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 β-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^ΔHep) and intestine-specific Fxr-null (Fxr^ΔIE) 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^ΔHep mice responded to OCA treatment in a manner similar to Fxr^fl/fl mice while Fxr^ΔIE 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 PGC1α 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.