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

J Hepatol. 2020 Jun;72(6):1122-1131. doi: 10.1016/j.jhep.2020.01.014. Epub 2020 Jan 28.


Background & aims: Cholestasis comprises a spectrum of liver diseases characterized by the accumulation of bile acids. Bile acids and activation of the farnesoid X receptor (FXR) can inhibit autophagy, a cellular self-digestion process necessary for cellular homeostasis and regeneration. In mice, autophagy appears to be impaired in cholestasis and induction of autophagy may reduce liver injury.

Methods: Herein, we explored autophagy in human cholestasis in vivo and investigated the underlying molecular mechanisms in vitro. FXR chromatin immunoprecipitation-sequencing and qPCR were performed in combination with luciferase promoter studies to identify functional FXR binding targets in a human cholestatic liver sample.

Results: Autophagic processing appeared to be impaired in patients with cholestasis and in individuals treated with the FXR ligand obeticholic acid (OCA). In vitro, chenodeoxycholic acid and OCA inhibited autophagy at the level of autophagosome to lysosome fusion in an FXR-dependent manner. Rubicon, which inhibits autophago-lysosomal maturation, was identified as a direct FXR target that is induced in cholestasis and by FXR-agonistic bile acids. Genetic inhibition of Rubicon reversed the bile acid-induced impairment of autophagic flux. In contrast to OCA, ursodeoxycholic acid (UDCA), which is a non-FXR-agonistic bile acid, induced autophagolysosome formation independently of FXR, enhanced autophagic flux and was associated with reduced Rubicon levels.

Conclusion: In models of human cholestasis, autophagic processing is impaired in an FXR-dependent manner, partly resulting from the 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.

Lay summary: Autophagy, a cellular self-cleansing process, is impaired in various forms of human cholestasis. Bile acids, which accumulate in cholestatic liver disease, induce Rubicon, a protein that inhibits proper execution of autophagy. Ursodeoxycholic acid, which is the first-line treatment option for many cholestatic liver diseases, induces hepatic autophagy along with reducing Rubicon.

Keywords: Bile acids; Nuclear receptors; Obeticholic acid; Ursodeoxycholic acid; Vesicle trafficking.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagosomes / metabolism
  • Autophagy / drug effects
  • Autophagy / genetics*
  • Autophagy-Related Proteins / genetics
  • Autophagy-Related Proteins / metabolism*
  • Chenodeoxycholic Acid / analogs & derivatives
  • Chenodeoxycholic Acid / metabolism
  • Chenodeoxycholic Acid / pharmacology
  • Chenodeoxycholic Acid / therapeutic use
  • Cholestasis / drug therapy
  • Cholestasis / metabolism*
  • Cytotoxins
  • Gene Knockdown Techniques
  • Hep G2 Cells
  • Humans
  • Liver / metabolism
  • Liver / pathology
  • Lysosomes / metabolism
  • Receptors, Cytoplasmic and Nuclear / agonists
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Retrospective Studies
  • Signal Transduction / genetics*
  • Transfection
  • Ursodeoxycholic Acid / metabolism
  • Ursodeoxycholic Acid / pharmacology


  • Autophagy-Related Proteins
  • Cytotoxins
  • RUBCN protein, human
  • Receptors, Cytoplasmic and Nuclear
  • obeticholic acid
  • farnesoid X-activated receptor
  • Chenodeoxycholic Acid
  • Ursodeoxycholic Acid