REGULATION OF THE BIOCHEMICAL SYNERGY BETWEEN MITOCHONDRIAL OXIDATIVE NETWORKS AND DE NOVO LIPOGENESIS IN THE LIVER

Abstract

The liver is a key metabolic organ responsible for whole-body energy metabolism by coordinating the regulation of carbohydrate, lipid, and amino acid metabolism across fed and fasted states. Hepatic mitochondria play a central role in regulating these networks that integrate nutrient utilization, biosynthetic pathways, and energy production. The metabolic flux through these networks dynamically adapts to nutritional and hormonal stimuli, which is essential for supporting the energy needs during animal growth and during the onset of metabolic challenges. Understanding how the flow of nutrients through mitochondrial oxidative networks establishes biochemical signatures that determine the metabolic phenotype of the liver is critical for identifying mechanisms underlying metabolic health during developmental periods and the onset of disease. This dissertation utilizes a combination of in-vivo (mice and chickens) and in-vitro (isolated mitochondria) systems coupled with stable isotope-based methodologies and molecular biology-based techniques to study the metabolic regulation of mitochondrial function. Metabolic dysfunction associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease worldwide and is characterized by excess lipid accumulation in the liver. Dysregulated mitochondrial metabolism, along with high and sustained rates of de novo lipogenesis (DNL) are a characteristic feature of people suffering from MASLD. Due to the close biochemical relation of DNL with mitochondria, I examined how a carbohydrate-rich diet that induces DNL can alter mitochondrial metabolism during fatty liver condition. Using murine models, I demonstrate that fructose-induced upregulation of lipogenesis occurs concurrently with upregulation of mitochondrial oxidative pathways. My results suggest that chronic induction of mitochondrial oxidative capacity can contribute to the progressive pathophysiology of MASLD. The embryonic to post-hatch development in chickens is characterized by a dramatic metabolic transition from lipolytic metabolism in the embryonic stages to lipogenic metabolism after hatch. While the provision of diet is known to induce this metabolic shift, the role of individual macronutrients in initiating this metabolic shift was unclear. My findings revealed that individual dietary macronutrients differentially influenced the initiation of this transition, highlighting nutrient-specific control of hepatic metabolic remodeling during early post-hatch development. Furthermore, hepatic mitochondria coordinate this metabolic switch through dynamic regulation of oxidative pathways along with nutrient transport mechanisms. In summary, this dissertation highlights the requirement for coordinated nutrient flux through mitochondrial metabolic networks for the establishment of specific metabolic phenotypes in the liver during development and during the onset of metabolic disease. My findings 1) establish a mechanistic link between upregulated lipogenesis and dysregulated mitochondrial oxidative pathways during MASLD and 2) identify the key nutritional regulator responsible for the metabolic switch during the embryonic to post-hatch transition. Overall, this dissertation provides a framework for understanding how the dynamic nature of mitochondrial networks shapes liver function, which in turn could be leveraged to optimize growth and development, and also for developing strategies to manage metabolic defects during MASLD.