Site-specific bidirectional regulation of Fgf15 transcription in the mouse ileum

Fibroblast growth factor 15 (FGF15) plays a crucial role in the negative feedback loop of bile acid (BA) production by reducing mRNA levels of hepatic Cyp7a1, a rate-limiting enzyme of BA synthesis. Here, we investigated the postprandial regulation of Fgf15 mRNA levels in the ileum to unveil the physiological regulation of FGF15 production by feeding in mice. The postprandial Fgf15 mRNA level reached the minimum level in the distal ileum following starvation for 20 h and subsequent feeding for 3 h. In mice lacking tauro-β-muricholic acid, which is an endogenous antagonist for the farnesoid-X-receptor (FXR), the Fgf15 mRNA level in the distal ileum was still 3 h-postprandially reduced. We further explored the postprandial regulation of Fgf15 transcription in various sites of the ileum and found that the 3 h-postprandial Fgf15 levels were reduced in the distal ileum while elevated in the proximal ileum. Furthermore, the 3 h-postprandial plasma FGF15 level was reduced despite the elevated Fgf15 mRNA level in the proximal ileum. In mice lacking Fxr in the intestine, the relative amount of 3 h-postprandial Fgf15 mRNA level was still reduced in the distal ileum, whereas the 3 h-postprandial elevation was blunt in the proximal ileum. Oral administration of soybean oil, fatty acids, and PPARγ agonist pioglitazone reduced Fgf15 expression in the distal ileum, indicating that PPARγ signaling is involved in the negative regulation of Fgf15 mRNA level. Collectively, our data show the complicated regulation of plasma FGF15 concentration by bidirectional change in Fgf15 mRNA levels by food intake in different sites of the ileum.NEW & NOTEWORTHY It is considered that feeding stimulates the release of bile acids, which ultimately bind to FXR to increase the Fgf15 transcription in the ileum. However, we found that Fgf15 mRNA levels were postprandially reduced, particularly in the distal ileum, and this reduction was mediated through fatty acid-PPARγ signaling. In the proximal ileum, however, we observed that Fgf15 mRNA levels were postprandially elevated through bile acid-FXR signaling, which was consistent with the current idea.