Effects of therapeutically approved individual bile acids on the development of metabolic dysfunction-associated steatohepatitis a low bile acid mouse model

• Published in: Toxicological sciences 2024-12, Vol.202 (2), p.179-195
• Main Authors: Taylor, Rulaiha, Basaly, Veronia, Kong, Bo, Yang, Ill, Brinker, Anita M, Capece, Gina, Bhattacharya, Anisha, Henry, Zakiyah R, Otersen, Katherine, Yang, Zhenning, Meadows, Vik, Mera, Stephanie, Joseph, Laurie B, Zhou, Peihong, Aleksunes, Lauren M, Roepke, Troy, Buckley, Brian, Guo, Grace L
• Format: Article
• Language: English
• Subjects: Animals; Bile Acids and Salts - metabolism; Cholestanetriol 26-Monooxygenase - genetics; Cholestanetriol 26-Monooxygenase - metabolism; Cholesterol 7-alpha-Hydroxylase - genetics; Cholesterol 7-alpha-Hydroxylase - metabolism; Cholic Acid; Deoxycholic Acid - toxicity; Disease Models, Animal; Fatty Liver - chemically induced; Fatty Liver - metabolism; Lipid Metabolism - drug effects; Liver - drug effects; Liver - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Non-alcoholic Fatty Liver Disease - chemically induced; Non-alcoholic Fatty Liver Disease - metabolism; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Ursodeoxycholic Acid - pharmacology
• ISSN: 1096-6080; 1096-0929; 1096-0929
• DOI: 10.1093/toxsci/kfae110

Abstract Bile acid (BA) signaling dysregulation is an important etiology for the development of metabolic dysfunction-associated steatotic liver disease (MASLD). As diverse signaling molecules synthesized in the liver by pathways initiated with CYP7A1 and CYP27A1, BAs are endogenous modulators of farnesoid x receptor (FXR). FXR activation is crucial in maintaining BA homeostasis, regulating lipid metabolism, and suppressing inflammation. Additionally, BAs interact with membrane receptors and gut microbiota to regulate energy expenditure and intestinal health. Complex modulation of BAs in vivo and the lack of suitable animal models impede our understanding of the functions of individual BAs, especially during MASLD development. Previously, we determined that acute feeding of individual BAs differentially affects lipid, inflammation, and oxidative stress pathways in a low-BA mouse model, Cyp7a1/Cyp27a1 double knockout (DKO) mice. Currently, we investigated to what degree cholic acid (CA), deoxycholic acid (DCA), or ursodeoxycholic acid (UDCA) at physiological concentrations impact MASLD development in DKO mice. The results showed that these 3 BAs varied in the ability to activate hepatic and intestinal FXR, disrupt lipid homeostasis, and modulate inflammation and fibrosis. Additionally, UDCA activated intestinal FXR in these low-BA mice. Significant alterations in lipid uptake and metabolism in DKO mice following CA and DCA feeding indicate differences in cholesterol and lipid handling across genotypes. Overall, the DKO were less susceptible to weight gain, but more susceptible to MASH diet induced inflammation and fibrosis on CA and DCA supplements, whereas WT mice were more vulnerable to CA-induced fibrosis on the control diet. Graphical abstract