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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
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.
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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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