FGF receptors 1 and 2 control chemically induced injury and compound detoxification in regenerating livers of mice.
FGF receptors 1 and 2 control chemically induced injury and compound detoxification in regenerating livers of mice.
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DOI：
10.1053/j.gastro.2010.06.069
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发表时间：
2010-10
期刊：
影响因子：
29.4
通讯作者：
Werner S
中科院分区：
文献类型：
--
作者：
Böhm F;Speicher T;Hellerbrand C;Dickson C;Partanen JM;Ornitz DM;Werner S
成纤维细胞生长因子受体（FGFR） 4控制胆汁酸代谢并保护肝脏免受纤维化，但FGFR1和FGFR2在成人肝脏中的作用在很大程度上是未知的。我们研究了这些受体在肝脏稳态、再生和纤维化中的功能和作用机制。我们培养了缺乏FGFR1和FGFR2的肝细胞小鼠，并使其遭受急性和慢性四氯化碳诱导的肝损伤和部分肝切除术；小鼠也注射FGF7。我们进行了组织学、组织形态计量学、实时反转录PCR和免疫印迹分析。在肝细胞中，FGFR1和FGFR2的缺失消除了对FGF7和相关FGF家族成员的反应性，但不影响毒素诱导的肝损伤和纤维化。然而，由于严重的肝细胞坏死，部分肝切除术后死亡率增加。这些影响似乎是由肝细胞在肝手术后未能诱导转录调节因子Dbp和Tef的表达介导的；这影响了它们编码解毒细胞色素P450酶的靶基因的表达。我们发现肝细胞中Dbp和Tef的表达直接受FGFR信号传导的控制。由于控制解毒的基因表达减少，部分肝切除术后残留的肝组织不能有效地代谢内源性化合物和用于麻醉/镇痛的药物。我们发现了FGFR1和FGFR2在再生肝脏中的一种新的细胞保护作用，并建议使用重组FGF7来提高手术切除大量肝组织后患者的生存率。
Fibroblast growth factor receptor (FGFR) 4 controls bile acid metabolism and protects the liver from fibrosis, but the roles of FGFR1 and FGFR2 in the adult liver are largely unknown. We investigated the functions and mechanisms of action of these receptors in liver homeostasis, regeneration, and fibrosis. We generated mice with hepatocytes that lack FGFR1 and FGFR2 and subjected them to acute and chronic carbon tetrachloride-induced liver injury and partial hepatectomy; mice were also injected with FGF7. We performed histology, histomorphometry, real-time reverse transcription PCR, and immunoblot analyses. In hepatocytes, loss of FGFR1 and FGFR2 eliminated responsiveness to FGF7 and related FGF family members, but did not affect toxin-induced liver injury and fibrosis. However, mortality after partial hepatectomy increased because of severe hepatocyte necrosis. These effects appeared to be mediated by a failure of hepatocyes to induce the expression of the transcriptional regulators Dbp and Tef upon liver surgery; this affected expression of their target genes, which encode detoxifying cytochrome P450 enzymes. We found that Dbp and Tef expression was directly controlled by FGFR signalling in hepatocytes. As a consequence of the reduced expression of genes that control detoxification, the liver tissue that remained after partial hepatectomy failed to efficiently metabolize endogenous compounds and the drugs applied for anaesthesia/analgesia. We identified a new, cytoprotective effect of FGFR1 and FGFR2 in the regenerating liver and suggest the use of recombinant FGF7 to increase survival of patients after surgical resection of large amounts of liver tissue.
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影响因子：
3.5
作者：
SUZUKI, M;ITOH, T;MITSUI, Y
通讯作者：
MITSUI, Y
DOI：
10.1084/jem.191.11.1975
发表时间：
2000-06-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Latta M;Künstle G;Leist M;Wendel A
通讯作者：
Wendel A
DOI：
10.1038/nrd2792
发表时间：
2009-03
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1073/pnas.0403412101
发表时间：
2004-07-20
影响因子：
11.1
作者：
Borowiak, M;Garratt, AN;Birchmeier, C
通讯作者：
Birchmeier, C
影响因子：
29
作者：
Gachon, Federic;Olela, Fabienne Fleury;Schibler, Ueli
通讯作者：
Schibler, Ueli