Oncotarget

Research Papers: Pathology:

Forced expression of fibroblast growth factor 21 reverses the sustained impairment of liver regeneration in hPPARαPAC mice due to dysregulated bile acid synthesis

Hui-Xin Liu, Ying Hu, Samuel W. French, Frank J. Gonzalez and Yu-Jui Yvonne Wan _

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Oncotarget. 2015; 6:9686-9700. https://doi.org/10.18632/oncotarget.3531

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Abstract

Hui-Xin Liu1, Ying Hu1, Samuel W. French2, Frank J. Gonzalez3 and Yu-Jui Yvonne Wan1

1 Department of Medical Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA

2 Department of Pathology & Laboratory Medicine, Harbor-UCLA Medical Center, Torrance, CA, USA

3 Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

Correspondence to:

Yu-Jui Yvonne, email:

Keywords: nuclear receptor, metabolism, proliferation, bile acid, species differences

Received: January 20, 2015 Accepted: February 17, 2015 Published: March 12, 2015

Abstract

Peroxisome proliferator activated receptor α (PPARα) stimulates hepatocellular proliferation is species-specific. Activation of mouse, but not human, PPARα induces hepatocellular proliferation, hepatomegaly, and liver cancer. Here we tested the hypothesis that human and mouse PPARα affects liver regeneration differentially. PPARα-humanized mice (hPPARαPAC) were similar to wild type mice in responding to fasting-induced PPARα signaling. However, these mouse livers failed to regenerate in response to partial hepatectomy (PH). The liver-to-body weight ratios did not recover even 3 months after PH in hPPARαPAC. The mouse PPARα-mediated down-regulation of let-7c was absent in hPPARαPAC, which might partially be responsible for impaired proliferation. After PH, hPPARαPAC displayed steatosis, necrosis, and inflammation mainly in periportal zone 1, which suggested bile-induced toxicity. Quantification of hepatic bile acids (BA) revealed BA overload with increased hydrophobic BA in hPPARαPAC. Forced FGF21 expression in partial hepatectomized hPPARαPAC reduced hepatic steatosis, prevented focal necrosis, and restored liver mass. Compared to mouse PPARα, human PPARα has a reduced capacity to regulate metabolic pathways required for liver regeneration. In addition, FGF21 can compensate for the reduced ability of human PPARα in stimulating liver regeneration, which suggests the potential application of FGF21 in promoting hepatic growth in injured and steatotic livers in humans.


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