Nuclear Receptor Signaling Through Growth Factor Loop

Science's STKE  15 Jul 2003:
Vol. 2003, Issue 191, pp. tw275-TW275
DOI: 10.1126/stke.2003.191.tw275

Bile acids have important roles in transport and excretion of fats and sterols, including cholesterol. However, excessive concentrations of bile acids are harmful, and their synthesis is tightly controlled. The nuclear receptor FXR (farnesoid X receptor) is activated by binding of bile acids and contributes to decreased expression of the gene encoding cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme in synthesis of bile acids. Thus, bile acid concentrations within a single cell can be regulated through FXR. Holt et al. show that this intracellular regulation may be reinforced by extracellular autocrine or paracrine signals mediated by fibroblast growth factor-19 (FGF-19). They show that expression of FGF-19 is stimulated as a consequence of FXR activation in primary human hepatocytes. A potential FXR-response element was detected in intron 2 of the FGF-19 gene. Thus, newly synthesized FGF-19 might be secreted and could activate its receptor, FGFR4, which is known to be expressed in hepatocytes. Indeed, treatment of hepatocytes with recombinant FGF-19 suppressed expression of CYP7A1, and amounts of CYP7A1 mRNA were decreased in livers of mice infected with adenovirus encoding human FGF-19. The results emphasize that, in addition to their roles in control of growth and differentiation, growth factors can also participate in homeostatic pathways. The findings also provide evidence for a feedback loop mediated by FGF-19 secretion that may complement direct regulation of gene expression mediated by FXR.

J. A. Holt, G. Luo, A. N. Billin, J. Bisi, Y. Y. McNeill, K. F. Kozarsky, M. Donahee, D. Y. Wang, T. A. Mansfield, S. A. Kliewer, B. Goodwin, S. A. Jones, Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev. 17, 1581-1591 (2003) [Abstract] [Full Text]