title: Fibroblast Growth Factor Signaling Controls Liver Size in Mice With Humanized Livers.
abstract: OBJECTIVE
  The ratio of liver size to body weight (hepatostat) is tightly controlled, but little is known about how the physiologic functions of the liver help determine its size. Livers of mice repopulated with human hepatocytes (humanized livers) grow to larger than normal; the human hepatocytes do not recognize the fibroblast growth factor (FGF)-15 produced by mouse intestine. This results in up-regulation of bile acid synthesis in the human hepatocytes and enlargement of the bile acid pool. We investigated whether abnormal bile acid signaling affects the hepatostat in mice.
  
  
  METHODS
  We crossed Fah(-/-), Rag2(-/-), Il2r(-/-) mice with nonobese diabetic mice to create FRGN mice, whose livers can be fully repopulated with human hepatocytes. We inserted the gene for human FGF19 (ortholog to mouse Fgf15), including regulatory sequences, into the FRGN mice to create FRGN19(+) mice. Livers of FRGN19(+) mice and their FRGN littermates were fully repopulated with human hepatocytes. Liver tissues were collected and bile acid pool sizes and RNA sequences were analyzed and compared with those of mice without humanized livers (controls).
  
  
  RESULTS
  Livers were larger in FRGN mice with humanized livers (13% of body weight), compared with control FRGN mice; they also had much larger bile acid pools and aberrant bile acid signaling. Livers from FRGN19(+) normalized to 7.8% of body weight, and their bile acid pool and signaling more closely resembled that of control FRGN19(+) mice. RNA sequence analysis showed activation of the Hippo pathway, and immunohistochemical and transcription analyses revealed increased hepatocyte proliferation, but not apoptosis, in the enlarged humanized livers of FRGN mice. Cell sorting experiments showed that although healthy human liver does not produce FGF19, nonparenchymal cells from cholestatic livers produce FGF19.
  
  
  CONCLUSIONS
  In mice with humanized livers, expression of an FGF19 transgene corrects bile acid signaling defects, resulting in normalization of bile acid synthesis, the bile acid pool, and liver size. These findings indicate that liver size is, in part, regulated by the size of the bile acid pool that the liver must circulate.
authors.affiliation: Department of Medicine, Division of Gastroenterology and Hepatology, Oregon Health & Science Center, Portland, Oregon; Oregon Stem Cell Center, Oregon Health & Science Center, Portland, Oregon. Electronic address: nauglers@ohsu.edu.
authors.forename: Willscott E
authors.initials: WE
authors.lastname: Naugler
authors.affiliation: Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science Center, Portland, Oregon.
authors.forename: Branden D
authors.initials: BD
authors.lastname: Tarlow
authors.affiliation: OHSU Transgenic Mouse Models Shared Resource, Oregon Health & Science Center, Portland, Oregon.
authors.forename: Lev M
authors.initials: LM
authors.lastname: Fedorov
authors.affiliation: Department of Hematology and Oncology, Oregon Health & Science Center, Portland, Oregon.
authors.forename: Matthew
authors.initials: M
authors.lastname: Taylor
authors.affiliation: Department of Pediatrics, Papé Family Pediatric Research Institute, Oregon Health & Science Center, Portland, Oregon.
authors.forename: Carl
authors.initials: C
authors.lastname: Pelz
authors.affiliation: Oregon Stem Cell Center, Oregon Health & Science Center, Portland, Oregon.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Medicine, Division of Gastroenterology and Hepatology, Oregon Health & Science Center, Portland, Oregon.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Darnell
authors.affiliation: Oregon Stem Cell Center, Oregon Health & Science Center, Portland, Oregon; Department of Hematology and Oncology, Oregon Health & Science Center, Portland, Oregon.
authors.forename: Markus
authors.initials: M
authors.lastname: Grompe
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D005346:Fibroblast Growth Factors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism / Q000637:transplantation*; D064593:Heterografts; D006801:Humans; D006867:Hydrolases / Q000172:deficiency / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000601:surgery*; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009929:Organ Size; D015375:Receptors, Interleukin-2 / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic
chemical_list: D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; C117476:FGF19 protein, human; C499308:Rag2 protein, mouse; D015375:Receptors, Interleukin-2; C108526:fibroblast growth factor 15, mouse; D005346:Fibroblast Growth Factors; D006867:Hydrolases; C020156:fumarylacetoacetase
keywords: CYP7A; Mouse Model; Regeneration; Signal Transduction