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 1 , Ying Hu 1 , Samuel W. French 2 , Frank J. Gonzalez 3 and Yu-Jui Yvonne Wan 1 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 (hPPARα PAC ) 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 hPPARα PAC . The mouse PPARα-mediated down-regulation of let-7c was absent in hPPARα PAC , which might partially be responsible for impaired proliferation. After PH, hPPARα PAC 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 hPPARα PAC . Forced FGF21 expression in partial hepatectomized hPPARα PAC 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.