title: Forced expression of fibroblast growth factor 21 reverses the sustained impairment of liver regeneration in hPPARα(PAC) mice due to dysregulated bile acid synthesis.
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.
authors.affiliation: Department of Medical Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA.
authors.forename: Hui-Xin
authors.initials: HX
authors.lastname: Liu
authors.affiliation: Department of Medical Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Pathology & Laboratory Medicine, Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: Samuel W
authors.initials: SW
authors.lastname: French
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: Department of Medical Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA.
authors.forename: Yu-Jui Yvonne
authors.initials: YJ
authors.lastname: Wan
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry; D001835:Body Weight; D005234:Fatty Liver; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005355:Fibrosis; D005786:Gene Expression Regulation; D006498:Hepatectomy; D006706:Homeostasis; D006801:Humans; D007249:Inflammation; D019394:Ki-67 Antigen / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000502:physiology*; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D001647:Bile Acids and Salts; D019394:Ki-67 Antigen; D035683:MicroRNAs; D047493:PPAR alpha; C414620:fibroblast growth factor 21; C542687:mirnlet7 microRNA, mouse; D005346:Fibroblast Growth Factors
keywords: bile acid; metabolism; nuclear receptor; pathology; proliferation; species differences