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

Panzitt, Katrin; Jungwirth, Emilian; Krones, Elisabeth; Lee, Jae Man; Pollheimer, Marion J.; Thallinger, Gerhard; Kolb-Lenz, Dagmar; Xiao, Rui; Thorell, Anders; Trauner, Michael; Fickert, Peter; Marschall, Hanns‐Ulrich; Moore, David D.; Wagner, Martin

doi:10.1016/j.jhep.2020.01.014

Cited by 61 publications

(51 citation statements)

References 38 publications

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“…These findings support the hypothesis that UDCA acts downstream of endosomal-lysosomal and autophagic dysfunction, making it an attractive target for drug-repurposing as a general neuroprotectant. One consideration in regards to the discrepancy between this study and previous studies looking at the effect of UDCA upon autophagic flux is that the majority of experiments looking at the role of UDCA on autophagy have been performed in hepatic or cancer cell lines ( Panzitt et al, 2020 ). It is important to consider that the metabolic energy demand and source of energy in neurons is distinct from other cell types, with neurons in the CNS less dependent upon autophagy as a source of amino acids and energy ( Boland and Nixon, 2006 ; Yue et al, 2009 ).…”

Section: Discussioncontrasting

confidence: 59%

“…UDCA has been shown to both promote ( Lim and Han, 2015 ; Pang et al, 2017 ; Panzitt et al, 2020 ; Wang et al, 2017 ) and inhibit autophagic flux ( Ye et al, 2020 ). The CHMP2B Intron5 mutation results in significant perturbations to endosomal-lysosomal ( Urwin et al, 2010 ) and autophagosomal trafficking ( Filimonenko et al, 2007 ; Ghazi-Noori et al, 2012 ; Lee et al, 2007 ).…”

Section: Discussionmentioning

confidence: 99%

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Neuroprotective activity of ursodeoxycholic acid in CHMP2B models of frontotemporal dementia

West

Ugbode

Fort-Aznar

et al. 2020

Neurobiology of Disease

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Frontotemporal dementia (FTD) is one of the most prevalent forms of early-onset dementia. It represents part of the FTD-Amyotrophic Lateral Sclerosis (ALS) spectrum, a continuum of genetically and pathologically overlapping disorders. FTD-causing mutations in CHMP2B , a gene encoding a core component of the heteromeric ESCRT-III Complex, lead to perturbed endosomal-lysosomal and autophagic trafficking with impaired proteostasis. While CHMP2B mutations are rare, dysfunctional endosomal-lysosomal signalling is common across the FTD-ALS spectrum. Using our established Drosophila and mammalian models of CHMP2B Intron5 induced FTD we demonstrate that the FDA-approved compound Ursodeoxycholic Acid (UDCA) conveys neuroprotection, downstream of endosomal-lysosomal dysfunction in both Drosophila and primary mammalian neurons. UDCA exhibited a dose dependent rescue of neuronal structure and function in Drosophila pan-neuronally expressing CHMP2B Intron5 . Rescue of CHMP2B Intron5 dependent dendritic collapse and apoptosis with UDCA in rat primary neurons was also observed. UDCA failed to ameliorate aberrant accumulation of endosomal and autophagic organelles or ubiquitinated neuronal inclusions in both models. We demonstrate the neuroprotective activity of UDCA downstream of endosomal-lysosomal and autophagic dysfunction, delineating the molecular mode of action of UDCA and highlighting its potential as a therapeutic for the treatment of FTD-ALS spectrum disorders.

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Section: Discussioncontrasting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Neuroprotective activity of ursodeoxycholic acid in CHMP2B models of frontotemporal dementia

West

Ugbode

Fort-Aznar

et al. 2020

Neurobiology of Disease

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“…Genes were mapped to corresponding orthologues of other species to correctly estimate the similarity between different species. The Human Genome (11) Different data sets used different analysis tools and strategies. Data sets marked with * were used for the pooled data set.…”

Section: Data Set Comparisonmentioning

confidence: 99%

Meta‐analysis and Consolidation of Farnesoid X Receptor Chromatin Immunoprecipitation Sequencing Data Across Different Species and Conditions

et al. 2021

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Farnesoid X receptor (FXR) is a nuclear receptor that controls gene regulation of different metabolic pathways and represents an upcoming drug target for various liver diseases. Several data sets on genome-wide FXR binding in different species and conditions exist. We have previously reported that these data sets are heterogeneous and do not cover the full spectrum of potential FXR binding sites. Here, we report the first meta-analysis of all publicly available FXR chromatin immunoprecipitation sequencing (ChIP-seq) data sets from mouse, rat, and human across different conditions using a newly generated analysis pipeline. All publicly available single data sets were biocurated in a standardized manner and compared on every relevant level from raw reads to affected functional pathways. Individual murine data sets were then virtually merged into a single unique "FXR binding atlas" spanning all potential binding sites across various conditions. Comparison of the single biocurated data sets showed that the overlap of FXR binding sites between different species is modest and ranges from 48% (mouse-human) to 55% (mouse-rat). Moreover, in vivo data among different species are more similar than human in vivo data compared to human in vitro data. The consolidated murine global FXR binding atlas virtually increases sequencing depth and allows recovering more and novel potential binding sites and signaling pathways that were missed in the individual data sets. The FXR binding atlas is publicly searchable (https://fxrat las.tugraz.at). Conclusion: Published single FXR ChIP-seq data sets and large-scale integrated omics data sets do not cover the full spectrum of FXR binding. Combining different individual data sets and creating an "FXR super-binding atlas" enhances understanding of FXR signaling capacities across different conditions. This is important when considering the potential wide spectrum for drugs targeting FXR in liver diseases. (Hepatology Communications 2021;0:1-16).F arnesoid X receptor (FXR) is bile acid-activated nuclear receptor and transcription factor that coordinates nutritional inputs and metabolic outputs of the liver and intestine. (1,2) In addition to transcriptional regulation of metabolic genes, FXR has anti-inflammatory and antifibrotic properties. This array of established effects has put FXR in the spotlight as a novel therapeutic target for various metabolic liver diseases, including bile acid disorders and fatty liver disease. (3) However, on a genomic level,

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“…Conjugated bile acids such as LCA and CDCA mainly interacted with the FXR receptor. However, UDCA acts as a TGR5 receptor agonist instead of a FXR agonist to regulate a series of activities [40,41]. Moreover, the function of TGR5 depends on the cell and tissue type.…”

Section: Discussionmentioning

confidence: 99%

Ursodeoxycholic Acid Suppresses The Malignant Progression of Colorectal Cancer Through TGR5-YAP Axis

Zhang

et al. 2021

Preprint

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Background: The Hippo/YAP pathway plays an important role in the development of cancers. Previous studies have reported that bile acids can activate YAP (Yes Associated Protein) to promote tumorigenesis and tumor progression. Ursodeoxycholic acid (UDCA) is a long-established old drug used for cholestasis treatment. So far, the effect of UDCA on YAP signaling in colorectal cancer (CRC) is not well defined. The study means to explore relationship of UDCA and YAP in CRC.Methods: The effect of UDCA on CRC cells proliferation was examined by MTT and clonogenic assay, western blotting (WB), real-time PCR, seperation of nucleoprotein and cytoplasmic protein and immunofluorescence (IF) assays were used to detect expression of YAP, WB, real-time PCR, GST-pull down assay and rhodamine-labeled phalloidin staining assays were used to detect activity of RhoA. After transfection of YAP5SA plasmids and RhoAV14 plasmids respectively, MTT, clonogenic assay, EdU incorporation assays and WB were performed. WB and ELISA were used to detect activity of cAMP/PKA axis, after blocking cAMP/PKA axis with siRNA and inhibitors, MTT, WB, IF and clonogenic assay were performed to test effect of UDCA on CRC cells. WB, IF and real-time PCR assays were used to detect expression of TGR5 in CRC cells after UDCA treatment, and then TGR5 agonist, TGR5 antagonist and siRNA were used to detect effect of UDCA on CRC cells. AOM/DSS-induced primary model was used to detect effect of UDCA, WB and Immunohistochemistry (IHC) were used to detect expression of related proteins.Results: UDCA suppressed YAP signaling by activating the membrane G‐protein‐coupled bile acid receptor (TGR5). TGR5 mainly regulated cAMP/PKA signaling pathway to inhibit RhoA activity, thereby suppressing YAP signaling. Moreover, the restoration of YAP expression alleviated the inhibitory effect of UDCA on CRC cell proliferation. In AOM/DSS-induced CRC model, UDCA inhibited tumor growth in a concentration-dependent manner and decreased expression of YAP and Ki67.Conclusion: UDCA plays a distinguished role in regulating YAP signaling and CRC growth from the primary bile acids and partial secondary bile acids, demonstrating the importance of maintaining normal intestinal bile acid metabolism in cancer patients. It also presents a potential therapeutic intervention for CRC.

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

Cited by 61 publications

References 38 publications

Neuroprotective activity of ursodeoxycholic acid in CHMP2B models of frontotemporal dementia

Neuroprotective activity of ursodeoxycholic acid in CHMP2B models of frontotemporal dementia

Meta‐analysis and Consolidation of Farnesoid X Receptor Chromatin Immunoprecipitation Sequencing Data Across Different Species and Conditions

Ursodeoxycholic Acid Suppresses The Malignant Progression of Colorectal Cancer Through TGR5-YAP Axis

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