Cited by 115Liver physiology and pathologyDrug Transport and Resistance MechanismsOrgan Transplantation Techniques and Outcomes

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

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Chen, Wei-Dong, Wang, Yan-Dong, Zhang, Lisheng, Shiah, Steven, Wang, Meihua, Yang, Fan, Yu, Donna, Forman, Barry M. +1 more·2010·Hepatology

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.)

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Authors
Chen, W.-D., Wang, Y.-D., Zhang, L., Shiah, S., Wang, M., Yang, F., Yu, D., Forman, B. M., & Huang, W.
Affiliations
City Of Hope National Medical Center (US)
Corresponding author
Huang, Wendong
Venue
Hepatology
Published
2010-03
Volume
51
Issue
3
Pages
953-962
ISSN
0270-9139 (ISSN-L)
OpenAlex
W1968928885
Cited by
115
References
45
Citations by year
2026: 4 · 2025: 3 · 2024: 3 · 2022: 5 · 2021: 7 · 2020: 5 · 2019: 5 · 2018: 3 · 2017: 8 · 2016: 6 · 2015: 10 · 2014: 15 · 2013: 16 · 2012: 9
FWCI
5.40
Type
journal article
Language
en
Open access
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Concern Foundation
  • Sidney Kimmel Foundation
  • City of Hope
  • University of California, Los Angeles
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30-DK-48522, P30DK048522)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
Keywords
farnesoid X receptor, FoxM1B, liver regeneration, aging, hepatocyte proliferation, cell cycle regulation
MeSH terms
Forkhead Box Protein M1, Receptor, Farnesoid X-Activated, Age Factors, Animals, Cells, Cultured, Liver Regeneration, Male, Mice, Inbred C57BL, Receptors, Cytoplasmic and Nuclear, Cell Proliferation, Mice, Forkhead Transcription Factors

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