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

Peroxisome proliferator activated receptor a (PPARa) stimulates hepatocellular proliferation is species-specific. Activation of mouse, but not human, PPARa induces hepatocellular proliferation, hepatomegaly, and liver cancer. Here we tested the hypothesis that human and mouse PPARa affects liver regeneration differentially. PPARa-humanized mice (hPPARa(PAC)) were similar to wild type mice in responding to fasting-induced PPARa 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 hPPARa(PAC). The mouse PPARa-mediated down-regulation of let-7c was absent in hPPARa(PAC), which might partially be responsible for impaired proliferation. After PH, hPPARa(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 hPPARa(PAC). Forced FGF21 expression in partial hepatectomized hPPARa(PAC) reduced hepatic steatosis, prevented focal necrosis, and restored liver mass. Compared to mouse PPARa, human PPARa has a reduced capacity to regulate metabolic pathways required for liver regeneration. In addition, FGF21 can compensate for the reduced ability of human PPARa in stimulating liver regeneration, which suggests the potential application of FGF21 in promoting hepatic growth in injured and steatotic livers in humans.