{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T19:45:46Z","timestamp":1790192746485,"version":"4.1.0"},"reference-count":28,"publisher":"American Diabetes Association","issue":"6","license":[{"start":{"date-parts":[[2017,5,22]],"date-time":"2017-05-22T00:00:00Z","timestamp":1495411200000},"content-version":"vor","delay-in-days":67,"URL":"http:\/\/www.diabetesjournals.org\/content\/license"}],"funder":[{"name":"Netherlands Organization of Scientific Research","award":["NWO-ZonMw grant no. 916.14.050"],"award-info":[{"award-number":["NWO-ZonMw grant no. 916.14.050"]}]},{"name":"Netherlands Organization of Scientific Research","award":["NWO-ALW grant no. 864.10.007"],"award-info":[{"award-number":["NWO-ALW grant no. 864.10.007"]}]},{"name":"Marie Curie Fellowship","award":["grant PIIF-GA-2012-332230"],"award-info":[{"award-number":["grant PIIF-GA-2012-332230"]}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,6,1]]},"abstract":"<jats:p>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 V1 and the integral membrane V0 subcomplex. 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.<\/jats:p>","DOI":"10.2337\/db16-0727","type":"journal-article","created":{"date-parts":[[2017,3,17]],"date-time":"2017-03-17T00:30:28Z","timestamp":1489710628000},"page":"1521-1534","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":70,"title":["Palmitate-Induced Vacuolar-Type H+-ATPase Inhibition Feeds Forward Into Insulin Resistance and Contractile Dysfunction"],"prefix":"10.2337","volume":"66","author":[{"given":"Yilin","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura K.M.","family":"Steinbusch","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miranda","family":"Nabben","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitris","family":"Kapsokalyvas","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"van Zandvoort","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Sch\u00f6nleitner","sequence":"additional","affiliation":[{"name":"Department of Physiology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gudrun","family":"Antoons","sequence":"additional","affiliation":[{"name":"Department of Physiology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Simons","sequence":"additional","affiliation":[{"name":"Bioceros BV, Utrecht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Will A.","family":"Coumans","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amber","family":"Geomini","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dipanjan","family":"Chanda","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan F.C.","family":"Glatz","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dietbert","family":"Neumann","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joost J.F.P.","family":"Luiken","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2017,3,16]]},"reference":[{"key":"2022031303503772600_B1","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1161\/CIRCRESAHA.107.160457","article-title":"Forgotten but not gone: the rediscovery of fatty heart, the most common unrecognized disease in America","volume":"101","author":"Szczepaniak","year":"2007","journal-title":"Circ Res"},{"key":"2022031303503772600_B2","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/s11892-008-0042-x","article-title":"The complexities of diabetic cardiomyopathy: lessons from patients and animal models","volume":"8","author":"Harmancey","year":"2008","journal-title":"Curr Diab Rep"},{"key":"2022031303503772600_B3","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1152\/physrev.00003.2009","article-title":"Membrane fatty acid transporters as regulators of lipid metabolism: implications for metabolic disease","volume":"90","author":"Glatz","year":"2010","journal-title":"Physiol Rev"},{"key":"2022031303503772600_B4","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1042\/BJ20070392","article-title":"Western diet, but not high fat diet, causes derangements of fatty acid metabolism and contractile dysfunction in the heart of Wistar rats","volume":"406","author":"Wilson","year":"2007","journal-title":"Biochem J"},{"key":"2022031303503772600_B5","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.yjmcc.2014.07.018","article-title":"High fat, high sucrose diet causes cardiac mitochondrial dysfunction due in part to oxidative post-translational modification of mitochondrial complex II","volume":"78","author":"Sverdlov","year":"2015","journal-title":"J Mol Cell Cardiol"},{"key":"2022031303503772600_B6","doi-asserted-by":"crossref","first-page":"3113","DOI":"10.2337\/diabetes.51.10.3113","article-title":"Insulin stimulates long-chain fatty acid utilization by rat cardiac myocytes through cellular redistribution of FAT\/CD36","volume":"51","author":"Luiken","year":"2002","journal-title":"Diabetes"},{"key":"2022031303503772600_B7","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.2337\/diabetes.53.7.1655","article-title":"Enhanced sarcolemmal FAT\/CD36 content and triacylglycerol storage in cardiac myocytes from obese Zucker rats","volume":"53","author":"Coort","year":"2004","journal-title":"Diabetes"},{"key":"2022031303503772600_B8","doi-asserted-by":"crossref","first-page":"1938","DOI":"10.1007\/s00125-007-0735-8","article-title":"Cardiac contractile dysfunction in insulin-resistant rats fed a high-fat diet is associated with elevated CD36-mediated fatty acid uptake and esterification","volume":"50","author":"Ouwens","year":"2007","journal-title":"Diabetologia"},{"key":"2022031303503772600_B9","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1161\/01.RES.0000264104.25265.b6","article-title":"CD36 deficiency rescues lipotoxic cardiomyopathy","volume":"100","author":"Yang","year":"2007","journal-title":"Circ Res"},{"key":"2022031303503772600_B10","doi-asserted-by":"crossref","first-page":"E618","DOI":"10.1152\/ajpendo.00106.2011","article-title":"Absence of fatty acid transporter CD36 protects against Western-type diet-related cardiac dysfunction following pressure overload in mice","volume":"301","author":"Steinbusch","year":"2011","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2022031303503772600_B11","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1152\/physrev.00024.2006","article-title":"Disordered lipid metabolism and the pathogenesis of insulin resistance","volume":"87","author":"Savage","year":"2007","journal-title":"Physiol Rev"},{"key":"2022031303503772600_B12","doi-asserted-by":"crossref","first-page":"C1549","DOI":"10.1152\/ajpcell.00334.2009","article-title":"Differential regulation of cardiac glucose and fatty acid uptake by endosomal pH and actin filaments","volume":"298","author":"Steinbusch","year":"2010","journal-title":"Am J Physiol Cell Physiol"},{"key":"2022031303503772600_B13","doi-asserted-by":"crossref","first-page":"36513","DOI":"10.1074\/jbc.M805232200","article-title":"The Ras\/cAMP\/protein kinase A pathway regulates glucose-dependent assembly of the vacuolar (H+)-ATPase in yeast","volume":"283","author":"Bond","year":"2008","journal-title":"J Biol Chem"},{"key":"2022031303503772600_B14","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1016\/j.cellsig.2011.03.003","article-title":"Structural bases of physiological functions and roles of the vacuolar H(+)-ATPase","volume":"23","author":"Ma","year":"2011","journal-title":"Cell Signal"},{"key":"2022031303503772600_B15","doi-asserted-by":"crossref","first-page":"117","DOI":"10.2174\/138920312800493142","article-title":"Targeting reversible disassembly as a mechanism of controlling V-ATPase activity","volume":"13","author":"Kane","year":"2012","journal-title":"Curr Protein Pept Sci"},{"key":"2022031303503772600_B16","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/S0022-2275(20)37241-2","article-title":"Uptake and metabolism of palmitate by isolated cardiac myocytes from adult rats: involvement of sarcolemmal proteins","volume":"38","author":"Luiken","year":"1997","journal-title":"J Lipid Res"},{"key":"2022031303503772600_B17","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1042\/BJ20120060","article-title":"CD36 inhibition prevents lipid accumulation and contractile dysfunction in rat cardiomyocytes","volume":"448","author":"Angin","year":"2012","journal-title":"Biochem J"},{"key":"2022031303503772600_B18","doi-asserted-by":"crossref","first-page":"2209","DOI":"10.1007\/s00125-010-1832-7","article-title":"Requirement for distinct vesicle-associated membrane proteins in insulin- and AMP-activated protein kinase (AMPK)-induced translocation of GLUT4 and CD36 in cultured cardiomyocytes","volume":"53","author":"Schwenk","year":"2010","journal-title":"Diabetologia"},{"key":"2022031303503772600_B19","doi-asserted-by":"crossref","first-page":"37530","DOI":"10.1074\/jbc.M112.363630","article-title":"Overexpression of vesicle-associated membrane protein (VAMP) 3, but not VAMP2, protects glucose transporter (GLUT) 4 protein translocation in an in vitro model of cardiac insulin resistance","volume":"287","author":"Schwenk","year":"2012","journal-title":"J Biol Chem"},{"key":"2022031303503772600_B20","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/j.cellsig.2007.11.007","article-title":"Identification of protein kinase D as a novel contraction-activated kinase linked to GLUT4-mediated glucose uptake, independent of AMPK","volume":"20","author":"Luiken","year":"2008","journal-title":"Cell Signal"},{"key":"2022031303503772600_B21","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1111\/j.1432-1033.1996.00564.x-i2","article-title":"The role of the intralysosomal pH in the control of autophagic proteolytic flux in rat hepatocytes","volume":"235","author":"Luiken","year":"1996","journal-title":"Eur J Biochem"},{"key":"2022031303503772600_B22","doi-asserted-by":"crossref","first-page":"2381","DOI":"10.1007\/s00125-015-3691-8","article-title":"Extremely rapid increase in fatty acid transport and intramyocellular lipid accumulation but markedly delayed insulin resistance after high fat feeding in rats","volume":"58","author":"Bonen","year":"2015","journal-title":"Diabetologia"},{"key":"2022031303503772600_B23","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1016\/j.yjmcc.2009.02.016","article-title":"Changes of intra-mitochondrial Ca2+ in adult ventricular cardiomyocytes examined using a novel fluorescent Ca2+ indicator targeted to mitochondria","volume":"46","author":"Kettlewell","year":"2009","journal-title":"J Mol Cell Cardiol"},{"key":"2022031303503772600_B24","doi-asserted-by":"crossref","first-page":"3077","DOI":"10.1073\/pnas.0630588100","article-title":"Triglyceride accumulation protects against fatty acid-induced lipotoxicity","volume":"100","author":"Listenberger","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022031303503772600_B25","doi-asserted-by":"crossref","first-page":"4081","DOI":"10.1210\/en.2015-1303","article-title":"Oleate abrogates palmitate-induced lipotoxicity and proinflammatory response in human bone marrow-derived mesenchymal stem cells and osteoblastic cells","volume":"156","author":"Gillet","year":"2015","journal-title":"Endocrinology"},{"key":"2022031303503772600_B26","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1186\/s12933-015-0237-9","article-title":"Protective role of oleic acid against cardiovascular insulin resistance and in the early and late cellular atherosclerotic process","volume":"14","author":"Perdomo","year":"2015","journal-title":"Cardiovasc Diabetol"},{"key":"2022031303503772600_B27"},{"key":"2022031303503772600_B28","doi-asserted-by":"crossref","first-page":"33850","DOI":"10.1074\/jbc.M114.590307","article-title":"S-palmitoylation and s-oleoylation of rabbit and pig sarcolipin","volume":"289","author":"Montigny","year":"2014","journal-title":"J Biol Chem"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/diabetes.diabetesjournals.org\/syndication\/doi\/10.2337\/db16-0727","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/66\/6\/1521\/535410\/db160727.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/66\/6\/1521\/535410\/db160727.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:32:48Z","timestamp":1667406768000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/66\/6\/1521\/40049\/Palmitate-Induced-Vacuolar-Type-H-ATPase"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,3,16]]},"references-count":28,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2017,3,16]]},"published-print":{"date-parts":[[2017,6,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db16-0727","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,3,16]]}}}