Farnesoid X Receptor Alleviates Age-Related Proliferation Defects in Regenerating Mouse Livers by Activating Forkhead Box M1b Transcription

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Abstract
Elucidating the mechanism of liver regeneration could lead to life-saving therapy for a large number of patients, especially elderly patients, after segmental liver transplantation or resection of liver tumors. The forkhead box m1b (Foxm1b) transcription factor is required for normal liver regeneration. Here we report that Foxm1b is the first direct farnesoid X receptor (FXR) target gene known to be involved in cell cycle regulation and that aging regenerating livers have delayed activation of FXR, which results in defective induction of Foxm1b and thereby contributes to defective liver regeneration. An inverted repeat 0 (IR-0) FXR response element, acting as an enhancer in intron 3 of the Foxm1b gene, was identified by a combination of transcriptional reporter, electrophoretic mobility shift, and chromatin immunoprecipitation assays. Diminished FXR binding to the IR-0 element was found in aging regenerating livers. FXR activation by a novel ligand in aging livers induced Foxm1b expression and elevated hepatocyte DNA replication to about 70% of the levels found in young regenerating livers, which were specifically suppressed by hepatic expression of anti-Foxm1b short hairpin RNA. Conclusion: Our results have revealed Foxm1b as the first known direct FXR target gene involved in cell cycle regulation and have demonstrated that defective activation of FXR could be an intrinsic defect in aging regenerating livers. Activation of FXR alone is largely able to alleviate age-related liver regeneration defects. These findings highlight FXR as a potential target of drug design for promoting liver regeneration in older subjects. (Hepatology 2010.)