The Tissue-Specific Functionality of the Farnesoid X Receptor in NASH Development

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PROJECT SUMMARY/ABSTRACT Non-alcoholic fatty liver disease (NAFLD) is a spectrum of conditions characterized by lipid accumulation in the liver known as steatosis. Approximately 25% of the US population have NAFLD and approximately 30% of that population suffer from non-alcoholic steatohepatitis (NASH). NASH is the more severe and progressive form of NAFL that is characterized by liver steatosis, hepatocellular ballooning, inflammation, and fibrosis. NASH is also the leading indicator for liver transplantation in the US. Other than lifestyle changes, there is no current FDA- approved therapeutic for NASH; however, one emerging target is the Farnesoid X Receptor (FXR). FXR is a ligand activated transcription factor highly expressed in numerous tissues such as the liver and intestine and is a major regulator in bile acid (BA) homeostasis. BAs have been implicated in NASH development and progression and FXR deficiency in male mice leads to more severe NASH development. Because FXR negatively regulates BA production, synthetic ligands that are whole-body FXR agonists have been developed to treat NASH. Although beneficial, these whole-body modulators contribute to unfavorable side effects such as cholesterol homeostasis imbalance, thereby explaining the importance of FXR tissue-specific activation in the development of novel therapeutics for NASH to negate any potential harmful consequences. Our preliminary data suggests that deletion of FXR expressed in the livers of mice is more critical in NASH development compared to the deletion of FXR expressed in the small intestine. The underlying mechanisms leading to these differences are not well elucidated. Understanding these mechanisms contributing to FXR functionality in a tissue-specific and cell-specific manner will allow scientists to develop safe, targeted, and efficacious therapies for NASH. In addition to determining which organ or cell type is most appropriate to target for the synthesis of pharmacological interventions for NASH, deciding whether FXR activation or inactivation is most beneficial in the treatment of NASH needs to be determined, particularly pertaining to FXR in the gut. Conflicting studies show that both intestinal FXR agonism and antagonism are beneficial in the treatment of NASH. Aim 1 will determine the tissue-specific role of the the farnesoid X receptor in NASH development in mice. Aim 2 will determine the effects of ursodeoxycholic acid, an FXR antagonist, on NASH prevention in mice. Through the completion of the research and training described in this F31 Fellowship, the Principal Investigator will be trained in basic biomedical research and biological processes contributing to metabolic disease development and prevention, focusing on NASH. The Principal Investigator will be prepared to conduct independent research and enhance the diversity of the scientific workforce, and to assist in improving the health and quality of life of individuals suffering from this chronic liver disease, which is in line with the mission and vision of the National Institute of Diabetes and Digestive and Kidney Diseases.