HARRTC Fellow - Dr. Nicholas Szary
HARRTC fellow Nicholas Szary, MD, is currently working on a translational science research project that examines environmental stressors applied to a novel polygenic rat model to study the role of aerobic capacity on metabolic health. Dr. Szary’s mentor for this project is Jamal A. Ibdah, MD, Senior Associate Dean for Research at the MU School of Medicine and Director of the Division of Gastroenterology and Hepatology in the Department of Internal Medicine. In addition, Dr. Szary is involved with a research study that examines the effect of exercise on insulin resistance and muscle morphology before and after exercise with or without the addition of a statin drug; his research has high relevance for human conditions that restrict physical activity and result in deconditioning syndromes. Dr. Szary’s mentor for this project is Dr. John Thyfault, Assistant Professor in the Department of Nutritional Science and the Department of Internal Medicine.
Research Plan
Title: The effect of environmental stressors such as obesity and ethanol applied to a genetically susceptible model.
Nonalcoholic fatty liver disease (NAFLD) is becoming a major public health problem in western societies. Mitochondrial trifunctional protein (MTP) is the enzyme complex responsible for catalyzing the last 3 steps in mitochondrial fatty acid β-oxidation. It is estimated that 1% of the US population is heterozygous for a defect in MTP, and its impairment leads to mitochondrial dysfunction and NAFLD development. We previously reported that heterozygosity for a genetic defect in mitochondrial trifunctional protein (MTPa+/-) causes development of NAFLD in aging (>9 months) but not young mice fed standard chow diet (12% cal from fat) (Gastroenterology, 128: 1381-90, 2005). For this project, e nvironmental stressors such as obesity and ethanol are applied to a novel polygenic model to study the role of metabolic function and its effects on health. Ethanol and high fat diet will be used as stressors to decipher the metabolic pathways leading to non alcoholic and alcoholic steatohepatitis (inflammation of the liver secondary to fat) and it's affects on health.
The broad objective of this project is to obtain information on metabolic pathways which lead to non alcoholic steatohepatitis. Ethanol will additionally be used as an environmental stressor to further decipher the pathways. Our lab has obtained a model where rats selectively bred for high or low running capacity intrinsically possess contrasting aerobic capacities. It has been shown that exercise capacity is a more powerful predictor of mortality among men than any other established risk factor including hypertension and diabetes. The rat groups designated HCR for high running capacity and LCR for low running capacity differ in their phenotype. The LCR group has hyperglycemia, increased insulin resistance, hypercholesterolemia, obesity and hypertension as compared to the HCR group. The LCR group can be though of as human equivalent of the metabolic syndrome. As ethanol is known to cause steatosis and fibrosis of the liver, we proposed that LCR animals fed ethanol will have synergistic increase in steatosis secondary to ethanol and previous steatosis from metabolic syndrome. Conversely the HCR group will be protected via damage from oxygen species due to its intrinsic genetic make up allowing the animals to withstand the environmental stressor ethanol.
Additionally, an already established model deficient in fatty acid oxidation will be used to again decipher the metabolic pathways which lead to non alcoholic steatohepatitis. Additional model is deficient in mitochondrial trifunctional protein (MTP) which catalyzes long-chain fatty acid oxidation and a mouse model deficient in MTP activity develops hepatic steatosis after aging providing evidence that hepatic mitochondrial dysfunction can induce NAFLD. We have shown that heterozygosity for MTP in mice causes susceptibility for development of NAFLD under dietary conditions rich in fat primarily due to impaired mitochondrial fatty acid oxidation with a secondary inhibition of CPT-1 leading to reduced fatty acids entry to the mitochondria. Our data suggest that addition of ethanol to fat-rich diet does not exacerbate susceptibility to development of hepatic steatosis but rather increases susceptibility to hepatic injury in mice heterozygous for MTP.
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