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J Hepatol. 2020 Jan 27. pii: S0168-8278(20)30031-3. doi: 10.1016/j.jhep.2020.01.014. [Epub ahead of print]

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

Author information

1
Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria; Research Unit for Translational Nuclear Receptor Research, Medical University Graz, Graz, Austria.
2
Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria; Research Unit for Translational Nuclear Receptor Research, Medical University Graz, Graz, Austria; Omics Center Graz, BioTechMed Graz, Austria; Institute of Computational Biotechnology, University of Technology, Graz, Austria.
3
Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria.
4
Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu, South Korea.
5
Institute of Pathology, Medical University Graz, Graz, Austria.
6
Omics Center Graz, BioTechMed Graz, Austria; Institute of Computational Biotechnology, University of Technology, Graz, Austria.
7
Center for Medical Research Medical University Graz and Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Austria.
8
Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
9
Karolinska Institutet, Department of Clinical Science, Danderyd Hospital and Department of Surgery, Ersta Hospital, Stockholm, Sweden.
10
Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
11
Department of Molecular and Clinical Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
12
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
13
Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria; Research Unit for Translational Nuclear Receptor Research, Medical University Graz, Graz, Austria; Omics Center Graz, BioTechMed Graz, Austria. Electronic address: martin.wagner@medunigraz.at.

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.

KEYWORDS:

bile acids; nuclear receptors; obeticholic acid/OCA; ursodeoxycholic acid/UDCA; vesicle trafficking

PMID:
32001325
DOI:
10.1016/j.jhep.2020.01.014
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