| الوصف: |
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States. Up to 54% of patients with a severe form of NAFLD, called nonalcoholic steatohepatitis (NASH), also have chronic kidney disease (CKD). NAFLD encompasses a spectrum of liver pathologies including steatosis, inflammation, fibrosis, hepatocellular ballooning, and is a risk factor for hepatocellular carcinoma. CKD is defined by proteinuria and reduced glomerular filtration rate. NAFLD and CKD share multiple risk factors including obesity, hyperlipidemia, insulin resistance, and hypertension. In addition, various environmental toxicants are implicated in pathogenesis and progression of NAFLD and CKD. This dissertation presents work on the role of microcystin-LR (MCLR) in the pathogenesis of NAFLD and CKD. Microcystin-LR is produced by blue-green algae that is found in surface water, and it is a well-known liver and kidney toxin. The central hypothesis defended in this dissertation is that MCLR irreversibly exacerbates the hepatic and renal manifestations of NASH. Exacerbation (Specific Aim 1) and irreversibility (Specific Aim 2) of the NASH phenotype by MCLR were tested in a diet-induced rodent NASH model. It was found that sub-chronic MCLR exposure induced a burnt-out NASH hepatic phenotype, characterized by loss of steatosis and increased fibrosis. It was also found that MCLR increased proteinuria and renal tubule cast formation in the rodent NASH model. Burnt-out NASH is a risk factor for mortality in NAFLD patients, and our findings suggest that MCLR exacerbates liver disease and increases the risk of death in NASH patients and be a risk factor for CKD in humans. Reversibility of MCLR toxicity was examined next. In NASH animals, MCLR-induced fibrosis persisted at least 4 weeks after toxin exposure discontinuation. Gene expression profiling (RNA-seq) further showed persistent overexpression of cancer-related genes 4 weeks post exposure. The data suggest the toxin has a long-lasting impact on the liver, that has the potential to increase the risk for hepato-cellular carcinoma in NASH patients. Collectively, the studies confirmed that MCLR exacerbates hepatic and renal pathology in NASH and confirmed partial irreversibility of the toxin action and the potential for short-term exposure to increase the risk for long-term adverse consequences. |
