FXR and MASH: an avenue for tissue-specific regulation
Creators: name: Henry, Zakiyah Renee
Publisher: name: No Publisher Supplied
Year: 2024

description: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a spectrum of conditions characterized by lipid accumulation in the liver known as steatosis not caused by excessive alcohol consumption. Approximately 25% of the US population have been diagnosed with MASLD, and approximately 30% of the MASLD population suffer from Metabolic Dysfunction-Associated Steatohepatitis (MASH). MASH is the more severe and progressive form of MASLD, characterized by liver steatosis, hepatocellular ballooning, inflammation, and varying degrees of fibrosis. MASH-induced cirrhosis is the leading indicator for liver transplantation in the US. Other than lifestyle changes, there is only one FDA-approved therapeutic for MASH, Resmetirom. Although therapies are limited, there are several promising therapeutic targets and one being 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. Dysregulation of BAs has been implicated in MASH development and progression and FXR deficiency in male mice leads to more severe MASH development. Because FXR negatively regulates BA and lipid production, and inhibits inflammation, synthetic ligands that are whole-body FXR agonists have been developed to treat MASH. Although beneficial, these whole-body agonists contribute to unfavorable side effects such as increases in LDL and pruritus, thereby explaining the importance of FXR tissue-specific activation in the development of novel therapeutics for MASH to negate any potential harmful consequences. Prior unpublished preliminary data suggest that deletion of FXR expressed in the livers of mice is more critical in promoting MASH development compared to the deletion of FXR expressed in the intestine. The underlying mechanisms leading to these tissue or cell-type 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 MASH. In addition to determining which organ or cell type is most appropriate to target for the synthesis of pharmacological interventions for MASH, deciding whether FXR activation or inactivation is most beneficial in the treatment of MASH needs to be determined, particularly pertaining to FXR in the gut. This is because conflicting studies show that either intestinal FXR agonism or antagonism has been beneficial in the treatment of MASH. The studies presented within this dissertation address these gaps in knowledge. Aim 1 addresses determining the tissue-specific role of the FXR in MASH development in mice. Aim 2 explores the effects of ursodeoxycholic acid, a postulated gut FXR antagonist, on MASH prevention in mice. These studies add to the literature detailing key findings regarding FXR tissue-restricted modulation in both male and female mice, and the relationship between UDCA, FXR, and MASH.