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

JOURNAL OF HEPATOLOGY

卷:72

Article

Panzitt, Katrin^1,2  Jungwirth, Emilian^1,2,3  Krones, Elisabeth¹  Lee, Jae Man⁴  Pollheimer, Marion⁵  Thallinger, Gerhard G.^3,6  Kolb-Lenz, Dagmar^7,8  Xiao, Rui⁹  Thorell, Anders^10,11  Trauner, Michael¹²  Fickert, Peter¹  Marschall, Hanns-Ulrich^13,14  Moore, David D.¹⁵  Wagner, Martin^1,2,3 

[1] Med Univ Graz, Div Gastroenterol & Hepatol, Graz, Austria

[2] Med Univ Graz, Res Unit Translat Nucl Receptor Res, Graz, Austria

[3] BioTechMed Graz, Omics Ctr Graz, Graz, Austria

[4] Kyungpook Natl Univ, BK21 Plus KNU Biomed Convergence Program, Dept Biochem & Cell Biol, Cell & Matrix Res Inst,Dept Biomed Sci,Sch Med, Daegu, South Korea

[5] Med Univ Graz, Inst Pathol, Graz, Austria

[6] Univ Technol, Inst Computat Biotechnol, Graz, Austria

[7] Med Univ Graz, Ctr Med Res, Graz, Austria

[8] Med Univ Graz, Gottfried Schatz Res Ctr Cell Signaling Metab & A, Div Cell Biol Histol & Embryol, Graz, Austria

[9] Baylor Coll Med, Mol & Human Genet, Houston, TX 77030 USA

[10] Ersta Hosp, Danderyd Hosp, Dept Clin Sci, Karolinska Inst, Stockholm, Sweden

[11] Ersta Hosp, Dept Surg, Stockholm, Sweden

[12] Med Univ Vienna, Dept Med 3, Div Gastroenterol & Hepatol, Vienna, Austria

[13] Univ Gothenburg, Dept Mol & Clin Med, Gothenburg, Sweden

[14] Sahlgrens Univ Hosp, Gothenburg, Sweden

[15] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA

关键词: Bile acids;    Obeticholic acid;    Ursodeoxycholic acid;    Nuclear receptors;    Vesicle trafficking;   

DOI  :  10.1016/j.jhep.2020.01.014

来源: Elsevier

【 摘 要 】

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. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V.

【 授权许可】

Free