Palmitate-Induced Vacuolar-Type H(+)-ATPase Inhibition Feeds Forward Into Insulin Resistance and Contractile Dysfunction

Yilin Liu, Laura K. M. Steinbusch, Miranda Nabben, Dimitris Kapsokalyvas, Marc van Zandvoort, Patrick Schonleitner, Gudrun Antoons, Peter J. Simons, Will A. Coumans, Amber Geomini, Dipanjan Chanda, Jan F. C. Glatz, Dietbert Neumann, Joost J. F. P. Luiken*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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 V-1 and the integral membrane V-0 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.

Original languageEnglish
Pages (from-to)1521-1534
Number of pages14
JournalDiabetes
Volume66
Issue number6
DOIs
Publication statusPublished - 1 Jun 2017

Keywords

  • FATTY-ACID UPTAKE
  • CARDIAC MYOCYTES
  • INDUCED LIPOTOXICITY
  • LIPID-ACCUMULATION
  • RATS
  • METABOLISM
  • GLUCOSE
  • CD36
  • DIET
  • PROTECTS

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