ItemArticle

Inhibiting extracellular cathepsin d reduces hepatic steatosis in spraguedawley rats y

Title
Inhibiting extracellular cathepsin d reduces hepatic steatosis in spraguedawley rats y
Creator
Khurana P.; Yadati T.; Goyal S.; Dolas A.; Houben T.; Oligschlaeger Y.; Agarwal A.K.; Kulkarni A.; Shiri-Sverdlov R.
Description
Dietary and lifestyle changes are leading to an increased occurrence of non-alcoholic fatty liver disease (NAFLD). Using a hyperlipidemic murine model for non-alcoholic steatohepatitis (NASH), we have previously demonstrated that the lysosomal protease cathepsin D (CTSD) is involved with lipid dysregulation and inflammation. However, despite identifying CTSD as a major player in NAFLD pathogenesis, the specific role of extracellular CTSD in NAFLD has not yet been investigated. Given that inhibition of intracellular CTSD is highly unfavorable due to its fundamental physiological function, we here investigated the impact of a highly specific and potent small-molecule inhibitor of extracellular CTSD (CTD-002) in the context of NAFLD. Treatment of bone marrow-derived macrophages with CTD-002, and incubation of hepatic HepG2 cells with a conditioned medium derived from CTD-002-treated macrophages, resulted in reduced levels of inflammation and improved cholesterol metabolism. Treatment with CTD-002 improved hepatic steatosis in high fat diet-fed rats. Additionally, plasma levels of insulin and hepatic transaminases were significantly reduced upon CTD-002 administration. Collectively, our findings demonstrate for the first time that modulation of extracellular CTSD can serve as a novel therapeutic modality for NAFLD. 2019 by the authors.
Source
Biomolecules, Vol-9, No. 5
Date
2019-01-01
Publisher
MDPI AG
Subject
Extracellular cathepsin D; Lysosomal enzyme; NAFLD; Small-molecule inhibitor
Coverage
Khurana P., Aten Porus Lifesciences Pvt Ltd., Bengaluru, 560068, Karnataka, India; Yadati T., Department of Molecular Genetics, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, ER 6229, Netherlands; Goyal S., Aten Porus Lifesciences Pvt Ltd., Bengaluru, 560068, Karnataka, India; Dolas A., Aten Porus Lifesciences Pvt Ltd., Bengaluru, 560068, Karnataka, India; Houben T., Department of Molecular Genetics, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, ER 6229, Netherlands; Oligschlaeger Y., Department of Molecular Genetics, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, ER 6229, Netherlands; Agarwal A.K., Department of Chemistry, CHRIST (Deemed to be University), Bengaluru, 560029, Karnataka, India; Kulkarni A., Aten Porus Lifesciences Pvt Ltd., Bengaluru, 560068, Karnataka, India, Avaliv Therapeutics, Naples, 34120, FL, United States; Shiri-Sverdlov R., Department of Molecular Genetics, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, ER 6229, Netherlands
Rights
All Open Access; Gold Open Access; Green Open Access
Relation
ISSN: 2218273X; PubMed ID: 31060228
Format
Online
Language
English
Type
Article

Collection

Articles

Citation

Khurana P.; Yadati T.; Goyal S.; Dolas A.; Houben T.; Oligschlaeger Y.; Agarwal A.K.; Kulkarni A.; Shiri-Sverdlov R., “Inhibiting extracellular cathepsin d reduces hepatic steatosis in spraguedawley rats y,” CHRIST (Deemed To Be University) Institutional Repository, accessed February 24, 2025, https://archives.christuniversity.in/items/show/16679.

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