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Aerobic Capacity Alters Susceptibility to Hepatic Steatosis via Bile Acid Signaling
Maurer, Adrianna
Maurer, Adrianna
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Abstract
Aerobic capacity refers to the maximal oxygen consumption an individual can achieve and is determined through genetic contributions (~50%) and by daily activity/exercise habits (~50%). Low aerobic capacity has been implicated as a major risk factor for chronic diseases such as type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), and overall early mortality, independent of obesity. High aerobic capacity protects against the development of chronic disease and is associated with adaptations in liver metabolism that include enhanced mitochondrial function, but the precise mechanisms remain unknown. Bile acids have recently emerged as active regulators of energy metabolism within the liver. Previous studies from our lab have utilized a rat model bred for intrinsic (genetic) running capacity to study hepatic metabolism and susceptibility for NAFLD. Similar to associations observed in humans, we have found that rats selectively bred for low aerobic fitness (low-capacity runner; LCR) are highly susceptible to high fat diet (HFD)-induced weight gain, insulin resistance, and NAFLD, and have reduced fatty acid oxidation. Conversely, rats bred for high aerobic fitness (high-capacity runner; HCR) are protected against HFD-induced pathologies and consistently display higher energy expenditure, mitochondrial function, and greater metabolic flexibility than LCRs. We have recently reported that the adaptability of HCRs to a HFD diet is associated with an upregulation in bile acid synthesis. This is supported by greater fecal bile acid excretion, and hepatic expression of bile acid synthesis genes (CYP7a1, & HMGCoA reductase) observed in HCRs, along with higher serum 7α-hydroxy-4-cholesten-3-one (C4), a proxy measure of bile acid synthesis. In the current dissertation we examine the role of divergent aerobic capacity and exercise training to modify bile acid in a similar fashion to our rodent model in human subjects. The first human study did not show higher bile acid synthesis in normal weight women with higher aerobic capacity (≥45 ml/kg/min) that were weight and age matched to normal weight women with lower aerobic fitness (≤35 ml/kg/min), however, big differences in circulating bile acids were found during an oral glucose tolerance test. In the second human study, we found that exercise training plus weight loss in obese, insulin resistance women did increase markers of bile acid synthesis while also improving insulin sensitivity. Finally, we conducted an additional study in the HCR/LCR rat model which revealed that high aerobic capacity is linked to an upregulation of bile acid synthesis, and fecal excretion, which may serve as a protective mechanism against NAFLD development. We also demonstrate how greater insulin sensitivity associated with a high aerobic capacity helps to regulate bile acid composition and pool size.
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2022-01-01
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University of Kansas
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Keywords
Physiology, bile acid, exercise, fitness, liver, metabolism