Vacuolar-type H+-ATPase as target to modulate fatty acid uptake into the heart: Application for treatment of diabetic cardiomyopathy

Summary

Lipid-induced heart failure is the main mortality cause in type-2 diabetic patients. Cardiac lipid uptake is regulated by the distribution of the long-chain fatty acid (LCFA) membrane transporter CD36 between intracellular acidic compartments (endosomes) and the sarcolemma. Upon lipid oversupply resulting from dietary lipid intake, CD36 translocates from endosomes to the sarcolemma to increase LCFA uptake, thereby initiating a vicious cycle of cardiac lipid accumulation and lipid-induced insulin resistance, ultimately leading to cardiac dysfunction. We recently discovered that intracellular CD36 retention requires proper endosomal acidification maintained by vacuolar H+-ATPase (v-ATPase; also named endosomal proton pump). V-ATPase consists of a membrane-bound V0-subcomplex and a cytoplasm-exposed V1-subcomplex. Lipid (palmitate) oversupply causes dissociation of the V1-subcomplex and its migration into the cytoplasm. This impairs v-ATPase activity, thus limits endosomal acidification, causing increased CD36 translocation to the sarcolemma, ultimately promoting lipid-induced cardiac dysfunction. Recent evidence suggests that increased glucose uptake (via glycolysis) stabilizes the V0/V1 complex (in yeast), whereas palmitoylation induces V0/V1 disassembly (in neuronal cells). We hypothesize that both glucose and LCFA availability inside cardiomyocytes regulate v-ATPase disassembly/re-assembly via distinct mechanisms, thereby controlling CD36 translocation. Our objectives are to: (1) Investigate the role of palmitoylation in LCFA-induced v-ATPase disassembly; (2) Delineate mechanisms inducing v-ATPase re-assembly, focussing on glycolysis; (3) Verify lipid-induced v-ATPase disassembly in palmitate-overexposed human stem cell-derived cardiomyocytes and in cardiac biopsies from diabetic human subjects. Together, this fundamental research is expected to yield detailed insight into the regulation of cellular LCFA uptake and uncover novel treatment strategies combatting diabetic cardiomyopathy.

Details

Project number

ALWOP.367

Main applicant

Dr. J.J.F.P. Luiken

Affiliated with

Maastricht University, Maastricht UMC+, CARIM - School for Cardiovascular Diseases

Duration

01/09/2018 to 28/02/2022

Budget

EUR254,474