Fibroblast growth factor 15 deficiency impairs liver regeneration in mice.
Fibroblast growth factor (FGF) 15 (human homolog, FGF19) is an endocrine FGF highly expressed in the small intestine of mice. Emerging evidence suggests that FGF15 is critical for regulating hepatic functions; however, the role of FGF15 in liver regeneration is unclear. This study assessed whether liver regeneration is altered in FGF15 knockout (KO) mice following 2/3 partial hepatectomy (PHx). The results showed that FGF15 KO mice had marked mortality, with the survival rate influenced by genetic background. Compared with wild-type mice, the KO mice displayed extensive liver necrosis and marked elevation of serum bile acids and bilirubin. Furthermore, hepatocyte proliferation was reduced in the KO mice because of impaired cell cycle progression. After PHx, the KO mice had weaker activation of signaling pathways that are important for liver regeneration, including signal transducer and activator of transcription 3, nuclear factor-κB, and mitogen-activated protein kinase. Examination of the KO mice at early time points after PHx revealed a reduced and/or delayed induction of immediate-early response genes, including growth-control transcription factors that are critical for liver regeneration. In conclusion, the results suggest that FGF15 deficiency severely impairs liver regeneration in mice after PHx. The underlying mechanism is likely the result of disrupted bile acid homeostasis and impaired priming of hepatocyte proliferation.
Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey;
Bo
B
Kong
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri;
Jiansheng
J
Huang
Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, Peoples Republic of China;
Yan
Y
Zhu
Department of Surgical Oncology, Cancer Treatment Center, Fourth Affiliated Hospital of Harbin Medical University, Harbin, Peoples Republic of China;
Guodong
G
Li
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
Jessica
J
Williams
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
Steven
S
Shen
Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey;
Lauren M
LM
Aleksunes
Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; and.
Jason R
JR
Richardson
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
Udayan
U
Apte
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri;
David A
DA
Rudnick
Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; guo@eohsi.rutgers.edu.
Grace L
GL
Guo
D000818:Animals; D001647:Bile Acids and Salts / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005346:Fibroblast Growth Factors / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D018816:Genes, cdc / Q000502:physiology; D006498:Hepatectomy / Q000401:mortality; D022781:Hepatocytes / Q000166:cytology; D008099:Liver / Q000473:pathology; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D050796:STAT3 Transcription Factor / Q000502:physiology
D001647:Bile Acids and Salts; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C108526:fibroblast growth factor 15, mouse; D005346:Fibroblast Growth Factors; D020928:Mitogen-Activated Protein Kinases
bile acids; farnesoid X receptor; partial hepatectomy