Subcellular Recycling of CD36 as Target to Rescue Lipid Overload‐induced Myocardial Contractile Dysfunction

Abstract

BackgroundDisturbances in cardiac metabolism are increasingly being recognized as crucial drivers of the development and progression of heart disease and ageing. In particular, lipid overload due to Western life style or obesity eventually elicits cardiac insulin resistance and contractile dysfunction (referred to as diabetic cardiomyopathy). As a result, there is an urgent unmet clinical need for treatments that can directly target metabolic defects in heart failure. The transmembrane protein CD36 both facilitates myocardial fatty acid uptake and regulates this process by its subcellular recycling between endosomes and the sarcolemma. In turn, CD36 recycling was recently found to be regulated by instantaneous changes in activity of vacuolar‐type H+‐ATPase (v‐ATPase) in the endosomes, as controlled by rapid assembly and disassembly of V0 and V1 subunits of v‐ATPase.HypothesisRegulation of subcellular recycling of CD36 by v‐ATPase is an effective target for metabolic modulation therapy in diabetic cardiomyopathy.ObjectiveTo investigate whether manipulating v‐ATPase activity, and thereby CD36 recycling, rescues insulin resistance and contractile dysfunction of the diabetic heart.MethodsIsolated rat cardiomyocytes and human (iPSC‐derived and differentiated) cardiomyocytes were treated with bafilomycin (v‐ATPase inhibitor) or energy substrates, i.e., fatty acids, glucose, amino acids (AAs) or b‐hydroxy butyrate (HB). In addition, rats in vivo were treated with AAs. v‐ATPase activity (assembly status), substrate transporter localization (CD36 and glucose transporter GLUT4) and fatty acid and glucose uptake rates (in absence or presence of insulin) were measured.ResultsIn rat and human cardiomyocytes both bafilomycin, excess palmitate and HB inhibited v‐ATPase activity, increased sarcolemmal CD36 content, increased fatty acid uptake and lipid accumulation, and elicited contractile dysfunction. However, the latter could be rescued by excess glucose or AAs, concomitant with in each case a similar increase of v‐ATPase activity and CD36 reinternalization, while glucose uptake was increased. Hence, v‐ATPase activity/assembly is required for retention of CD36 in endosomes. In case of AAs, v‐ATPase (re)assembly was dependent on mTORC1 activation. In high fat diet‐fed rats, AAs had a similar beneficial action at the myocellular level.ConclusionsThese novel data suggest a pivotal role for endosomal v‐ATPase activity and subcellular CD36 recycling in determining myocardial substrate preference, in particular fatty acids versus glucose. The molecular mechanism involves assembly/disassembly of the V0 and V1 subunits of v‐ATPase, allowing a rapid change in activity. Lipid accumulation and contractile dysfunction in diabetic cardiomyopathy is aggravated by HB but resolved by AAs.PerspectiveSpecific amino acids acting through v‐ATPase reassembly may be an effective nutraceutical therapy in diabetic cardiomyopathy, but ketone bodies should not be used as these may aggravate lipid accumulation and contractile dysfunction.