Effects of individual bile acids and exposure to environmental chemicals on fatty liver disease development in mice
Creators: name: Taylor, Rulaiha Elizabeth
Publisher: name: No Publisher Supplied
Year: 2024

description: Bile acids (BA) are diverse, essential endocrine signaling molecules that carry many functions in vivo including the activation of farnesoid x receptor (FXR). Individual BAs differ in their potency to produce their effects on FXR and other nuclear receptors. FXR is a critical regulator of many genes and pathways spanning from BA enterohepatic circulation to lipid, glucose and energy metabolism, metabolic homeostasis, and inflammation. FXR is a pharmacological target of interest to treat various liver pathologies including metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD is a spectrum of steatotic liver diseases characterized by excessive accumulation of lipids in the liver, which is highly associated with insulin resistance and other cardiometabolic disorders. MASLD is a silent disease with a complex and multifactorial etiology and no FDA therapeutic to alleviate the medical burden. The progression of steatotic liver to metabolic dysfunction-associated steatohepatitis (MASH) is inflammation and varying degrees of fibrosis in the liver. Dysregulation of BA signaling via FXR is tightly associated with MASH and progression of liver injury. Increase in total BA levels or alterations of several individual BAs, e.g. deoxycholic acid (DCA), are shown in MASH patients. However, individual BA functions in activating receptors or causing cell injury have been mainly determined in vitro. Because (1) mice or humans have more than 30 BA isoforms in vivo, (2) there are human/mouse species difference in BA composition, and (3) BAs are constantly modified in vivo, the role of each individual BAs in vivo to alter BA homeostasis and lipid metabolism, induce inflammation and oxidative stress remain largely unknown, especially during MASH development. To understand individual BA function in vivo is critical, because not all BAs function similarly and alterations in individual BA levels are more prevalent in human MASH patients, suggesting that alteration in individual BAs than overall BA levels may be more critical in the development of MASH. The studies presented within include three BAs of interest, cholic acid (CA), deoxycholic acid (DCA), ursodeoxycholic acid (UDCA), which are biologically relevant and FDA approved therapeutics. Individual BAs were investigated for their effects on FXR-Fibroblast growth factor 15 (FGF15) signaling axis using a novel low BA in vivo mouse model. Individual BAs were also investigated for their effects in the development and progression of MASH in low BA conditions. Lastly, the studies presented within support environmental chemical alteration of BA signaling. Myclobutanil-mediated disruption of BA signaling through alteration of liver-gut FXR-FGF15 signaling. Myclobutanil was studied for its effects on BA signaling in the development of MASLD in WT mice. These studies add to the literature detailing the complexity of individual BA signaling and further illuminate the relationship between BA signaling dysregulation via FXR-FGF15 signaling in the development of MASLD.