1. The lipid droplet-associated protein ABHD5 protects the heart through proteolysis of HDAC4.
- Author
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Jebessa ZH, Shanmukha KD, Dewenter M, Lehmann LH, Xu C, Schreiter F, Siede D, Gong XM, Worst BC, Federico G, Sauer SW, Fischer T, Wechselberger L, Müller OJ, Sossalla S, Dieterich C, Most P, Gröne HJ, Moro C, Oberer M, Haemmerle G, Katus HA, Tyedmers J, and Backs J
- Subjects
- 3T3-L1 Cells, Animals, Heart Failure prevention & control, Humans, Mice, Protein Binding, Proteolysis, Serine Proteases metabolism, 1-Acylglycerol-3-Phosphate O-Acyltransferase metabolism, Histone Deacetylases metabolism, Lipid Droplets, Repressor Proteins metabolism
- 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., Competing Interests: Competing Interests Statement Z.H.J., L.H.L, O.J.M, H.A.K. and J.B. filed a patent on HDAC4-NT and ABHD5 gene therapy (US9914912B2). All other authors declare no conflict of interest.
- Published
- 2019
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