Small-Molecule Inhibitors Targeting Lipolysis in Human Adipocytes
[Image: see text] Chronically elevated circulating fatty acid levels promote lipid accumulation in nonadipose tissues and cause lipotoxicity. Adipose triglyceride lipase (ATGL) critically determines the release of fatty acids from white adipose tissue, and accumulating evidence suggests that inactiv...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9011347/ https://www.ncbi.nlm.nih.gov/pubmed/35362954 http://dx.doi.org/10.1021/jacs.1c10836 |
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author | Grabner, Gernot F. Guttenberger, Nikolaus Mayer, Nicole Migglautsch-Sulzer, Anna K. Lembacher-Fadum, Christian Fawzy, Nermeen Bulfon, Dominik Hofer, Peter Züllig, Thomas Hartig, Lennart Kulminskaya, Natalia Chalhoub, Gabriel Schratter, Margarita Radner, Franz P. W. Preiss-Landl, Karina Masser, Sarah Lass, Achim Zechner, Rudolf Gruber, Karl Oberer, Monika Breinbauer, Rolf Zimmermann, Robert |
author_facet | Grabner, Gernot F. Guttenberger, Nikolaus Mayer, Nicole Migglautsch-Sulzer, Anna K. Lembacher-Fadum, Christian Fawzy, Nermeen Bulfon, Dominik Hofer, Peter Züllig, Thomas Hartig, Lennart Kulminskaya, Natalia Chalhoub, Gabriel Schratter, Margarita Radner, Franz P. W. Preiss-Landl, Karina Masser, Sarah Lass, Achim Zechner, Rudolf Gruber, Karl Oberer, Monika Breinbauer, Rolf Zimmermann, Robert |
author_sort | Grabner, Gernot F. |
collection | PubMed |
description | [Image: see text] Chronically elevated circulating fatty acid levels promote lipid accumulation in nonadipose tissues and cause lipotoxicity. Adipose triglyceride lipase (ATGL) critically determines the release of fatty acids from white adipose tissue, and accumulating evidence suggests that inactivation of ATGL has beneficial effects on lipotoxicity-driven disorders including insulin resistance, steatohepatitis, and heart disease, classifying ATGL as a promising drug target. Here, we report on the development and biological characterization of the first small-molecule inhibitor of human ATGL. This inhibitor, designated NG-497, selectively inactivates human and nonhuman primate ATGL but not structurally and functionally related lipid hydrolases. We demonstrate that NG-497 abolishes lipolysis in human adipocytes in a dose-dependent and reversible manner. The combined analysis of mouse- and human-selective inhibitors, chimeric ATGL proteins, and homology models revealed detailed insights into enzyme–inhibitor interactions. NG-497 binds ATGL within a hydrophobic cavity near the active site. Therein, three amino acid residues determine inhibitor efficacy and species selectivity and thus provide the molecular scaffold for selective inhibition. |
format | Online Article Text |
id | pubmed-9011347 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-90113472022-04-18 Small-Molecule Inhibitors Targeting Lipolysis in Human Adipocytes Grabner, Gernot F. Guttenberger, Nikolaus Mayer, Nicole Migglautsch-Sulzer, Anna K. Lembacher-Fadum, Christian Fawzy, Nermeen Bulfon, Dominik Hofer, Peter Züllig, Thomas Hartig, Lennart Kulminskaya, Natalia Chalhoub, Gabriel Schratter, Margarita Radner, Franz P. W. Preiss-Landl, Karina Masser, Sarah Lass, Achim Zechner, Rudolf Gruber, Karl Oberer, Monika Breinbauer, Rolf Zimmermann, Robert J Am Chem Soc [Image: see text] Chronically elevated circulating fatty acid levels promote lipid accumulation in nonadipose tissues and cause lipotoxicity. Adipose triglyceride lipase (ATGL) critically determines the release of fatty acids from white adipose tissue, and accumulating evidence suggests that inactivation of ATGL has beneficial effects on lipotoxicity-driven disorders including insulin resistance, steatohepatitis, and heart disease, classifying ATGL as a promising drug target. Here, we report on the development and biological characterization of the first small-molecule inhibitor of human ATGL. This inhibitor, designated NG-497, selectively inactivates human and nonhuman primate ATGL but not structurally and functionally related lipid hydrolases. We demonstrate that NG-497 abolishes lipolysis in human adipocytes in a dose-dependent and reversible manner. The combined analysis of mouse- and human-selective inhibitors, chimeric ATGL proteins, and homology models revealed detailed insights into enzyme–inhibitor interactions. NG-497 binds ATGL within a hydrophobic cavity near the active site. Therein, three amino acid residues determine inhibitor efficacy and species selectivity and thus provide the molecular scaffold for selective inhibition. American Chemical Society 2022-04-01 2022-04-13 /pmc/articles/PMC9011347/ /pubmed/35362954 http://dx.doi.org/10.1021/jacs.1c10836 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Grabner, Gernot F. Guttenberger, Nikolaus Mayer, Nicole Migglautsch-Sulzer, Anna K. Lembacher-Fadum, Christian Fawzy, Nermeen Bulfon, Dominik Hofer, Peter Züllig, Thomas Hartig, Lennart Kulminskaya, Natalia Chalhoub, Gabriel Schratter, Margarita Radner, Franz P. W. Preiss-Landl, Karina Masser, Sarah Lass, Achim Zechner, Rudolf Gruber, Karl Oberer, Monika Breinbauer, Rolf Zimmermann, Robert Small-Molecule Inhibitors Targeting Lipolysis in Human Adipocytes |
title | Small-Molecule
Inhibitors Targeting Lipolysis in Human
Adipocytes |
title_full | Small-Molecule
Inhibitors Targeting Lipolysis in Human
Adipocytes |
title_fullStr | Small-Molecule
Inhibitors Targeting Lipolysis in Human
Adipocytes |
title_full_unstemmed | Small-Molecule
Inhibitors Targeting Lipolysis in Human
Adipocytes |
title_short | Small-Molecule
Inhibitors Targeting Lipolysis in Human
Adipocytes |
title_sort | small-molecule
inhibitors targeting lipolysis in human
adipocytes |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9011347/ https://www.ncbi.nlm.nih.gov/pubmed/35362954 http://dx.doi.org/10.1021/jacs.1c10836 |
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