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Novel therapies for NAFLD




Nivala, Angela Marie, author
Pagliassotti, Michael, advisor
Vivanco, Jorge, committee member
Frye, Melinda, committee member
Vanamala, Jairam, committee member

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Background/Aims Non Alcoholic Fatty Liver Disease (NAFLD) is a chronic liver disease often associated with metabolic disorders like type 2 diabetes, cardiovascular disease, obesity, and metabolic syndrome. It is characterized by hepatic fat accumulation (steatosis) that is at or above 5% of liver weight in the absence of excessive alcohol consumption (< 20 g/day). Current treatment for NAFLD focuses on reducing body weight and improving insulin action. The intent of this thesis was to identify therapies that targeted the liver. In the first aim, we examined whether secretions from plant roots contained compounds that restricted lipid accumulation or improved insulin action. The second aim examined whether taurine could prevent characteristic features of disease progression. Specifically, we hypothesized that (1) onion root exudates will prevent or reduce lipid accumulation and improve insulin signaling and (2) taurine will prevent or reduce endoplasmic reticulum (ER) stress, oxidative stress and liver injury. Methods To examine these hypotheses, liver cells and dietary models of NAFLD were employed. Analyses focused on hepatic triglycerides, insulin signaling, ER stress, oxidative stress and inflammation using basic biochemical methods such as western blotting, Real Time PCR, immunohistochemistry and enzyme-linked assays. Results Onion root exudates prevented fatty acid-mediated lipid accumulation and enhanced insulin signaling in H4IIE liver cells. Onion root exudates reduced plasma glucose, free fatty acids (FFA), and improved insulin action in rats fed a high fat diet. Taurine mitigated palmitate-mediated caspase-3 activity, cell death, ER stress, and oxidative stress in H4IIE liver cells and primary hepatocytes. In rats fed a high sucrose diet, taurine supplementation significantly reduced hepatic lipid accumulation, liver injury, inflammation, plasma triglycerides and insulin levels. The high sucrose diet resulted in an induction of multiple components of the unfolded protein response (UPR) in the liver consistent with ER stress which was ameliorated by taurine supplementation. Treatment of mice with the ER stress inducing agent tunicamycin resulted in liver injury, UPR induction and hepatic lipid accumulation, and this was significantly ameliorated by supplementation with taurine. Conclusion Both onion root exudates and taurine reduced metabolic abnormalities associated with NAFLD. Onion root exudates appear to exert this effect through reduced lipid accumulation and enhanced insulin sensitivity in the liver, while taurine reduced hepatic steatosis, ER stress, oxidative stress and liver injury. Overall, onion root exudates and taurine show promise as novel therapies for the treatment of NAFLD.


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hepatic steatosis
insulin resistance
root exudates


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