Control Mechanisms Of Fatty Acid Oxidation In Bovine Liver

Author : Mitchell Tyler Lavarias
Publisher :
ISBN 13 :
Total Pages : pages
Book Rating : 4.:/5 (129 download)

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Download or read book The Physiological Role of Fatty Acid Oxidation in the Intestine written by Mitchell Tyler Lavarias and published by . This book was released on 2021 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: The small intestine plays a pivotal role in lipid metabolism and energy balance. It assimilates dietary nutrients, produces triacylglycerol-rich chylomicrons, interacts with the microbiota, provides immune defense, and signals nutritional status to help maintain homeostasis. To support these processes the intestine is a major consumer of energy, thought to primarily from the amino acids, glutamine and glutamate. Growing evidence however, suggests that the intestine is capable of oxidizing fatty acids as fuel. Using genetically engineered mice, work in this thesis examines the physiological role of fatty acid oxidation (FAO) in the intestine.In response to high-fat diets and fasting, two states marked by high lipid availability, I found that the intestine exhibits induced capacity for FAO. To explore the role of intestinal FAO during these conditions, I generated mice with an intestine specific deletion of Cpt2 (Cpt2IKO), an enzyme required for mitochondrial oxidation of long-chain fatty acids. Compared to littermate controls, Cpt2IKO mice had accelerated absorption of dietary fats into circulation when challenged to a high-fat meal, suggesting intestinal FAO normally restricts the delivery of dietary fat to other tissues. Even following a prolonged fast, when the intestine is not handling dietary nutrients, Cpt2IKO had reduced blood glucose and elevated plasma TG, indicating the impact of intestinal FAO in modulating systemic nutrient availability. When fed a ketogenic diet, high in fat with limited carbohydrate and protein, Cpt2IKO mice developed hypertriglyceridemia, hepatic steatosis, hypoglycemia, and muscular atrophy. These changes in Cpt2IKO mice were ameliorated when the ketogenic diet was supplemented with protein or medium-chain fatty acids, which can be oxidized without Cpt2. Altogether these data show that intestinal FAO is modulated by dietary conditions and it in turn modulates systemic responses to dietary conditions. I then examined the impacts of suppressing intestinal FAO when mice were fed a diet either rich in refined carbohydrates or in fats. Intestinal FAO gene expression is highly induced upon high-fat feeding, however its role in metabolic adaptation to a high-fat diet is yet unknown. I found that when fed a high-fat diet, Cpt2IKO mice had reduced weight gain as a result of reduced food intake. Cpt2IKO mice had no difference in meal size, but ate less meals throughout the day, indicating increased satiety. When given a choice between low- and high-fat diets, Cpt2IKO mice exhibited reduced preference for the high-fat diet compared to controls, showing the importance of intestinal metabolism in the regulation of macronutrient preference. Independent of its role in regulating food intake, intestinal Cpt2 also played a role in maintaining glucose homeostasis. When fed a processed diet with refined carbohydrates - either low or rich in fat - Cpt2IKO mice exhibited enhance glycemic control when glucose was provided orally, but not intraperitoneally. That the differences were only seen when glucose was administrated through the gastrointestinal tract highlights the effects of intestinal metabolism. Importantly, induced deletion of intestinal Cpt2 in adult mice reduced intake of a high-fat diet and improved glucose homeostasis through increased glucose oxidation. The recapitulation of reduced weight gain and enhanced glycemic control by acute inhibition of intestinal Cpt2 supports the idea that intestinal metabolism of nutrients can be targeted to treat obesity and diabetes. Lastly, I showed that loss of intestinal Cpt2 affects stem cell proliferation. Intestinal stem cells are critical to maintain the epithelial layer which renews itself every 3-5 days. Previous data has shown that lipid metabolism is critical for intestinal stem cell function. Specifically, upon fasting mice have increased stem cell proliferation, which is in part mediated by Cpt1a, an enzyme which catalyzes the step in FAO before Cpt2. While intestine-specific knockout of Cpt1a reduced proliferation of stem cells during fasting, I found that intestine-specific loss of Cpt2 promotes intestinal stem cell proliferation upon fasting. Together, the data suggest that acylcarnitines may play an important role in regulating stem cell function in the intestine. In summation, this body of work reveals intestinal FAO as a critical regulator of systemic energy balance. It highlights the importance of intestinal nutrient metabolism on regulating several key aspects of metabolism related to diseases such as obesity, diabetes, and cardiovascular disease. Future studies are needed to determine the mechanisms by which FAO in the intestine modulates food intake. Additionally, the colonization of gut microbiota has also been shown to reduce intestinal FAO and enhance fat absorption in germ-free mice. Cpt2IKO mice re-derived germ-free can be used to specifically determine if intestinal FAO contributes to the resistance to obesity and diabetes seen in germ-free mice. Lastly, future studies are needed to investigate the mechanisms by which intestinal fatty acid oxidation is linked to stem cell functions.