• Transcription Factor Binding Site Analysis Reveals Mechanistic Features in the Progression of Non-Alcoholic Steatohepatits

      Cherrington, Nathan J.; Chaput, Alexandria Laurel; Cherrington, Nathan J.; Smith, Cathy; Vaillancourt, Richard (The University of Arizona., 2015)
      The liver has a unique capability for regeneration and is particularly resilient to insult. It plays an essential role in drug disposition and metabolism, regulating numerous pathways involved in ADME (absorption, distribution, metabolism, and excretion) processes. In order for a drug to be effective, it must be able to get to its target site in a timely manner and at an appropriate concentration. Chronic liver disease has been of increasing significance and elucidating the driving forces behind disease progression is key to understanding adverse drug reactions and many cases of liver toxicity. Coordinate regulation of liver transporters and drug metabolism enzymes is essential for maintaining homeostasis and effective liver functionality. Nonalcoholic steatohepatitis, a severe inflammatory disease state that progresses from normal steatosis and Nonalcoholic Fatty Liver Disease has shown significant changes in gene expression as pathological disease progression occurs. Transcription factor binding site analysis proves lucrative in elucidating key signaling pathways in disease progression. Several up and down-regulated genes have enriched transcription factor binding sites in the NASH disease state, including members of the HNF, SOX, and LXR families. These transporters and drug metabolizing enzymes are involved in key processes, including inflammatory signaling, liver cell maintenance, bile acid regulation and other processes that are driving factors in liver repair and insult. By identifying key transcription factors in disease progression and looking at the signaling pathways behind the enriched transcription factors, potential driving factors behind disease progression are discovered. As a major contributor to the progression of the disease state, the significance of driving factors for hepatic fibrosis are discussed. The immune system and inflammatory processes are key drivers of fibrosis and cirrhosis, often mediated by cytokines, such as IL-4 and IL-6.