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

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FXR-dependent Rubicon induction impairs autophagy in models of human cholestasis
Journal of Hepatology ( IF 26.8 ) Pub Date : 2020-06-01 , DOI: 10.1016/j.jhep.2020.01.014
Katrin Panzitt ₁ , Emilian Jungwirth ₂ , Elisabeth Krones ₃ , Jae Man Lee ₄ , Marion Pollheimer ₅ , Gerhard G Thallinger ₆ , Dagmar Kolb-Lenz ₇ , Rui Xiao ₈ , Anders Thorell ₉ , Michael Trauner ₁₀ , Peter Fickert ₃ , Hanns-Ulrich Marschall ₁₁ , David D Moore ₁₂ , Martin Wagner ₁₃

Affiliation

Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria; Research Unit for Translational Nuclear Receptor Research, Medical University Graz, Graz, Austria.
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.
Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria.
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.
Institute of Pathology, Medical University Graz, Graz, Austria.
Omics Center Graz, BioTechMed Graz, Austria; Institute of Computational Biotechnology, University of Technology, Graz, Austria.
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.
Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Karolinska Institutet, Department of Clinical Science, Danderyd Hospital and Department of Surgery, Ersta Hospital, Stockholm, Sweden.
Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
Department of Molecular and Clinical Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
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.

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.

中文翻译：

FXR 依赖性 Rubicon 诱导损害人类胆汁淤积模型中的自噬

背景和目的胆汁淤积包括一系列以胆汁酸积累为特征的肝脏疾病。胆汁酸和胆汁酸受体 FXR 的激活可以抑制自噬，这是细胞稳态和再生所必需的细胞自我消化过程。在小鼠中，自噬似乎在胆汁淤积中受损，并且自噬的诱导可以减少肝损伤。方法在这里，我们在体内探索了人类胆汁淤积中的自噬，并在体外研究了潜在的分子机制。结果在胆汁淤积患者和接受 FXR 配体奥贝胆酸 (OCA) 治疗的个体中，自噬过程似乎受损。在体外，鹅去氧胆酸和 OCA 在自噬体与溶酶体融合水平上以 FXR 依赖性方式抑制自噬。人类胆汁淤积肝脏样本中的 FXR ChIP-seq 和 ChIP-qPCR 结合荧光素酶启动子研究表明，抑制自噬溶酶体成熟的 Rubicon 是 FXR 的直接靶标，并在胆汁淤积和 FXR 激动剂胆汁酸中诱导。Rubicon 的遗传抑制可逆转胆汁酸诱导的自噬通量损伤。与 OCA 相比，熊去氧胆酸 (UDCA) 是一种非 FXR 激动剂胆汁酸，可独立诱导自噬溶酶体形成 FXR，并随着 Rubicon 的减少而增强自噬通量。结论自噬过程在人类胆汁淤积状况模型中以 FXR 依赖性方式受损，部分是由于 Rubicon 的诱导。UDCA 是一种有效的肝自噬诱导剂。操纵自噬和 Rubicon 可能代表了一种治疗胆汁淤积性肝病的新概念。

更新日期：2020-06-01

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