Department of Molecular Biology, Genentech, Inc., South San Francisco, California, United States of America.
PLoS One. 2011 Mar 18;6(3):e17868. doi: 10.1371/journal.pone.0017868.
Fibroblast growth factor 19 (FGF19) is a hormone-like protein that regulates carbohydrate, lipid and bile acid metabolism. At supra-physiological doses, FGF19 also increases hepatocyte proliferation and induces hepatocellular carcinogenesis in mice. Much of FGF19 activity is attributed to the activation of the liver enriched FGF Receptor 4 (FGFR4), although FGF19 can activate other FGFRs in vitro in the presence of the coreceptor βKlotho (KLB). In this report, we investigate the role of FGFR4 in mediating FGF19 activity by using Fgfr4 deficient mice as well as a variant of FGF19 protein (FGF19v) which is specifically impaired in activating FGFR4. Our results demonstrate that FGFR4 activation mediates the induction of hepatocyte proliferation and the suppression of bile acid biosynthesis by FGF19, but is not essential for FGF19 to improve glucose and lipid metabolism in high fat diet fed mice as well as in leptin-deficient ob/ob mice. Thus, FGF19 acts through multiple receptor pathways to elicit pleiotropic effects in regulating nutrient metabolism and cell proliferation.
成纤维细胞生长因子 19（FGF19）是一种类似激素的蛋白，可调节碳水化合物、脂质和胆汁酸代谢。在生理超剂量下，FGF19 还可增加肝细胞增殖，并在小鼠中诱导肝细胞癌发生。FGF19 的大部分活性归因于富含肝脏的 FGF 受体 4（FGFR4）的激活，尽管在存在核心受体 βKlotho（KLB）的情况下，FGF19 可在体外激活其他 FGFR。在本报告中，我们通过使用 Fgfr4 缺陷型小鼠以及一种特定于激活 FGFR4 的 FGF19 蛋白变体（FGF19v）来研究 FGFR4 在介导 FGF19 活性中的作用。我们的结果表明，FGFR4 激活介导了 FGF19 诱导的肝细胞增殖和胆汁酸生物合成的抑制，但对于 FGF19 在高脂肪饮食喂养的小鼠以及瘦素缺乏型 ob/ob 小鼠中改善葡萄糖和脂质代谢并非必需。因此，FGF19 通过多种受体途径发挥作用，在调节营养代谢和细胞增殖方面产生多效性效应。
