Abstract
Activation of bile acid (BA) receptor, farnesoid X receptor (FXR) has been shown to inhibit inflammatory responses and improve tissue ischemia-reperfusion injury (IRI). This study investigated the effect of FXR deficiency on liver IRI, using a liver warm IRI mouse model. We demonstrate that liver IRI resulted in decreased FXR expression in the liver of WT mice. FXR-/-mice displayed greater liver damage and inflammatory responses than WT mice, characterized by significant increases in liver weight, serum AST and ALT, hepatocyte apoptosis and liver inflammatory cytokines. Liver IRI increased expression of X box binding protein 1 (XBP1) and FGF21 in WT liver, but not in FXR-/- liver, which conversely increased CHOP expression, suggesting a loss of ER stress protection in the absence of FXR. FXR deficiency increased circulating total BAs and altered BA composition with reduced TUDCA and hepatic BA synthesis markers. FXR deficiency also reshaped gut microbiota composition with increased Bacteroidetes and Proteobacteria and decreased Firmicutes. Curiously, Bacteroidetes were positively and Firmicutes were negatively correlated with serum ALT levels. Administration of FXR agonist CDCA inhibited NF-κB activity and TNFα expression in vitro and improved liver IRI in vivo. Our findings demonstrate that FXR signaling plays an important role in the modulation of liver IRI.
Footnotes
↵* RX and YL are co-first authors
Financial support: This work was supported in part by the CTSA grant (CTSA TR000430) to DPY, NIH grants P30DK42086 (DDRCC) and DK097268 to EBC and NIH grant DK020595 to the Metabolic Core at the University of Chicago.
Abbreviations
- BA
- bile acid
- CDCA
- chenodeoxycholic acid
- EDEM
- ERAD-enhancing α-mannosidase-like protein
- ER
- Endoplasmic reticulum
- ERAD
- ER associated degradation
- FXR
- farnesoid X receptor
- GRP94
- glucose-regulated protein 94
- IRI
- ischemia reperfusion injury
- SHP
- small heterodimer partner
- TUNEL
- Terminal deoxynucleotidyl transferase dUTP nick end labeling
- XBP1
- X box binding protein 1