Fibroblast Growth Factor Signaling Controls Liver Size in Mice with Humanized Livers

Willscott (Scott) Naugler, Branden D. Tarlow, Lev Fedorov, Matthew Taylor, Carl Pelz, Bin Li, Jennifer Darnell, Markus Grompe

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Background & Aims 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.

Original languageEnglish (US)
Pages (from-to)728e15-740e15
JournalGastroenterology
Volume149
Issue number3
DOIs
StatePublished - Sep 1 2015

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Fibroblast Growth Factors
Bile Acids and Salts
Liver
Hepatocytes
Body Weight
RNA Sequence Analysis
Inbred NOD Mouse
Hepatomegaly
Transgenes

Keywords

  • CYP7A
  • Mouse Model
  • Regeneration
  • Signal Transduction

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Fibroblast Growth Factor Signaling Controls Liver Size in Mice with Humanized Livers. / Naugler, Willscott (Scott); Tarlow, Branden D.; Fedorov, Lev; Taylor, Matthew; Pelz, Carl; Li, Bin; Darnell, Jennifer; Grompe, Markus.

In: Gastroenterology, Vol. 149, No. 3, 01.09.2015, p. 728e15-740e15.

Research output: Contribution to journalArticle

Naugler, Willscott (Scott) ; Tarlow, Branden D. ; Fedorov, Lev ; Taylor, Matthew ; Pelz, Carl ; Li, Bin ; Darnell, Jennifer ; Grompe, Markus. / Fibroblast Growth Factor Signaling Controls Liver Size in Mice with Humanized Livers. In: Gastroenterology. 2015 ; Vol. 149, No. 3. pp. 728e15-740e15.
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abstract = "Background & Aims 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.",
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AU - Naugler, Willscott (Scott)

AU - Tarlow, Branden D.

AU - Fedorov, Lev

AU - Taylor, Matthew

AU - Pelz, Carl

AU - Li, Bin

AU - Darnell, Jennifer

AU - Grompe, Markus

PY - 2015/9/1

Y1 - 2015/9/1

N2 - Background & Aims 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.

AB - Background & Aims 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.

KW - CYP7A

KW - Mouse Model

KW - Regeneration

KW - Signal Transduction

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