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Inhibition of Extracellular Cathepsin D Reduces Hepatic Lipid Accumulation and Leads to Mild Changes in Inflammationin NASH Mice

BACKGROUND & AIMS: The 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...

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Autores principales: Yadati, Tulasi, Houben, Tom, Bitorina, Albert, Oligschlaeger, Yvonne, Gijbels, Marion J., Mohren, Ronny, Lütjohann, Dieter, Khurana, Princy, Goyal, Sandeep, Kulkarni, Aditya, Theys, Jan, Cillero-Pastor, Berta, Shiri-Sverdlov, Ronit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323051/
https://www.ncbi.nlm.nih.gov/pubmed/34335574
http://dx.doi.org/10.3389/fimmu.2021.675535
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author Yadati, Tulasi
Houben, Tom
Bitorina, Albert
Oligschlaeger, Yvonne
Gijbels, Marion J.
Mohren, Ronny
Lütjohann, Dieter
Khurana, Princy
Goyal, Sandeep
Kulkarni, Aditya
Theys, Jan
Cillero-Pastor, Berta
Shiri-Sverdlov, Ronit
author_facet Yadati, Tulasi
Houben, Tom
Bitorina, Albert
Oligschlaeger, Yvonne
Gijbels, Marion J.
Mohren, Ronny
Lütjohann, Dieter
Khurana, Princy
Goyal, Sandeep
Kulkarni, Aditya
Theys, Jan
Cillero-Pastor, Berta
Shiri-Sverdlov, Ronit
author_sort Yadati, Tulasi
collection PubMed
description BACKGROUND & AIMS: The 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. METHODS: Low-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. RESULTS: Ldlr-/- 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. CONCLUSION: We 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.
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spelling pubmed-83230512021-07-31 Inhibition of Extracellular Cathepsin D Reduces Hepatic Lipid Accumulation and Leads to Mild Changes in Inflammationin NASH Mice Yadati, Tulasi Houben, Tom Bitorina, Albert Oligschlaeger, Yvonne Gijbels, Marion J. Mohren, Ronny Lütjohann, Dieter Khurana, Princy Goyal, Sandeep Kulkarni, Aditya Theys, Jan Cillero-Pastor, Berta Shiri-Sverdlov, Ronit Front Immunol Immunology BACKGROUND & AIMS: The 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. METHODS: Low-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. RESULTS: Ldlr-/- 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. CONCLUSION: We 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. Frontiers Media S.A. 2021-07-16 /pmc/articles/PMC8323051/ /pubmed/34335574 http://dx.doi.org/10.3389/fimmu.2021.675535 Text en Copyright © 2021 Yadati, Houben, Bitorina, Oligschlaeger, Gijbels, Mohren, Lütjohann, Khurana, Goyal, Kulkarni, Theys, Cillero-Pastor and Shiri-Sverdlov https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Yadati, Tulasi
Houben, Tom
Bitorina, Albert
Oligschlaeger, Yvonne
Gijbels, Marion J.
Mohren, Ronny
Lütjohann, Dieter
Khurana, Princy
Goyal, Sandeep
Kulkarni, Aditya
Theys, Jan
Cillero-Pastor, Berta
Shiri-Sverdlov, Ronit
Inhibition of Extracellular Cathepsin D Reduces Hepatic Lipid Accumulation and Leads to Mild Changes in Inflammationin NASH Mice
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 Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323051/
https://www.ncbi.nlm.nih.gov/pubmed/34335574
http://dx.doi.org/10.3389/fimmu.2021.675535
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