Understanding the Role of Liver Acetyl-CoA Carboxylases in Normal Physiology, Metabolic Disease, and Liver Cancer [thesis]

Marin Healy
The liver has a high capacity to store excess nutrients, primarily in the form of fat. However, excess lipid deposition in the liver can be problematic, as it is associated with metabolic disorders including fatty liver disease, type II diabetes, and liver cancer. The acetyl-CoA carboxylase (ACC) enzymes are major regulators of liver lipid content by catalyzing the conversion of excess glucose in the liver to fat, and by inhibiting mitochondrial fat oxidation. Thus, the ACC enzymes are
more » ... drug targets because altering their activity could correct disease states associated with excess fat deposition. Using mice with genetic inhibition of liver ACC activity, we have uncovered a novel role for these enzymes in regulating protein acetylation that contributes to broad changes in cellular metabolism. At the level of whole-body physiology, we found that when a source of dietary fat was absent, LDKO mice have increased glucose disposal into the liver, reduction of peripheral adiposity, and improved whole-body glucose tolerance compared to controls. Under high-fat diet conditions, LDKO mice are protected from diet-induced fatty liver. However, a decrease in liver fat in this case is not sufficient to ameliorate dietinduced glucose intolerance. Finally, we investigated the role of ACC activity in tumorigenesis. Unexpectedly, inhibition of ACC activity increased susceptibility to carcinogen-induced liver tumor. Increased liver antioxidant defenses in LDKO mice protected cells from carcinogen-induced apoptosis and promoted tumor cell proliferation. This study identifies a protective role for ACC enzymes against tumorigenesis. Taken together, this work increases our understanding of liver nutrient metabolism and ACC activity, and highlights the complexity of liver metabolic compensatory mechanisms. II ACKNOWLEDGEMENTS I am grateful for this opportunity to develop as a scientist at the University of Virginia. The past four years have been some of the best of my life, and this can be attributed to the wonderful people in my life. I would like to start by thanking my family. My husband, Bobby Healy, did not hesitate to move to the other side of the country for this program. He has always encouraged me to push on through those long days in the lab and long nights studying. My brother, Owen Nelson, is always there to lift my spirits. Even as his older sister, I hope to be half as clever as he is one day. My mother, Leslie Nelson, is the best mother anyone could hope for. She's been in my corner from day one and has always challenged me to think big and pursue my dreams. Her confidence in me gives me the extra motivation to keep going, even if I'm not always quite as confident in myself. I dedicate my work to the memory of my father, Don Nelson, who passed away from cancer before his time. He instilled in me a curiosity for how things work and a passion to make the world a better place for those around me. I hope to carry his legacy forward by living life to the fullest, not taking a day for granted, and valuing relationships above accomplishments or possessions. To my best friend, Chérie Nel, it's been quite an adventure! I remember years ago chatting about our hopes and dreams, and what life would look like when we were adults. Well, I still don't feel like an adult, but it's fun to look back and see how far we've come.
doi:10.18130/v32v9z fatcat:ubanw5cufzd4xabueevku64vo4