The lipid-droplet-associated protein ABHD5 protects the heart through proteolysis of HDAC4
| Autor: | Guenter Haemmerle, Christoph Dieterich, Tamás Fischer, Sven W. Sauer, Monika Oberer, Jens Tyedmers, Hugo A. Katus, Patrick Most, Lorenz H. Lehmann, Oliver J. Müller, Lisa Wechselberger, Barbara C. Worst, Dominik Siede, Samuel Sossalla, Kumar D Shanmukha, Friederike C. Schreiter, Zegeye H Jebessa, Chang Xu, Johannes Backs, Matthias Dewenter, Giuseppina Federico, Xue-Min Gong, Cedric Moro, Herrmann-Josef Gröne |
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| Rok vydání: | 2019 |
| Předmět: |
Endocrinology
Diabetes and Metabolism Transgene Proteolysis Article Histone Deacetylases Mice 3T3-L1 Cells Physiology (medical) Lipid droplet Gene expression Internal Medicine medicine Animals Humans Heart Failure Serine protease biology medicine.diagnostic_test Chemistry Lipid Droplets Cell Biology 1-Acylglycerol-3-Phosphate O-Acyltransferase medicine.disease HDAC4 Cell biology Repressor Proteins Neutral lipid storage disease biology.protein Perilipin Serine Proteases Protein Binding |
| Zdroj: | Nature metabolism |
| ISSN: | 2522-5812 |
| DOI: | 10.1038/s42255-019-0138-4 |
| Popis: | Catecholamines stimulate the first step of lipolysis by PKA-dependent release of the lipid droplet-associated protein ABHD5 from perilipin to co-activate the lipase ATGL. Here, we unmask a yet unrecognized proteolytic and cardioprotective function of ABHD5. ABHD5 acts in vivo and in vitro as a serine protease cleaving HDAC4. Through the production of an N-terminal polypeptide of HDAC4 (HDAC4-NT), ABHD5 inhibits MEF2-dependent gene expression and thereby controls glucose handling. ABHD5-deficiency leads to neutral lipid storage disease in mice. Cardiac-specific gene therapy of HDAC4-NT does not protect from intra-cardiomyocyte lipid accumulation but strikingly from heart failure, thereby challenging the concept of lipotoxicity-induced heart failure. ABHD5 levels are reduced in failing human hearts and murine transgenic ABHD5 expression protects from pressure-overload induced heart failure. These findings represent a conceptual advance by connecting lipid with glucose metabolism through HDAC4 proteolysis and enable new translational approaches to treat cardiometabolic disease. |
| Databáze: | OpenAIRE |
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