Uncovering a novel role for FXR-SHP axis in liver physiology, diseases and beyond

Liver performs a multitude of functions ranging from detoxification, metabolism and digestion. To execute these tasks, one of the mechanisms that the liver utilizes is nuclear receptor signaling, which in turn can transcriptionally regulate gene networks. My doctoral thesis focuses on studying the role of two nuclear receptors, FXR and SHP in maintaining liver function. Farnesoid X Receptor (FXR) and Small Heterodimer Partner (SHP) are well-known regulators of glucose, fat and bile acid homeostasis. Here, I uncover novel roles for FXR-SHP axis not only in the liver but also in extrahepatic organs, like heart. In Chapter 2, I discuss how hepatic loss of FXR and SHP results in increased glycosylation of liver proteins and structural defects in Golgi apparatus, and ultimately liver cancer. Chapter 3 focuses on comprehending how FXR-SHP ablation results in increased drug metabolic capacity of the liver. Finally, chapter 4 discusses how liver dysfunction, caused by loss of FXR and SHP, can induce metabolic and functional defects in heart. Taken together, these projects will help understand some of the FXR and SHP transcriptional networks under different physiological and pathological contexts and may open avenues for pharmacological manipulation to treat various diseases.U of I OnlyAuthor requested U of Illinois access only (OA after 2yrs) in Vireo ETD syste