Yu Chundong, Wang Fen, Jin Chengliu, Wu Xiaochong, Chan Wai-kin, McKeehan Wallace L
Department of Biochemistry and Biophysics, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, 2121 W. Holcombe Boulevard, Houston, TX 77030-3303, USA.
Am J Pathol. 2002 Dec;161(6):2003-10. doi: 10.1016/S0002-9440(10)64478-1.
Carbon tetrachloride (CCl(4)) intoxification in rodents is a commonly used model of both acute and chronic liver injury. Recently, we showed that mice in which FGFR4 was ablated from the germline exhibited elevated cholesterol metabolism and bile acid synthesis coincident with unrepressed levels of cytochrome P450 7A (CYP7A), the rate-limiting enzyme in cholesterol disposal. Of the four fibroblast growth factor (FGF) receptor genes expressed in adult liver, FGFR4 is expressed specifically in mature hepatocytes. To determine whether FGFR4 plays a broader role in liver-specific metabolic functions, we examined the impact of both acute and chronic exposure to CCl(4) in FGFR4-deficient mice. Following acute CCl(4) exposure, the FGFR4-deficient mice exhibited accelerated liver injury, a significant increase in liver mass and delayed hepatolobular repair. Chronic CCl(4) exposure resulted in severe fibrosis in livers of FGFR4-deficient mice compared to normal mice. Analysis at both mRNA and protein levels indicated an 8-hour delay in FGFR4-deficient mice in the down-regulation of cytochrome P450 2E1 (CYP2E1) protein, the major enzyme whose products underlie CCl(4)-induced injury. These results show that hepatocyte FGFR4 protects against acute and chronic insult to the liver and prevents accompanying fibrosis. The results show that FGFR4 acts by promotion of processes that restore hepatolobular architecture rather than cellularity while limiting damage due to prolonged CYP2E1 activity.
啮齿动物四氯化碳（CCl₄）中毒是常用的急性和慢性肝损伤模型。最近，我们发现种系中FGFR4基因被敲除的小鼠胆固醇代谢和胆汁酸合成增加，同时细胞色素P450 7A（CYP7A）水平未受抑制，CYP7A是胆固醇代谢的限速酶。在成体肝脏中表达的四个成纤维细胞生长因子（FGF）受体基因中，FGFR4特异性表达于成熟肝细胞。为了确定FGFR4是否在肝脏特异性代谢功能中发挥更广泛的作用，我们研究了FGFR4缺陷小鼠急性和慢性暴露于CCl₄的影响。急性暴露于CCl₄后，FGFR4缺陷小鼠肝损伤加速，肝脏重量显著增加，肝小叶修复延迟。与正常小鼠相比，慢性暴露于CCl₄导致FGFR4缺陷小鼠肝脏出现严重纤维化。mRNA和蛋白质水平分析表明，FGFR4缺陷小鼠细胞色素P450 2E1（CYP2E1）蛋白下调延迟8小时，CYP2E1是其产物导致CCl₄诱导损伤的主要酶。这些结果表明，肝细胞FGFR4可保护肝脏免受急性和慢性损伤，并预防随之而来的纤维化。结果表明，FGFR4通过促进恢复肝小叶结构而非细胞数量的过程发挥作用，同时限制因CYP2E1活性延长导致的损伤。
