Fibroblast growth factor 15 (FGF15) plays a crucial role in the negative feedback loop of 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 20h and subsequent feeding for 3h. In mice lacking tauro--muricholic acid, which is an endogenous antagonist for farnesoid-X-receptor (FXR), Fgf15 mRNA level in the distal ileum was still 3h-postprandially reduced. We further explored the postprandial regulation of Fgf15 transcription in various sites of ileum and found that 3h-postprandial Fgf15 levels were reduced in the distal ileum, while elevated in the proximal ileum. Furthermore, 3h-postprandial plasma FGF15 level was reduced despite the elevated Fgf15 mRNA level in the proximal ileum. In mice lacking Fxr in the intestine, relative amount 3h-postprandial Fgf15 mRNA level was still reduced in the distal ileum, whereas 3h-postprandial elevation was blunt in the proximal ileum. Oral administration of soybean oil, fatty acids and PPAR agonist pioglitazone reduced Fgf15 expression in the distal ileum, indicating that PPAR 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.
Katafuchi et al. (Thu,) studied this question.