FXR-dependent Rubicon induction impairs autophagy in models of human cholestasis

Abstract Background and Aim Cholestasis comprises a spectrum of liver diseases characterized by accumulation of bile acids. Bile acids and activation of the bile acid receptor FXR can inhibit autophagy, a cellular self-digestion process necessary for cell homeostasis and regeneration. In mice autophagy appears to be impaired in cholestasis and induction of autophagy may reduce liver injury. Methods Here we explored autophagy in human cholestasis in vivo and investigated the underlying molecular mechanisms in vitro. Results In cholestatic patients and individuals treated with the FXR ligand obeticholic acid (OCA) autophagy processing appeared to be impaired. In vitro, chenodeoxycholic acid and OCA inhibited autophagy at the level of autophagosome-to-lysosome fusion in an FXR dependent manner. FXR ChIP-seq and ChIP-qPCR in a human cholestatic liver sample combined with luciferase promoter studies revealed that Rubicon, which inhibits autophago-lysosomal maturation, is a direct FXR target and is induced in cholestasis and by FXR agonistic bile acids. Genetic inhibition of Rubicon reversed bile acid induced autophagic flux impairment. In contrast to OCA, ursodeoxycholic acid (UDCA), which is a non-FXR-agonistic bile acid, induced autophago-lysosome formation FXR independently and enhanced autophagic flux along with reduction of Rubicon. Conclusion Autophagy processing is impaired in models of human cholestatic conditions in an FXR dependent manner, in part by induction of Rubicon. UDCA is a potent inducer of hepatic autophagy. Manipulating autophagy and Rubicon may represent a novel treatment concept for cholestatic liver diseases.