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

Catecholamines stimulate the first step of lipolysis through protein kinase A (PKA)-dependent release of the lipid-droplet-associated protein abhydrolase domain containing 5 (ABHD5) from perilipin to coactivate the lipase adipose triglyceride lipase (ATGL). Here, we unmask a proteolytic and cardioprotective function of ABHD5. ABHD5 acts in vivo and in vitro as a serine protease that cleaves histone deacetylase 4 (HDAC4). Through the production of an amino-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 using the gene encoding HDAC4-NT does not protect against intracardiomyocyte lipid accumulation, but strikingly protects against 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 against 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 treating cardiometabolic disease.