Abstract: Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease. The spectrum of NAFLD ranges from simple steatosis, to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and potentially hepatocellular carcinoma. Dietary factors and chemical exposure have been associated with the disease progression. In addition, the presence of NAFLD changes the metabolism of drugs and chemicals, which may in turn increase the susceptibility of the liver to xenobiotic induced toxicity. To examine the potential interplay of chemicals on diet-induced NAFLD, three studies were conducted in this dissertation project. In the first study, a mouse model was established that recapitulated the spectrum of liver damages seen in human NAFLD. Using a high fat diet (HFD), steatosis, NASH, progressive fibrosis, and liver tumor formation were produced in mice. Modulations of nuclear receptors involved in metabolism of endogenous and xenobiotic compounds were characterized at various stages of NAFLD. Using this mouse model, a second study examined if perfluorooctanoate (PFOA), a ubiquitous environmental contaminant, modulated the progression of NASH. The results showed PFOA induced hepatic DNA synthesis and liver inflammation were exacerbated in the mice fed with HFD. In contrast, PFOA decreased the severity of hepatic steatosis and fibrosis induced by HFD. To further investigate the mechanisms underlying these observed effects, a third study was performed that analyzed the hepatic transcriptome in liver samples taken from studies 1 and 2. The results of the third study demonstrated that cytokine and chemokine-related genes played important role in the development of both inflammation and fibrosis in NAFLD. Comparing PFOA to vehicle controls in HFD fed mice, PFOA disrupted the lipid homeostasis to favor clearance in the fatty liver, as most of the genes were enriched in the fatty acid oxidation pathways. In summary, this project established and a mouse model of HFD induced NAFLD and characterized the interplay of diet and chemicals in the disease progression. The results from this dissertation also indicated that patients with NAFLD may respond differently compared with healthy individuals. The potential susceptibility of this population to chemically induced hepatotoxicity needs to be carefully considered when assessing risk.
Keywords: High fat diet,Non-alcoholic fatty liver disease,PFOA,RNA-seq, Xenobiotics