Elevated cholesterol metabolism and bile acid synthesis in mice lacking membrane tyrosine kinase receptor FGFR4
Elevated cholesterol metabolism and bile acid synthesis in mice lacking membrane tyrosine kinase receptor FGFR4
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DOI：
10.1074/jbc.275.20.15482
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发表时间：
2000-05-19
影响因子：
4.8
通讯作者：
McKeehan, WL
中科院分区：
文献类型：
--
作者：
Yu, CD;Wang, F;McKeehan, WL
硫酸乙酰肝素调节的跨膜酪氨酸激酶受体 FGFR4 是成熟肝细胞中主要的 FGFR 同种型。成纤维细胞生长因子与表达 FGFR4 的前肠内胚层肝脏的定义以及体外刺激肝细胞 DNA 合成有关。在此，我们表明，缺乏 FGFR4 的小鼠的肝脏表现出正常形态，并且响应部分肝切除正常再生。然而，FGFR4 (-/-) 小鼠表现出胆囊耗尽、胆汁酸库升高和胆汁酸排泄升高。胆固醇和胆汁酸控制的肝脏胆固醇 7 α-羟化酶（胆汁酸合成的限制酶）升高，对膳食胆固醇无反应，但通常受到膳食胆酸盐的抑制。FGFR4 (-/-) 小鼠中的表达模式和胆酸盐依赖性、胆固醇诱导的肝肿大表明，受体相互作用蛋白 140（前馈激活剂肝 X 受体 α 的共阻遏物）的激活可能介导FCFR4 和胆酸盐对胆固醇和胆汁酸控制的肝脏胆固醇 7 α-羟化酶转录进行负调节。结果表明，跨膜传感器与代谢物控制的转录网络相互作用，并表明细胞周基质控制的肝脏 FGFR4 特别可以确保细胞结构和信号转导有足够的胆固醇。
Heparan sulfate-regulated transmembrane tyrosine kinase receptor FGFR4 is the major FGFR isotype in mature hepatocytes. Fibroblast growth factor has been implicated in the definition of liver from foregut endoderm where FGFR4 is expressed and stimulation of hepatocyte DNA synthesis in vitro, Here we show that livers of mice lacking FGFR4 exhibited normal morphology and regenerated normally in response to partial hepatectomy, However, the FGFR4 (-/-) mice exhibited depleted gallbladders, an elevated bile acid pool and elevated excretion of bile acids. Cholesterol- and bile acid-controlled liver cholesterol 7 alpha-hydroxylase, the limiting enzyme for bile acid synthesis, was elevated, unresponsive to dietary cholesterol, but repressed normally by dietary cholate, Expression pattern and cholate-dependent, cholesterol-induced hepatomegaly in the FGFR4 (-/-) mice suggested that activation of receptor interacting protein 140, a co-repressor of feed-forward activator liver X receptor alpha, may mediate the negative regulation of cholesterol- and bile acid-controlled liver cholesterol 7 alpha-hydroxylase transcription by FCFR4 and cholate, The results demonstrate that transmembrane sensors interface with metabolite-controlled transcription networks and suggest that pericellular matrix-controlled liver FGFR4 in particular may ensure adequate cholesterol for cell structures and signal transduction.