Fibroblast Growth Factor Signaling Controls Liver Size in Mice With Humanized Livers.
Fibroblast Growth Factor Signaling Controls Liver Size in Mice With Humanized Livers.
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DOI：
10.1053/j.gastro.2015.05.043
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发表时间：
2015-09
期刊：
影响因子：
29.4
通讯作者：
Grompe M
中科院分区：
文献类型：
--
作者：
Naugler WE;Tarlow BD;Fedorov LM;Taylor M;Pelz C;Li B;Darnell J;Grompe M
肝脏大小与体重的比例（hepatostat）受到严格控制，但对肝脏的生理功能如何帮助确定其大小知之甚少。用人肝细胞（人源化肝脏）重新填充的小鼠的肝脏生长至比正常的大;人肝细胞不识别由小鼠肠产生的成纤维细胞生长因子-15（FGF 15）。这导致人肝细胞中胆汁酸合成的上调和胆汁酸池的扩大。我们研究了异常胆汁酸信号传导是否影响小鼠的肝细胞。我们将Fah−/−、Rag 2 −/−、Il 2 r −/−小鼠与NOD小鼠杂交，以创建FRGN小鼠，其肝脏可以完全用人类肝细胞重新填充。我们将人FGF 19（小鼠Fgf 15的直系同源物）的基因（包括调控序列）插入FRGN小鼠中以产生FRGN 19+小鼠。FRGN 19+小鼠及其FRGN同窝仔的肝脏完全用人肝细胞重新填充。收集肝脏组织，分析胆汁酸池大小和RNA序列，并与没有人源化肝脏的小鼠（对照）进行比较。与对照FRGN小鼠相比，具有人源化肝脏的FRGN小鼠的肝脏更大（体重的13%）;它们还具有更大的胆汁酸池和异常的胆汁酸信号传导。来自FRGN 19+的肝脏标准化至体重的7.8%，并且它们的胆汁酸池和信号传导更接近于对照FRGN 19+小鼠。RNA序列分析显示Hippo通路的激活，免疫组织化学和转录分析显示，在FRGN小鼠的扩大的人源化肝脏中，肝细胞增殖增加，但不凋亡。细胞分选实验表明，尽管健康人肝脏不产生FGF 19，但来自胆汁淤积性肝脏的非实质细胞产生FGF 19。在具有人源化肝脏的小鼠中，FGF 19转基因的表达校正胆汁酸信号传导缺陷，导致胆汁酸合成、胆汁酸库和肝脏大小的正常化。这些发现表明，肝脏的大小在一定程度上是由肝脏必须循环的胆汁酸池的大小调节的。
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 fibroblast growth factor-15 (FGF15) produced by mouse intestine. This results in upregulation 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. We crossed Fah−/−, Rag2−/−, Il2r−/− mice with NOD 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). Livers were larger in FRGN mice with humanized livers (13% of body weight), compared to 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, non-parenchymal cells from cholestatic livers produce FGF19. 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.