FXR agonist GW4064 improves liver and intestinal pathology and alters bile acid metabolism in rats undergoing small intestinal resection.

Abstract

Mortality associated with liver disease has been observed in patients with short bowel syndrome (SBS); however, its mechanism remains unclear, but bile acid (BA) dysmetabolism has been proposed as a possible cause. The farnesoid X receptor (FXR) is the key regulator of BA synthesis. Here, we showed that, in a rat model of short bowel resection associated with liver disease (SBR-ALD), the BA composition of hepatic tissues reflected a larger proportion of primary and secondary unconjugated BAs, whereas that of the colon contents and serum showed an increased ratio of secondary unconjugated BAs. Both hepatic and intestinal regulation of BA synthesis was characterized by a blunted hepatic FXR activation response. The mRNA expression levels of cholesterol 7a-hydroxylase (CYP7A1), sterol 12a-hydroxylase (CYP8B1), and sterol 27 hydroxylase (CYP27A1), the key enzymes in BA synthesis, were upregulated. After intervention with the FXR agonist GW4064, both the liver histology and serum transaminase activity were improved, which demonstrated the attenuation of SBR-ALD. The BA compositions of hepatic tissue, the colon contents, and serum recovered and were closer to those of the sham group. The expression levels of hepatic FXR increased, and its target genes were activated. Consistent with this, the expression levels of CYP7A1, CYP8B1, and CYP27A1 were downregulated. Ileum tissue FXR and its target genes were slightly elevated. This study showed that the FXR agonist GW4064 could correct BA dysmetabolism to alleviate hepatotoxicity in SBR animals. GW4064 intervention resulted in a decrease in fecal bile excretion and elevated plasma/hepatic conjugated BA levels. GW4064 increased the reabsorption of conjugated BAs by inducing apical sodium-dependent bile salt transporter expression in the ileum. Concomitantly, FXR activation in the presence of GW4064 decreased BA production by repressing the expression of key synthetases, including CYP7A1, CYP8B1, and CYP27A1. These findings provide a clinical research direction for the prevention of liver disease in patients with SBS.NEW & NOTEWORTHY This study assessed the impact of treatment with GW4064, a farnesoid X receptor agonist, on the development of short bowel resection (SBR) associated with liver disease in a rat model of SBR. GW4064 was able to correct bile acid dysmetabolism and alleviate hepatotoxicity in SBR animals.