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

Artikel i vetenskaplig tidskrift
Författare Katrin Panzitt
Emilian Jungwirth
Elisabeth Krones
Jae Man Lee
Marion Pollheimer
Gerhard G Thallinger
Dagmar Kolb-Lenz
Rui Xiao
Anders Thorell
Michael Trauner
Peter Fickert
Hanns-Ulrich Marschall
David D Moore
Martin Wagner
Publicerad i Journal of hepatology
Volym 72
Nummer/häfte 6
Sidor 1122-1131
ISSN 1600-0641
Publiceringsår 2020
Publicerad vid Wallenberglaboratoriet
Institutionen för medicin, avdelningen för molekylär och klinisk medicin
Sidor 1122-1131
Språk en
Länkar dx.doi.org/10.1016/j.jhep.2020.01.0...
www.ncbi.nlm.nih.gov/entrez/query.f...
Ämnesord Bile acids, Nuclear receptors, Obeticholic acid, Ursodeoxycholic acid, Vesicle trafficking
Ämneskategorier Gastroenterologi

Sammanfattning

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.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.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.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.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.

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