors, metabolic processes, and microRNA regulation. Coordination of these signaling components requires a concerted response by multiple cell types in the liver. Chapter one focuses on the importance of maintaining normal liver regeneration, key regulatory mechanisms, and the role of the multiple cell types found in the liver. Chapter two discusses the importance and role of microRNAs as regulatory mechanisms of liver regeneration. In particular, we investigate the landscape of microRNA changes in response to acute injury with and without ethanol adaptation in a rat model. Using a global assay to examine 420 well-characterized microRNAs, we identified several cohorts showing differential expression in response to injury, ethanol adaptation, or both. In vivo microRNA manipulation revealed a possible microRNA regulatory network with critical importance to liver regeneration. This network appears to be particularly important in the response of hepatic stellate cells to liver injury, indicating an outsized influence of this cell type relative to its abundance in the regenerative response. Chapter three explores a computational model developed to simulate select signaling pathways activated in hepatic stellate cells in response to injury. In particular, we focused on the IL-1, IL-6, and TGF-β signaling pathways alongside microRNA regulation of downstream signaling components. Our simulations were able to recapitulate observed physiological phenotypes and show that timing of these signaling components is critical for generating the initial dynamics of changes in microRNA expression. We were also able to demonstrate that cessation of these signals returns our system to baseline according to relative expression. Chapter four describes the changes in metabolism and metabolic networks occurring in patients with alcoholic liver disease. Several genes and metabolites related to various energetic processes were differentially expressed in diseased patients compared to healthy controls. Network analysis of these pathways, with a focus on the tricyclic acid cycle, provides evidence for the utilization of non-standard energetic pathways, such as the pentose-phosphate shunt. These alternate pathways are less energetically efficient, and may contribute to the loss of function seen in these diseased livers. In summary, the results presented in this thesis examine the mechanisms behind liver regeneration from the perspective of their regulatory components.
Parrish, Austin, "Systems-Level Analysis of Regulatory Networks Involved in Alcoholic Liver Disease" (2021). ETD Collection for Thomas Jefferson University. AAI28776635.