biostudies-literatureJebessa ZHBundesministerium für Bildung und ForschungAustrian Science Fund FWFDeutsche Forschungsgemeinschaft1157-1167https://www.ebi.ac.uk/biostudies/studies/S-EPMC6861130biostudies-literatureUnknown1(11)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 <i>in vivo</i> and <i>in vitro</i> 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.Nature metabolismThe lipid droplet-associated protein ABHD5 protects the heart through proteolysis of HDAC4.PMC6861130BA 2258/2-1F 7303DZHKBA 2258/9-1F73 SFBP 24857Fischer TSiede DMost PDewenter MHaemmerle GGrone HJMuller OJXu CJebessa ZHWorst BCDieterich CLehmann LHShanmukha KDBacks JWechselberger LKatus HAFederico GMoro CGong XMSossalla SOberer MSauer SWTyedmers JSchreiter FfalseThe lipid droplet-associated protein ABHD5 protects the heart through proteolysis of HDAC4.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 <i>in vivo</i> and <i>in vitro</i> 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.2019-01-01T00:00:00Z2019 Nov2024-11-09T03:23:02.751Z2020-05-22T20:08:27ZS-EPMC68611303174224810.1038/s42255-019-0138-4