Dietary and Cellular Mechanisms Regulating Hepatocyte Proliferation and Cancer
2017-08
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Dietary and Cellular Mechanisms Regulating Hepatocyte Proliferation and Cancer
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2017-08
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Obesity is well-documented to promote the development of nonalcoholic fatty liver disease (NAFLD) including its more advanced stages such as non-alcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma (HCC). While metabolic perturbations describing obesogenic progression from NAFLD to HCC have largely been investigated, our knowledge of the role lipolysis plays in this process is scant. This research project is aimed at understanding the role fasting lipid metabolism plays in pathologic features of carcinogenesis as well as synergistically combining with lifestyle factors to prevent obesity driven progression of NAFLD to HCC. To elucidate these features, we employed two seminal studies. The first study characterized the role of adipose triglyceride lipase (ATGL) in limiting a major cell cycle regulator, cyclin D1, and hepatocellular proliferation both in vitro and in vivo. We show that lipid catabolism via ATGL antagonizes cell proliferation. Additionally, we recapitulate these findings using a partial hepatectomy model to drive hepatocellular proliferation in vivo. In the second study, we conduct a long-term carcinogenesis study that examines the role of dietary fat composition and lifestyle factors that promote fasting lipid metabolism. Animals were calorically restricted (CR) or exposed to regular endurance exercise. Using the hepatic carcinogen diethylnitrosamine (DEN), we show CR prevents hepatic tumor formation independent of dietary fat composition. RNA sequencing of non-transformed liver tissues revealed changes in metabolic pathways and reduced inflammation, cytokine production, stellate cell activation and migration, and genes associated with liver injury and oncogenesis. Taken together, fasting hepatic lipid metabolism plays a significant role in mitigating proliferative effects often associated with overconsumption of calories. Furthermore, lifestyle factors that promote lipolysis in the liver robustly protected mice from developing tumors. Further investigation is warranted to define the molecular mechanisms ATGL plays in limiting hepatic proliferation as well as characterizing the role of ATGL and fasting in hepatic tumorigenesis.
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University of Minnesota Ph.D. dissertation. August 2017. Major: Nutrition. Advisor: Douglas Mashek. 1 computer file (PDF); xi, 139 pages.
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Ploeger, Jonathan. (2017). Dietary and Cellular Mechanisms Regulating Hepatocyte Proliferation and Cancer. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/198372.
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