Date of Award
Open Access Dissertation
Environmental Health Sciences
Non-alcoholic fatty liver disease (NAFLD) is an emerging worldwide pandemic which is highly prevalent among obese individuals including children and adults. In a NAFLD condition, exposure to environmental contaminants or toxins can act as a second/ multiple hit, which leads to the progression of simple steatosis to NASH and ultimately may result in liver cirrhosis. With climate change today, elevated levels of microcystins are an emerging problem in fresh water bodies, which are a source of drinking water. Individuals are therefore at risk of exposure to microcystin through consuming contaminated water. In the progression of NAFLD from one clinical stage to another, microcystin can play an important role. Research has proved that the main mechanism of the Microcystin-LR is to work as an exogenous Protein phosphatase 2A (PP2A) inhibitor. In this thesis we test the hypothesis that microcystin activates Kupffer cells as well as the hepatic stellate cells, which are the crucial mediators in hepatic inflammation and fibrogenesis via NOX2 dependent pathway in NAFLD condition. Results showed that microcystin exposure via intraperitoneal routes in mice that have mild steatosis will lead to advanced histopathological characteristics of NAFLD. Further, we looked at the effect of early microcystin exposure in young mice, which were then fed a high fat diet to induce obesity/NAFLD. Early exposure to microcystin resulted in exacerbation of NAFLD clinical pathology with increased expression of proinflammatory cytokines, compared to vehicle control treated mice. This process has been shown to be reduced in mice that lacked miR21, p47 phox , or NLRP3 genes. In addition, inhibition of AKT pathway reduced microcystin -induced NOX2 activation as well as upregulation of miR21. All things considered, it was observed that microcystin exposure exacerbated NAFLD pathology via activating NOX2-dpendent peroxynitare generation by increasing miR21 levels. Moreover, early childhood exposure to microcystin will exacerbate adult hepatic injury following HFD via NLRP3 inflammasomes.
Albadrani, M.(2019). Microcystin Exposure and Liver Injury Outcomes in NAFLD. (Doctoral dissertation). Retrieved from https://scholarcommons.sc.edu/etd/5505