期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2009
卷号：106
期号：34
页码：14379-14384
DOI：10.1073/pnas.0907812106
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：FGF19 is a hormone that regulates bile acid and glucose homeostasis. Progress has been made in identifying cofactors for receptor activation. However, several functions of FGF19 have not yet been fully defined, including the actions of FGF19 on target tissues, its FGF receptor specificity, and the contributions of other cofactors, such as heparin. Here, we explore the requirements for FGF19-FGFR/co-receptor interactions and signaling in detail. We show that {beta}Klotho was essential for FGF19 interaction with FGFRs 1c, 2c, and 3c, but FGF19 was able to interact directly with FGFR4 in the absence of {beta}Klotho in a heparin-dependent manner. Further, FGF19 activated FGFR4 signaling in the presence or absence of {beta}Klotho, but activation of FGFRs 1c, 2c, or 3c was completely {beta}Klotho dependent. We then generated an FGF19 molecule, FGF19dCTD, which has a deletion of the C-terminal region responsible for {beta}Klotho interaction. We determined that {beta}Klotho-dependent FGFR1c, 2c, and 3c interactions and activation were abolished, and {beta}Klotho-independent FGFR4 activation was preserved; therefore, FGF19dCTD is an FGFR4-specific activator. This unique FGF19 molecule specifically activated FGFR4-dependent signaling in liver and suppressed CYP7A1 expression in vivo, but was unable to activate signaling in adipose where FGFR4 expression is very low. Interestingly, unlike FGF19, treatment of ob/ob mice with FGF19dCTD failed to improve glucose levels and insulin sensitivity. These results suggest that FGF19-regulated liver bile acid metabolism could be independent of its glucose-lowering effect, and direct FGFR activation in adipose tissue may play an important role in the regulation of glucose homeostasis.
