Uncovering the role of bile acid signaling in facilitating sex differences during hepatocarcinogenesis and liver metabolism

Sex differences in liver physiology and metabolism have been known for several decades, and many of these differences are attributed to estrogen, androgen, or growth hormone signaling.Here, we focus on sex differences in bile acids, which are known for fat digestion, and their metabolism is orchestrated between the host and the gut microbiota.Bile acid homeostasis is altered during hepatocellular carcinoma (HCC), and therefore, we will examine if they are sexspecific.Bile acid can also signal through receptors and regulate many metabolic processes in the liver.Chapter 1 covers the background of this dissertation, and how nutrients impact bile acid composition and levels is detailed in Chapter 2. A review of sex differences in multiple nuclear receptors along the digestive tract is addressed in Chapter 3. Using a mouse model of bile acid dysregulation that develops cancer, we examine the interactions between bile acids and microbiota in a sex-dependent manner in Chapter 4. Next, we investigate if bile acids can bind to estrogen receptor α and if this interaction between signaling pathways can mediate amino acid metabolism in Chapter 5. Finally, Chapter 6 demonstrates that the endogenous bile acid receptor, FXR, can mediate ductular reaction and heme biosynthesis.These studies show that bile acid homeostasis is complex and controlled by the host and microbiota.Bile acid signaling also controls multiple facets of sex-dependent liver metabolism in physiology and pathology.several years, she has given me so much support and guidance during my time in her lab.Her enthusiasm for a new result and story never waned, and she consistently provided encouragement and suggestions when experimental protocols were not going as planned.Her value of collaborative work provided me with many opportunities to interact with collaborators worldwide and make new connections.Working with her during my PhD has provided me with many academic and leadership opportunities for which I am very grateful.I also want to acknowledge Dr. Auinash Kalsotra for the great insights he gave on the work I was conducting.Further, I would like to thank my dissertation committee -Dr.John