Hepatoprotective mechanisms of eicosapentaenoic acid in high-fat fed mice and identification of biomarkers for Non-Alcoholic Fatty Liver Disease in humans

Non-alcoholic fatty liver disease (NAFLD) is a rising epidemic, in part due to its association with obesity and obesity-related metabolic abnormalities. However, the relationship between body weight, NAFLD, and insulin resistance is not well characterized in humans, especially in populations that develop metabolic complications at lower body mass index, such as South Asians. Therefore, research that can lead to effective diagnostic as well as prevention/ treatment strategies for NAFLD and related diseases is greatly needed.
Several studies in animal and humans used dietary interventions, such as omega-3 (n-3) polyunsaturated fatty acids (PUFAs), to reduce NAFLD as well as inflammation-related metabolic disorders. While the anti-inflammatory and hypotriglyceridemic properties of n-3 PUFAs are well-known, mechanisms mediating their benefits in liver and in NAFLD are less understood. Previous studies in our lab have shown reduced hepatic triglyceride accumulation, despite similar body weights, between high-fat fed mice and those supplemented with eicosapentaenoic acid (EPA), a metabolite of n-3 PUFA. Hence, our objectives were: 1. Determine metabolic, inflammatory, and molecular changes in serum biomarkers in humans with NAFLD, and determine whether these are independent of body weight; and 2. Determine mechanisms by which n-3 PUFA reduces fatty liver in diet-induced obese mice, independent of adiposity. In our human study, we found central adiposity, subcutaneous and visceral adipocyte area, fasting blood glucose, and serum resistin to be the best indicators of NAFLD in South Asian women. Moreover, in liver tissues from mice and in HepG2 human hepatoma cells cultured in an inflammatory environment, we demonstrated that EPA ameliorated high-fat diet-induced NAFLD and improved energy metabolism. This was mediated by reduced de novo lipogenesis and triglyceride synthesis and by up-regulated lipid catabolism. Furthermore, gene and protein markers of inflammation were reduced with EPA. Interestingly, we found these processes to be mediated, in part, by EPA-regulated microRNA (miRNA) known to affect these hepatic processes. In conclusion, this work contributed significant knowledge towards understanding the link between NAFLD, obesity, insulin resistance and inflammation. Moreover, our animal studies provide novel science-based rationale for EPA supplementation in NAFLD patients, especially in South Asian populations with metabolic complications that are independent of body weight.

This dissertation won 1st Place in the Texas Tech University Outstanding Thesis and Dissertation Award, Biological Life Sciences, 2019.

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