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Small-Molecule Inhibitors Targeting Lipolysis in Human Adipocytes.

ABSTRACT: 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.

SUBMITTER: Grabner GF

PROVIDER: S-EPMC9011347 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Small-Molecule Inhibitors Targeting Lipolysis in Human Adipocytes.

Grabner Gernot F GF Guttenberger Nikolaus N Mayer Nicole N Migglautsch-Sulzer Anna K AK Lembacher-Fadum Christian C Fawzy Nermeen N Bulfon Dominik D Hofer Peter P Züllig Thomas T Hartig Lennart L Kulminskaya Natalia N Chalhoub Gabriel G Schratter Margarita M Radner Franz P W FPW Preiss-Landl Karina K Masser Sarah S Lass Achim A Zechner Rudolf R Gruber Karl K Oberer Monika M Breinbauer Rolf R Zimmermann Robert R

Journal of the American Chemical Society 20220401 14

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 an ...[more]

PMID: 35362954

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Dataset Information

Small-Molecule Inhibitors Targeting Lipolysis in Human Adipocytes.

Publications

Small-Molecule Inhibitors Targeting Lipolysis in Human Adipocytes.

Similar Datasets

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