The lipid droplet-associated protein ABHD5 protects the heart through proteolysis of HDAC4.

Abstract

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.

• Authors: Zegeye H Jebessa, Kumar D Shanmukha, Matthias Dewenter, Lorenz H Lehmann, Chang Xu, Friederike Schreiter, Dominik Siede, Xue-Min Gong, Barbara C Worst, Giuseppina Federico, Sven W Sauer, Tamas Fischer, Lisa Wechselberger, Oliver J Müller, Samuel Sossalla, Christoph Dieterich, Patrick Most, Herrmann-Josef Gröne, Cedric Moro, Monika Oberer, Guenter Haemmerle, Hugo A Katus, Jens Tyedmers, Johannes Backs
• Journal: Nature metabolism (Nat Metab) Vol. 1 Issue 11 Pg. 1157-1167 (11 2019) ISSN: 2522-5812 [Electronic] Germany
• PMID: 31742248 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Repressor Proteins
• 1-Acylglycerol-3-Phosphate O-Acyltransferase
• ABHD5 protein, human
• Serine Proteases
• HDAC4 protein, human
• Histone Deacetylases

Topics

• 1-Acylglycerol-3-Phosphate O-Acyltransferase (metabolism)
• 3T3-L1 Cells
• Animals
• Heart Failure (prevention & control)
• Histone Deacetylases (metabolism)
• Humans
• Lipid Droplets
• Mice
• Protein Binding
• Proteolysis
• Repressor Proteins (metabolism)
• Serine Proteases (metabolism)