RT Journal Article
SR Electronic
T1 Mice Lacking FXR Are Susceptible to Liver Ischemia-Reperfusion Injury
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 739839
DO 10.1101/739839
A1 Yuxin Li
A1 Rui Xu
A1 Prahlad K. Rao
A1 Charles K Gomes
A1 E. Richard Moran
A1 Michelle Puchowicz
A1 Eugene B. Chang
A1 Deng Ping Yin
A1 Joseph F. Pierre
YR 2019
UL http://biorxiv.org/content/early/2019/08/19/739839.abstract
AB 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.BAbile acidCDCAchenodeoxycholic acidEDEMERAD-enhancing α-mannosidase-like proteinEREndoplasmic reticulumERADER associated degradationFXRfarnesoid X receptorGRP94glucose-regulated protein 94IRIischemia reperfusion injurySHPsmall heterodimer partnerTUNELTerminal deoxynucleotidyl transferase dUTP nick end labelingXBP1X box binding protein 1