Nuclear Hormone Receptor-Mediated Changes of Cholesterol, Triglyceride, and Bile Acid Physiology in Response to Alterations in Cholesterol Absorption and Bile Acid Pool Size in Mice




Jones, Ryan Dale

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The regulation of lipid metabolism is an interwoven series of pathways and events acting in concert to control the nutritional and metabolic needs of the body. When alterations in lipid balance occur they can result in disease, thus an understanding of the pathophysiology, as well as the molecular mediators of these alterations are vital to the advancement of treatment for these diseases. Many of these mediators are members of a class of proteins called nuclear hormone receptors, which respond to lipophilic compounds to regulate gene transcription. I have undertaken three separate, but related projects relating to lipid metabolism with a particular focus on nuclear hormone receptor function. First, I sought to understand how a drug that blocks cholesterol absorption can ameliorate the onset of hepatic steatosis. What I found was that in the early stages of disease onset, Ezetimibe prevents hepatic steatosis independently from the nuclear hormone receptor liver X receptor, and actually paradoxically stimulates hepatic lipogenesis despite decreased liver TG levels. Second, I determined the molecular and physiological changes that occur with bile acid pool size restoration in mice that have a bile acid deficiency. This project highlighted the importance of bile acids in cholesterol absorption, the function of the bile acid-responsive nuclear hormone receptor farnesoid X receptor, and whole body lipid homeostasis. Additionally, we established a rationale for feeding low physiological amounts of bile acids to experimental animals, especially when those animals have a defect in bile acid production. Lastly, I studied the tissue distribution and nuclear hormone receptor-mediated regulation of a class of enzymes called carboxylesterases. This family of enzymes, which participate in neutral lipid hydrolysis, often came up on microarray analysis of metabolic studies, yet little was known about their regulation or function with regards to lipids. Therefore, I classified the tissue distribution of each of the carboxylestase family members in mice, and tested their gene expression upon treatment with synthetic agonists for the lipid-sensing NHRs. Thus, the information provided in this dissertation provides a valuable resource as the molecular mechanisms of disease and the role of nuclear hormone receptors begin to become clearer.

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