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Meng Z, Wang Y, Wang L, Jin W, Liu N, Pan H, Liu L, Wagman L, Forman BM, Huang W: FXR Regulates Liver Repair after CCl4-Induced Toxic Injury. Mol Endocrinol. 2010 Mar 8.
Liver repair is key to resuming homeostasis and preventing fibrogenesis as well as other liver diseases. Farnesoid X receptor (FXR, NR1H4) is an emerging liver metabolic regulator and cell protector. Here we show that FXR is essential to promote liver repair after carbon tetrachloride (CCl4)-induced injury. Expression of hepatic FXR in wild-type mice was strongly suppressed by CCl4 treatment, and bile acid homeostasis was disrupted. Liver injury was induced in both wild-type and FXR (-/-) mice by CCl4, but FXR (-/-) mice had more severe defects in liver repair than wild-type mice. FXR (-/-) livers had a decreased peak of regenerative DNA synthesis and reduced induction of genes involved in liver regeneration. Moreover, FXR (-/-) mice displayed increased mortality and enhanced hepatocyte deaths. During the early stages of liver repair after CCl4 treatment, we observed overproduction of TNFalpha and a strong decrease of phosphorylation and DNA-binding activity of signal transducer and activator of transcription 3 in livers from FXR (-/-) mice. Exogenous expression of a constitutively active signal transducer and activator of transcription 3 protein in FXR (-/-) liver effectively reduced hepatocyte death and liver injury after CCl4 treatment. These results suggest that FXR is required to regulate normal liver repair by promoting regeneration and preventing cell death. |
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