Division of Gastroenterology (MU)The Division of Gastroenterology is a division in the Department of Internal Medicine at the University of Missouri-Columbia.https://hdl.handle.net/10355/69912024-03-29T09:37:29Z2024-03-29T09:37:29ZInterdisciplinary Approach to Examine the Effects of Lifestyle Modifications on Nonalcoholic Fatty Liver DiseaseRector, R. Scott (Randy Scott)Uptergrove, Grace M.E.Booth, Frank W., Ph. D.Thyfault, John P.Ibdah, Jamal A.https://hdl.handle.net/10355/62022020-06-18T22:11:06Z2010-01-01T00:00:00ZInterdisciplinary Approach to Examine the Effects of Lifestyle Modifications on Nonalcoholic Fatty Liver Disease
Rector, R. Scott (Randy Scott); Uptergrove, Grace M.E.; Booth, Frank W., Ph. D.; Thyfault, John P.; Ibdah, Jamal A.
A critical complication of the obesity epidemic experienced in Westernized societies is nonalcoholic fatty liver disease (NAFLD). NAFLD, fatty liver not due to alcohol consumption, is the most common chronic liver disease and associated with increasing morbidity, mortality, and demand for liver transplantation. NAFLD is a progressive disease with a histological spectrum ranging from hepatic steatosis to nonalcoholic steatohepatitis, advanced fibrosis, and cirrhosis. Approximately one third of all US adults (90 million) have fatty livers, with prevalence rates as high as 75-100% in the obese and morbidly obese. With growing health problems associated with NAFLD, major questions facing research scientists and health care providers are what are the mechanisms responsible for NAFLD development and what is the best treatment strategy. Since drug interventions appear to be only marginally successful, the cornerstone therapy for NAFLD remains lifestyle modifications of exercise and weight loss. However, while recent cross-sectional observations suggest that being more physically active is inversely associated with NAFLD, studies which attempt to identify molecular mechanisms underlying the effects of lifestyle modifications on NAFLD are lacking. To address these clinical questions, we have taken an interdisciplinary approach with collaborations from experts in multiple departments and facilities at the University of Missouri, including Nutrition and Exercise Physiology, Hepatology, Veterinary Biomedical Sciences, and VA investigators. In addition, we have utilized a unique animal model, the hyperphagic Otsuka Long-Evans Tokushima Fatty (OLETF) rat that develops obesity, insulin resistance and overt type 2 diabetes, a model which we liken to overeating, sedentary, obese humans. Through a series of experiments, we found that the natural progression pattern of fatty liver disease in the sedentary OLETF rat closely resembles the human condition (progression from simple hepatic steatosis to hepatocyte ballooning, fibrosis, and inflammation). We also have compelling evidence that hepatic mitochondrial dysfunction is present at an early age and mitochondrial content, function, and mitochondrial health are disrupted with disease progression, suggesting a potential primary event in NAFLD in this animal model. However and perhaps even more important, when OLETF rats are given access to voluntary running wheels and allowed to exercise daily, the initiation and progression of NAFLD is completely prevented. These benefits occur through modification in both peripheral and hepatic factors, including maintenance of glycemic control and enhancement of hepatic mitochondrial content and function. We are currently in the process of translating these very exciting findings in a randomized, human clinical trial examining the impact of different lifestyle modifications in the treatment of NAFLD. Findings from our research group have important public health application, particularly for the 60-80% of Americans who overeat, who are overweight, and who are physically inactive.
Comparative Medicine - OneHealth and Comparative Medicine Poster Session
2010-01-01T00:00:00ZTranslational Approach to Examine the Importance of Aerobic Fitness on Nonalcoholic Fatty Liver Disease [abstract]Morris, E. MatthewRector, R. Scott (Randy Scott)Britton, Steve L.Ibdah, Jamal A.Thyfault, John P.https://hdl.handle.net/10355/63202020-06-18T22:11:05Z2010-01-01T00:00:00ZTranslational Approach to Examine the Importance of Aerobic Fitness on Nonalcoholic Fatty Liver Disease [abstract]
Morris, E. Matthew; Rector, R. Scott (Randy Scott); Britton, Steve L.; Ibdah, Jamal A.; Thyfault, John P.
Low cardiorespiratory fitness, independent of physical activity levels, is the best predictor of early mortality and is linked to type 2 diabetes and CVD. In the absence of exercise training, it is believed that genetic inheritance accounts for up to 70% of the variation in intrinsic aerobic fitness. Recent cross-sectional reports in humans also have linked low aerobic fitness with nonalcoholic fatty liver disease (NAFLD). NAFLD, fatty liver not due to alcohol consumption, encompasses a gamut of liver maladaptations and is a primary cause of chronic liver disease and liver-related morbidity and mortality. NAFLD occurs in ~30% of US adults, 75-100% of obese and extremely obese individuals, and is considered the hepatic component of the metabolic syndrome. Despite the recent observations in humans between low fitness and NAFLD, there is a paucity of mechanistic information detailing this link. In order to address this important clinical problem, we have developed an interdisciplinary team across multiple institutions and fields of study and have taken a translational approach, employing both novel whole animal model studies and isolated primary hepatocyte cell culture experiments, to gain mechanistic insight into the human observational studies. We have utilized a novel rat model in which rats are artificially selected over several generations for high and low intrinsic endurance capacity, resulting in high capacity runners (HCR) with high aerobic fitness and low capacity runners (LCR) with significantly lower aerobic fitness (Science, 307:418-20, 2005). These rats display contrasting phenotypes without the influence of exercise training, making them an excellent model to mechanistically assess the role of aerobic fitness on NAFLD. Utilizing this model, we have provided the first mechanistic evidence that the LCR rats have reduced hepatic mitochondrial content and oxidative capacity, increased hepatic de novo lipogenic profiles, and develop hepatic steatosis with progression to greater fibrosis and apoptosis compared to the HCR rats. The LCR rats also are unable to maintain systemic insulin sensitivity following exposure to high-fat feeding. However, since it is impossible to completely eliminate the influence of peripheral factors on liver metabolism, we have subsequently isolated primary hepatocytes from HCR and LCR rats. We have observed a similar phenotype in the primary hepatocytes from LCR animals, with significant reductions in fatty acid oxidation and the inability to maintain insulin signaling in response to lipid exposure compared with HCR hepatocytes. These findings have important clinical implications, as low aerobic fitness due to physical inactivity and/or genetic inheritability may lead to increased susceptibility to NAFLD, and suggest that the clinical measurement of aerobic fitness may serve as a valuable prognostic tool. We are currently conducting a human clinical trial to assess the efficacy of exercise in improving aerobic fitness and reducing NAFLD, and because exercise is the proven method to increase aerobic fitness, it should remain the cornerstone therapy for fatty liver disease.
Comparative Medicine - OneHealth and Comparative Medicine Poster Session.
2010-01-01T00:00:00ZTranslational medicine: from discovery to healthIbdah, Jamal A.https://hdl.handle.net/10355/67862021-01-12T00:16:59Z2010-03-01T00:00:00ZTranslational medicine: from discovery to health
Ibdah, Jamal A.
Jamal Ibdah spoke on the topic "National Movement of Clinical and Translational Science and Drug Discovery."
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2010-03-01T00:00:00Z