Inhibition of Extracellular Cathepsin D Reduces Hepatic Lipid Accumulation and Leads to Mild Changes in Inflammationin NASH Mice
Background & AimsThe lysosomal enzyme, cathepsin D (CTSD) has been implicated in the pathogenesis of non-alcoholic steatohepatitis (NASH), a disease characterised by hepatic steatosis and inflammation. We have previously demonstrated that specific inhibition of the extracellular CTSD leads t...
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| Format: | Article |
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Frontiers Media S.A.
2021-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.675535/full |
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| author | Tulasi Yadati Tom Houben Albert Bitorina Yvonne Oligschlaeger Marion J. Gijbels Marion J. Gijbels Ronny Mohren Dieter Lütjohann Princy Khurana Sandeep Goyal Aditya Kulkarni Jan Theys Berta Cillero-Pastor Ronit Shiri-Sverdlov |
| author_facet | Tulasi Yadati Tom Houben Albert Bitorina Yvonne Oligschlaeger Marion J. Gijbels Marion J. Gijbels Ronny Mohren Dieter Lütjohann Princy Khurana Sandeep Goyal Aditya Kulkarni Jan Theys Berta Cillero-Pastor Ronit Shiri-Sverdlov |
| author_sort | Tulasi Yadati |
| collection | DOAJ |
| description | Background & AimsThe lysosomal enzyme, cathepsin D (CTSD) has been implicated in the pathogenesis of non-alcoholic steatohepatitis (NASH), a disease characterised by hepatic steatosis and inflammation. We have previously demonstrated that specific inhibition of the extracellular CTSD leads to improved metabolic features in Sprague-Dawley rats with steatosis. However, the individual roles of extracellular and intracellular CTSD in NASH are not yet known. In the current study, we evaluated the underlying mechanisms of extracellular and intracellular CTSD fractions in NASH-related metabolic inflammation using specific small-molecule inhibitors.MethodsLow-density lipoprotein receptor knock out (Ldlr-/-) mice were fed a high-fat, high cholesterol (HFC) diet for ten weeks to induce NASH. Further, to investigate the effects of CTSD inhibition, mice were injected either with an intracellular (GA-12) or extracellular (CTD-002) CTSD inhibitor or vehicle control at doses of 50 mg/kg body weight subcutaneously once in two days for ten weeks.ResultsLdlr-/- mice treated with extracellular CTSD inhibitor showed reduced hepatic lipid accumulation and an associated increase in faecal bile acid levels as compared to intracellular CTSD inhibitor-treated mice. Furthermore, in contrast to intracellular CTSD inhibition, extracellular CTSD inhibition switched the systemic immune status of the mice to an anti-inflammatory profile. In line, label-free mass spectrometry-based proteomics revealed that extra- and intracellular CTSD fractions modulate proteins belonging to distinct metabolic pathways.ConclusionWe have provided clinically translatable evidence that extracellular CTSD inhibition shows some beneficial metabolic and systemic inflammatory effects which are distinct from intracellular CTSD inhibition. Considering that intracellular CTSD inhibition is involved in essential physiological processes, specific inhibitors capable of blocking extracellular CTSD activity, can be promising and safe NASH drugs. |
| first_indexed | 2024-12-18T01:41:22Z |
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| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-18T01:41:22Z |
| publishDate | 2021-07-01 |
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| series | Frontiers in Immunology |
| spelling | doaj.art-cf1bfc25035041d38fc19938d67eb7f42022-12-21T21:25:18ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-07-011210.3389/fimmu.2021.675535675535Inhibition of Extracellular Cathepsin D Reduces Hepatic Lipid Accumulation and Leads to Mild Changes in Inflammationin NASH MiceTulasi Yadati0Tom Houben1Albert Bitorina2Yvonne Oligschlaeger3Marion J. Gijbels4Marion J. Gijbels5Ronny Mohren6Dieter Lütjohann7Princy Khurana8Sandeep Goyal9Aditya Kulkarni10Jan Theys11Berta Cillero-Pastor12Ronit Shiri-Sverdlov13Department of Molecular Genetics, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, NetherlandsDepartment of Molecular Genetics, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, NetherlandsDepartment of Molecular Genetics, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, NetherlandsDepartment of Molecular Genetics, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, NetherlandsDepartment of Medical Biochemistry, Experimental Vascular Biology, Amsterdam UMC, University of Amsterdam, Amsterdam, NetherlandsDepartment of Pathology CARIM, Cardiovascular Research Institute Maastricht, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, NetherlandsMaastricht Multimodal Molecular Imaging Institute (M4I), Division of Imaging Mass Spectrometry, Maastricht University, Maastricht, NetherlandsInstitute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, GermanyAten Porus Lifesciences Pvt Ltd, Bengaluru, IndiaAten Porus Lifesciences Pvt Ltd, Bengaluru, IndiaAten Porus Lifesciences Pvt Ltd, Bengaluru, IndiaThe M-Lab, Department of Precision Medicine, GROW - School for Oncology, Maastricht University, Maastricht, NetherlandsMaastricht Multimodal Molecular Imaging Institute (M4I), Division of Imaging Mass Spectrometry, Maastricht University, Maastricht, NetherlandsDepartment of Molecular Genetics, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, NetherlandsBackground & AimsThe lysosomal enzyme, cathepsin D (CTSD) has been implicated in the pathogenesis of non-alcoholic steatohepatitis (NASH), a disease characterised by hepatic steatosis and inflammation. We have previously demonstrated that specific inhibition of the extracellular CTSD leads to improved metabolic features in Sprague-Dawley rats with steatosis. However, the individual roles of extracellular and intracellular CTSD in NASH are not yet known. In the current study, we evaluated the underlying mechanisms of extracellular and intracellular CTSD fractions in NASH-related metabolic inflammation using specific small-molecule inhibitors.MethodsLow-density lipoprotein receptor knock out (Ldlr-/-) mice were fed a high-fat, high cholesterol (HFC) diet for ten weeks to induce NASH. Further, to investigate the effects of CTSD inhibition, mice were injected either with an intracellular (GA-12) or extracellular (CTD-002) CTSD inhibitor or vehicle control at doses of 50 mg/kg body weight subcutaneously once in two days for ten weeks.ResultsLdlr-/- mice treated with extracellular CTSD inhibitor showed reduced hepatic lipid accumulation and an associated increase in faecal bile acid levels as compared to intracellular CTSD inhibitor-treated mice. Furthermore, in contrast to intracellular CTSD inhibition, extracellular CTSD inhibition switched the systemic immune status of the mice to an anti-inflammatory profile. In line, label-free mass spectrometry-based proteomics revealed that extra- and intracellular CTSD fractions modulate proteins belonging to distinct metabolic pathways.ConclusionWe have provided clinically translatable evidence that extracellular CTSD inhibition shows some beneficial metabolic and systemic inflammatory effects which are distinct from intracellular CTSD inhibition. Considering that intracellular CTSD inhibition is involved in essential physiological processes, specific inhibitors capable of blocking extracellular CTSD activity, can be promising and safe NASH drugs.https://www.frontiersin.org/articles/10.3389/fimmu.2021.675535/fullNASHlysosomal enzymeslipoprotein metabolisminflammationextracellular cathepsin Dsmall-compound inhibitors |
| spellingShingle | Tulasi Yadati Tom Houben Albert Bitorina Yvonne Oligschlaeger Marion J. Gijbels Marion J. Gijbels Ronny Mohren Dieter Lütjohann Princy Khurana Sandeep Goyal Aditya Kulkarni Jan Theys Berta Cillero-Pastor Ronit Shiri-Sverdlov Inhibition of Extracellular Cathepsin D Reduces Hepatic Lipid Accumulation and Leads to Mild Changes in Inflammationin NASH Mice Frontiers in Immunology NASH lysosomal enzymes lipoprotein metabolism inflammation extracellular cathepsin D small-compound inhibitors |
| title | Inhibition of Extracellular Cathepsin D Reduces Hepatic Lipid Accumulation and Leads to Mild Changes in Inflammationin NASH Mice |
| title_full | Inhibition of Extracellular Cathepsin D Reduces Hepatic Lipid Accumulation and Leads to Mild Changes in Inflammationin NASH Mice |
| title_fullStr | Inhibition of Extracellular Cathepsin D Reduces Hepatic Lipid Accumulation and Leads to Mild Changes in Inflammationin NASH Mice |
| title_full_unstemmed | Inhibition of Extracellular Cathepsin D Reduces Hepatic Lipid Accumulation and Leads to Mild Changes in Inflammationin NASH Mice |
| title_short | Inhibition of Extracellular Cathepsin D Reduces Hepatic Lipid Accumulation and Leads to Mild Changes in Inflammationin NASH Mice |
| title_sort | inhibition of extracellular cathepsin d reduces hepatic lipid accumulation and leads to mild changes in inflammationin nash mice |
| topic | NASH lysosomal enzymes lipoprotein metabolism inflammation extracellular cathepsin D small-compound inhibitors |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.675535/full |
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