Ursodeoxycholic acid acts as an ileal FXR agonist in male mice with hepatic deficiency of FXR.

Background: Farnesoid X receptor (FXR) has been identified as a therapeutic target for metabolic dysfunction-associated steatohepatitis (MASH). Hepatic FXR is especially critical in suppressing liver inflammation. FXR agonism and antagonism have both proven to be beneficial in the mitigation of MASH, leading to much controversy in the field, particularly regarding FXR signalling in the gut. The objective of this study was to determine the effects of ursodeoxycholic acid (UDCA), a postulated gut FXR antagonist with liver protective effects, on the mitigation and prevention of MASH development in mice with hepatic FXR deficiency.

Methods: For this experiment, six-week-old to eight week-old male and female liver-specific FXR knockout (FXR^hep-/-) and control (FXR^{hep flox/flox}) mice were fed either a low-fat control diet (CTL) or a MASH 'Fast Food' diet (Western diet with 21% milk fat, 1.25% cholesterol and 34% sucrose) both supplemented with or without 0.1% (weight/weight; w/w) UDCA for 16 weeks.

Results: UDCA feeding tended to reduce alanine aminotransferase levels and decrease liver lipids in the male mice. Supplementation of UDCA showed a trend towards increased UDCA and tauroursodeoxycholic acid (TUDCA) levels in serum, liver and intestine, although the male mice displayed more than twice the amount of these bile acids compared with the female mice. CTL-UDCA feeding resulted in a significant induction of Fxr and Fgf15 mRNA expression in the ileum of the male mice.

Conclusion: The data strongly suggest that UDCA seems to act as an FXR agonist, especially in the ileum, which contrasts with previous reports that UDCA acts as a gut FXR antagonist. In addition, UDCA seems to be exerting liver protective effects predominantly in the male mice.