title: Palmitate-Induced Vacuolar-Type H+-ATPase Inhibition Feeds Forward Into Insulin Resistance and Contractile Dysfunction.
abstract: Dietary fat overconsumption leads to myocardial lipid accumulation through mechanisms that are incompletely resolved. Previously, we identified increased translocation of the fatty acid transporter CD36 from its endosomal storage compartment to the sarcolemma as the primary mechanism of excessive myocellular lipid import. Here, we show that increased CD36 translocation is caused by alkalinization of endosomes resulting from inhibition of proton pumping activity of vacuolar-type H+-ATPase (v-ATPase). Endosomal alkalinization was observed in hearts from rats fed a lard-based high-fat diet and in rodent and human cardiomyocytes upon palmitate overexposure, and appeared as an early lipid-induced event preceding the onset of insulin resistance. Either genetic or pharmacological inhibition of v-ATPase in cardiomyocytes exposed to low palmitate concentrations reduced insulin sensitivity and cardiomyocyte contractility, which was rescued by CD36 silencing. The mechanism of palmitate-induced v-ATPase inhibition involved its dissociation into two parts: the cytosolic V1and the integral membrane V0subcomplex. Interestingly, oleate also inhibits v-ATPase function, yielding triacylglycerol accumulation but not insulin resistance. In conclusion, lipid oversupply increases CD36-mediated lipid uptake that directly impairs v-ATPase function. This feeds forward to enhanced CD36 translocation and further increased lipid uptake. In the case of palmitate, its accelerated uptake ultimately precipitates into cardiac insulin resistance and contractile dysfunction.
authors.affiliation: Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands.
authors.forename: Yilin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands.
authors.forename: Laura K M
authors.initials: LKM
authors.lastname: Steinbusch
authors.affiliation: Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands.
authors.forename: Miranda
authors.initials: M
authors.lastname: Nabben
authors.affiliation: Department of Molecular Cell Biology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Kapsokalyvas
authors.affiliation: Department of Molecular Cell Biology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands.
authors.forename: Marc
authors.initials: M
authors.lastname: van Zandvoort
authors.affiliation: Department of Physiology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schönleitner
authors.affiliation: Department of Physiology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Antoons
authors.affiliation: Bioceros BV, Utrecht, the Netherlands.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Simons
authors.affiliation: Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands.
authors.forename: Will A
authors.initials: WA
authors.lastname: Coumans
authors.affiliation: Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands.
authors.forename: Amber
authors.initials: A
authors.lastname: Geomini
authors.affiliation: Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands.
authors.forename: Dipanjan
authors.initials: D
authors.lastname: Chanda
authors.affiliation: Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands.
authors.forename: Jan F C
authors.initials: JFC
authors.lastname: Glatz
authors.affiliation: Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands.
authors.forename: Dietbert
authors.initials: D
authors.lastname: Neumann
authors.affiliation: Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands j.luiken@maastrichtuniversity.nl.
authors.forename: Joost J F P
authors.initials: JJFP
authors.lastname: Luiken
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018955:CD36 Antigens / Q000378:metabolism*; D002250:Carbon Radioisotopes; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000378:metabolism; D059305:Diet, High-Fat; D011992:Endosomes / Q000187:drug effects* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006321:Heart / Q000187:drug effects*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057026:Induced Pluripotent Stem Cells; D007333:Insulin Resistance; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics; D010168:Palmitates / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D014280:Triglycerides / Q000378:metabolism; D014316:Tritium; D020107:Troponin T / Q000235:genetics; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors*
chemical_list: D018955:CD36 Antigens; D002250:Carbon Radioisotopes; D010168:Palmitates; D012333:RNA, Messenger; D014280:Triglycerides; D020107:Troponin T; D014316:Tritium; D003847:Deoxyglucose; D025262:Vacuolar Proton-Translocating ATPases; D018995:Myosin Heavy Chains; D005947:Glucose