| First Author | Fu T | Year | 2016 |
| Journal | Mol Endocrinol | Volume | 30 |
| Issue | 1 | Pages | 92-103 |
| PubMed ID | 26505219 | Mgi Jnum | J:234054 |
| Mgi Id | MGI:5788831 | Doi | 10.1210/me.2015-1226 |
| Citation | Fu T, et al. (2016) FXR Primes the Liver for Intestinal FGF15 Signaling by Transient Induction of beta-Klotho. Mol Endocrinol 30(1):92-103 |
| abstractText | The bile acid (BA)-sensing nuclear receptor, farnesoid X receptor (FXR), regulates postprandial metabolic responses, including inhibition of BA synthesis, by inducing the intestinal hormone, fibroblast growth factor (FGF)15 (FGF19 in human). In this study, we tested a novel hypothesis that FXR not only induces intestinal FGF15 but also primes the liver for effectively responding to the signal by transcriptional induction of the obligate coreceptor for FGF15, beta-Klotho (betaKL). Activation of FXR by a synthetic agonist, GW4064, in mice increased occupancy of FXR and its DNA-binding partner, retinoid X receptor-alpha, at FGF15-signaling component genes, particularly betaKL, and induced expression of these genes. Interestingly, mRNA levels of Fgfr4, the FGF15 receptor, were not increased by GW4064, but protein levels increased as a result of betaKL-dependent increased protein stability. Both FGF receptor 4 and betaKL protein levels were substantially decreased in FXR-knockout (KO) mice, and FGF19 signaling, monitored by phosphorylated ERK, was blunted in FXR-KO mice, FXR-KO mouse hepatocytes, and FXR-down-regulated human hepatocytes. Overexpression of betaKL in FXR-lacking hepatocytes partially restored FGF19 signaling and inhibition by FGF19 of Cyp7a1, which encodes the rate-limiting BA biosynthetic enzyme. In mice, transient inductions of intestinal Fgf15 and hepatic betaKL were temporally correlated after GW4064 treatment, and pretreatment of hepatocytes with GW4064 before FGF19 treatment enhanced FGF19 signaling, which was abolished by transcriptional inhibition or betaKL down-regulation. This study identifies FXR as a gut-liver metabolic coordinator for FGF15/19 action that orchestrates transient induction of hepatic betaKL and intestinal Fgf15/19 in a temporally correlated manner. |
