Date of Award
Doctor of Philosophy (PhD)
Ketone body metabolism plays the fundamental metabolic role of generating alternative fuel sources, in the form of circulating ketone bodies, derived from breakdown of fatty acids, traditionally during states of carbohydrate depletion. Ketone bodies are produced in the mitochondria of the liver via ketogenesis, a process driven by activity of the fate-committing ketogenic enzyme, mitochondrial 3-hydroxymethylglutaryl-CoA synthase (HMGCS2). Nonalcoholic fatty liver disease (NAFLD) spectrum disorders affect nearly one billion individuals worldwide and approximately 30% of all adults in the United States. NAFLD is defined by pathological lipid accumulation in the liver, is strongly correlated with obesity and the metabolic syndrome, and can progress to the more severe non-alcoholic steatohepatitis (NASH) if left untreated. Despite this, the mechanisms driving hepatic steatosis and steatohepatitis are still unknown, and few therapies exist to address this spectrum of liver disorders. In particular, the role of mitochondrial metabolism, the central organelle in fatty acid oxidation, remains incompletely defined. Ketogenesis is positioned at a pivotal juncture in the hepatic mitochondria, amongst the tricarboxylic acid (TCA) cycle, gluconeogenesis, and fatty acid oxidation. In this dissertation, I utilize novel mouse models, mass spectrometry and nuclear magnetic resonance imaging of 13C-labeled substrate flux in vivo, and measures of mitochondrial morphology and function among other biochemical and systems physiology techniques to demonstrate a critical role for hepatic ketogenesis in regulating mitochondrial metabolism and liver injury in the context of the neonatal period, during feeding and fasting in adulthood, and in overnutrition. Using a novel murine model of HMGCS2-deficiency, I show that ketogenesis insufficient, fasting, adult mice are markedly steatotic with concomitant hyperglycemia. However, upon high-fat diet feeding, an inability to generate ketone bodies from fatty acids instead results in severe liver inflammation and injury, which is associated with a redirection of acetyl-CoA flux towards de novo lipogenesis (DNL) and sequestration of free coenzyme A, further disrupting mitochondrial metabolic pathways. I further demonstrate that this metabolic reprogramming in the ketogenesis insufficient context provokes shifts in the hepatic phospholipidome, as well as mitochondrial morphology and function. These studies implicate a significant role for hepatic ketogenesis in regulating complex metabolic pathways in the liver in a classically non-ketogenic, carbohydrate replete state, and establish it as a compelling target to better understand and address the metabolic dysfunction seen in the livers of obese and diabetic individuals.
Chair and Committee
Peter Crawford & Brian Finck
Thomas Baranski, David Rudnick, Joel Schilling, Clay Semenkovich,
Ercal, Baris Can, "Hepatic Ketogenesis as a Novel Regulator of Liver Metabolism and Injury" (2017). Arts & Sciences Electronic Theses and Dissertations. 1099.
Available for download on Saturday, May 15, 2117