Mitochondrial Remodeling During Obesity and Fatty Liver Disease: The biochemistry of metabolism is substantially being altered with the epidemics of obesity, fatty liver and type II diabetes mellitus (T2DM). Our research interest is in identifying shared metabolic defects in pathways of glucose, lipid and protein metabolism, contributing to the progression of insulin resistance, T2DM and fatty liver disease. We are particularly interested in how dynamic alteration in mitochondrial fuel metabolism leads to lipid accumulation (simple steatosis) in the liver and its subsequent transition to nonalcoholic steatohepatitis (NASH). From our previous research, we have identified overactive hepatic mitochondrial metabolism as a central feature of nonalcoholic fatty liver disease (simple steatosis and NASH). Overactive mitochondrial pathways have the potential to further drive pathways of reactive oxygen species production and inflammation thus potentially aiding the progression of simple steatosis to NASH. Our goal is to identify mechanisms contributing to dysfunctional mitochondrial oxidative flux and are significant modulators of cellular inflammation and oxidative stress.

Branched Chain Amino Acids and Mitochondrial Function: Branched Chain Amino Acids (BCAAs; leucine, isoleucine, valine) can fuel mitochondrial tri-carboxylic acid (TCA) cycle by providing carbon substrates (anaplerosis). More importantly, BCAAs have potent signaling functions through proteins (e.g. mTORC1, PGC1α, AMPK), which are also master regulators of mitochondrial fatty acid metabolism. Elevated BCAAs and defects in their tissue specific metabolism are associated with indices of insulin resistance and have helped predict onset of type II diabetes (T2DM). However the causal mechanisms remain unknown. Further, recent publications have demonstrated several lines of evidence pointing to a significant interaction between BCAAs and mitochondrial lipid metabolism during insulin resistance. We propose that BCAAs have a significant role in establishing dysfunctional hepatic mitochondrial metabolism during insulin resistance. Our goal is to elucidate the mechanisms by which BCAAs impact mitochondrial function and establish the relevance of these mechanisms in the treatment of fatty liver disease and also in promoting normal cellular functions.

Mitochondrial Metabolism during Embryonic to Post-hatch Development:  The late term embryonic chicken derives >90% of its energy through oxidation of yolk lipids in the liver. Furthermore, during metabolic transition of an embryo to a neonatal chick, there is a dramatic transition from lipid oxidation to up regulation of new lipid synthesis immediately post-hatch.  This period of metabolic transition provides us a unique opportunity to investigate mitochondrial mechanisms responsible of efficient utilization and disposal/storage of lipids. Our objective is to develop a ‘dual-intent’ research model to probe a) factors which improve metabolic efficiency during embryonic-neonatal transition, a question of significant interest to poultry production and management and  b) mechanisms regulating high rates of mitochondrial lipid oxidation, and  new lipid synthesis in the liver, a question of significant interest in developing strategies to manage fatty liver disease.