Understanding Mechanisms that Regulate Liver Growth and Function

Project Abstract Chronic liver diseases are on the rise and are associated with almost $100 billion in healthcare costs in the United States. Since the liver is a primary site for detoxification and metabolizes a variety of chemicals, prescription drugs, and nutrients, it is prone to constant damage. To cope with the insults, the liver has inherent mechanisms, including division of labor, polyploidy, and injury-associated liver regeneration. Although liver metabolism and liver diseases exhibit sexual dimorphism, studies focused on understanding sex differences in liver injury and regeneration are lacking. The nuclear receptor, Constitutive Androstane receptor (CAR), controls detoxification, and several metabolic pathways and is linked to liver growth. But spatiotemporal and sex-specific CAR-mediated regulation remains unexplored. We still do not know if and how CAR (i) regulates zonation and if CAR targets distinct genes in the different zones of the liver, (ii) controls polyploidy and injury- associated regeneration, (iii) influences estrogen receptor α (ERα)-mediated signaling, and (iv) contributes to the sex differences seen in liver metabolism and functions. This study is designed to address these gaps. In this renewal, we combine high throughput analysis of transcriptomes and cistromes using a novel epitope-tagged FLAG-CAR mouse and different chemical-based liver injury models to decipher how CAR orchestrates various aspects of hepatic metabolism and functions. In specific aim 1, we will determine if CAR is necessary for metabolic maturation and maintaining heterogeneity of hepatocytes, whereas in specific aim 2, we will determine the role of the CAR- ERα axis in regulating sex differences in polyploidy and regeneration in the liver. The long-term objective of these studies is to gain comprehensive understanding of the molecular mechanisms that integrate metabolic functions and liver regeneration and growth. Our proposed studies will uncover new insights and elaborate on a fundamental aspect of CAR in controlling the metabolic fitness of hepatocytes. This knowledge, in turn, can be maneuvered to prevent and or treat liver diseases.