{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T19:30:37Z","timestamp":1784921437483,"version":"3.55.0"},"reference-count":27,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,2,23]],"date-time":"2020-02-23T00:00:00Z","timestamp":1582416000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"a Dekker grant from the Dutch Heart Foundation","award":["nr. 2019T041"],"award-info":[{"award-number":["nr. 2019T041"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The diabetic heart is characterized by a shift in substrate utilization from glucose to lipids, which may ultimately lead to contractile dysfunction. This substrate shift is facilitated by increased translocation of lipid transporter CD36 (SR-B2) from endosomes to the sarcolemma resulting in increased lipid uptake. We previously showed that endosomal retention of CD36 is dependent on the proper functioning of vacuolar H+-ATPase (v-ATPase). Excess lipids trigger CD36 translocation through inhibition of v-ATPase function. Conversely, in yeast, glucose availability is known to enhance v-ATPase function, allowing us to hypothesize that glucose availability, via v-ATPase, may internalize CD36 and restore contractile function in lipid-overloaded cardiomyocytes. Increased glucose availability was achieved through (a) high glucose (25 mM) addition to the culture medium or (b) adenoviral overexpression of protein kinase-D1 (a kinase mediating GLUT4 translocation). In HL-1 cardiomyocytes, adult rat and human cardiomyocytes cultured under high-lipid conditions, each treatment stimulated v-ATPase re-assembly, endosomal acidification, endosomal CD36 retention and prevented myocellular lipid accumulation. Additionally, these treatments preserved insulin-stimulated GLUT4 translocation and glucose uptake as well as contractile force. The present findings reveal v-ATPase functions as a key regulator of cardiomyocyte substrate preference and as a novel potential treatment approach for the diabetic heart.<\/jats:p>","DOI":"10.3390\/ijms21041520","type":"journal-article","created":{"date-parts":[[2020,2,24]],"date-time":"2020-02-24T03:33:43Z","timestamp":1582515223000},"page":"1520","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Augmenting Vacuolar H+-ATPase Function Prevents Cardiomyocytes from Lipid-Overload Induced Dysfunction"],"prefix":"10.3390","volume":"21","author":[{"given":"Shujin","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Genetics &amp; Cell Biology, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200-MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Yen","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Genetics &amp; Cell Biology, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200-MD Maastricht, The Netherlands"},{"name":"Department of Clinical Genetics, Maastricht University Medical Center+, 6200-MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4316-684X","authenticated-orcid":false,"given":"Dietbert","family":"Neumann","sequence":"additional","affiliation":[{"name":"Departments of Pathology, CARIM School for Cardiovascular Diseases, Maastricht University, 6200-MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Genetics &amp; Cell Biology, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200-MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aomin","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Genetics &amp; Cell Biology, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200-MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gudrun","family":"Antoons","sequence":"additional","affiliation":[{"name":"Departments of Physiology, CARIM School for Cardiovascular Diseases, Maastricht University, 6200-MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Strzelecka","sequence":"additional","affiliation":[{"name":"Department of Genetics &amp; Cell Biology, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200-MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan F.C.","family":"Glatz","sequence":"additional","affiliation":[{"name":"Department of Genetics &amp; Cell Biology, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200-MD Maastricht, The Netherlands"},{"name":"Department of Clinical Genetics, Maastricht University Medical Center+, 6200-MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5691-1634","authenticated-orcid":false,"given":"Miranda","family":"Nabben","sequence":"additional","affiliation":[{"name":"Department of Genetics &amp; Cell Biology, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200-MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joost J.F.P.","family":"Luiken","sequence":"additional","affiliation":[{"name":"Department of Genetics &amp; Cell Biology, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200-MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,23]]},"reference":[{"key":"ref_1","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":"ref_2","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1186\/s12933-018-0762-4","article-title":"Association between insulin resistance and the development of cardiovascular disease","volume":"17","author":"Ormazabal","year":"2018","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1194\/jlr.R082933","article-title":"Dynamic role of the transmembrane glycoprotein CD36 (SR-B2) in cellular fatty acid uptake and utilization","volume":"59","author":"Glatz","year":"2018","journal-title":"J. Lipid Res."},{"key":"ref_4","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":"ref_5","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":"ref_6","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.2337\/db16-0727","article-title":"Palmitate-Induced Vacuolar-Type H(+)-ATPase Inhibition Feeds Forward Into Insulin Resistance and Contractile Dysfunction","volume":"66","author":"Liu","year":"2017","journal-title":"Diabetes"},{"key":"ref_7","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":"ref_8","first-page":"117","article-title":"Targeting reversible disassembly as a mechanism of controlling V-ATPase activity. Curr. Protein","volume":"13","author":"Kane","year":"2012","journal-title":"Pept. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1128\/MMBR.70.1.177-191.2006","article-title":"The where, when, and how of organelle acidification by the yeast vacuolar H+-ATPase. Microbiol","volume":"70","author":"Kane","year":"2006","journal-title":"Mol. Biol. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1128\/MCB.25.2.575-589.2005","article-title":"Phosphatidylinositol 3-kinase-mediated effects of glucose on vacuolar H+-ATPase assembly, translocation, and acidification of intracellular compartments in renal epithelial cells","volume":"25","author":"Sautin","year":"2005","journal-title":"Mol. Cell. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"24495","DOI":"10.1074\/jbc.M702598200","article-title":"Physical interaction between aldolase and vacuolar H+-ATPase is essential for the assembly and activity of the proton pump","volume":"282","author":"Lu","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"19236","DOI":"10.1016\/S0021-9258(19)47292-X","article-title":"Biochemical characterization of the yeast vacuolar H(+)-ATPase","volume":"264","author":"Kane","year":"1989","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s11010-005-9030-5","article-title":"Cardiac substrate uptake and metabolism in obesity and type-2 diabetes: role of sarcolemmal substrate transporters","volume":"299","author":"Coort","year":"2007","journal-title":"Mol. Cell. Biochem."},{"key":"ref_14","first-page":"331","article-title":"Glucose transporters in cardiac metabolism and hypertrophy","volume":"6","author":"Shao","year":"2011","journal-title":"Compr. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"274","DOI":"10.2337\/diab.41.3.274","article-title":"Glucose and insulin chronically regulate insulin action via different mechanisms in BC3H1 myocytes: Effects on glucose transporter gene expression","volume":"41","author":"Mayor","year":"1992","journal-title":"Diabetes"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/S0167-4889(01)00133-1","article-title":"Factor (s) released by glucose-deprived astrocytes enhance glucose transporter expression and activity in rat brain endothelial cells","volume":"1540","author":"Morchoisne","year":"2001","journal-title":"Biochim. Biophys. Acta-Mol. Cell Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5871","DOI":"10.1074\/jbc.M111.281881","article-title":"Protein kinase D1 is essential for contraction-induced glucose uptake but is not involved in fatty acid uptake into cardiomyocytes","volume":"287","author":"Dirkx","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.yjmcc.2014.08.017","article-title":"Protein kinase-D1 overexpression prevents lipid-induced cardiac insulin resistance","volume":"76","author":"Dirkx","year":"2014","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8017","DOI":"10.1073\/pnas.91.17.8017","article-title":"gp160, a tissue-specific marker for insulin-activated glucose transport","volume":"91","author":"Kandror","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1152\/physiol.00037.2010","article-title":"Protein kinase D signaling: multiple biological functions in health and disease","volume":"26","author":"Rozengurt","year":"2011","journal-title":"Physiology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1038\/ncb1648","article-title":"SNARE proteins mediate fusion between cytosolic lipid droplets and are implicated in insulin sensitivity","volume":"9","author":"Andersson","year":"2007","journal-title":"Nat. Cell Biol."},{"key":"ref_22","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":"ref_23","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.yjmcc.2012.11.005","article-title":"Overexpression of AMP-activated protein kinase or protein kinase D prevents lipid-induced insulin resistance in cardiomyocytes","volume":"55","author":"Steinbusch","year":"2013","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_24","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":"ref_25","doi-asserted-by":"crossref","first-page":"E225","DOI":"10.1152\/ajpendo.00655.2013","article-title":"Calcium signaling recruits substrate transporters GLUT4 and CD36 to the sarcolemma without increasing cardiac substrate uptake","volume":"307","author":"Angin","year":"2014","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_26","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":"ref_27","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"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/4\/1520\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:01:04Z","timestamp":1760173264000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/4\/1520"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,23]]},"references-count":27,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,2]]}},"alternative-id":["ijms21041520"],"URL":"https:\/\/doi.org\/10.3390\/ijms21041520","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,23]]}}}