Intestinal farnesoid X receptor signaling controls hepatic fatty acid oxidation

In addition to maintaining bile acid, cholesterol and glucose homeostasis, farnesoid X receptor (FXR) also regulates fatty acid beta-oxidation (FAO). To explore the different roles of hepatic and intestinal FXR in liver FAO, FAO-associated metabolites, including acylcarnitines and fatty acids, and FXR target gene mRNAs were profiled using an integrated metabolomic and transcriptomic analysis in control (Fxr(fl/fl)) , liver-specific Fxr-null (Fxr(Delta Hep)) and intestine-specific Fxr-null (Fxr(Delta)(IE)) mice, treated either with the FXR agonist obeticholic acid (OCA) or vehicle (VEH). Activation of FXR by OCA treatment significantly increased fatty acyl-CoA hydrolysis (Acot1) and decreased FAO-associated mRNAs in Fxr(fl/fl) mice, resulting in reduced levels of total acylcarnitines and relative accumulation of long/medium chain acylcarnitines and fatty acids in liver. Fxr(Delta Hep) mice responded to OCA treatment in a manner similar to Fxr(fl/fl) mice while Fxr(Delta)(IE) mice responded differently, thus illustrating that intestinal FXR plays a critical role in the regulation of hepatic FAO. A significant negative-correlation between intestinal FXR-FGF15 and hepatic CREB-PGC1A pathways was observed after both VEH and OCA treatment, suggesting that OCA-induced activation of the intestinal FXR-FGF15 axis downregulates hepatic PGC1 alpha signaling via inactivation of hepatic CREB, thus repressing FAO. This mechanism was confirmed in experiments based on human recombinant FGF19 treatment and intestinal Fgf15-null mice. This study revealed an important role for the intestinal FXR-FGF15 pathway in hepatic FAO repression.

Automated summary

This study revealed the critical role of intestinal FXR in regulating hepatic FAO, with FXR activation suppressing FAO through downregulation of hepatic PGC1 alpha signaling via inactivation of hepatic CREB.