Augmenting Vacuolar H+-ATPase Function Prevents Cardiomyocytes from Lipid-Overload Induced Dysfunction

Shujin Wang, Li-Yen Wong, Dietbert Neumann, Yilin Liu, Aomin Sun, Gudrun Antoons, Agnieszka Strzelecka, Jan F. C. Glatz, Miranda Nabben, Joost J. F. P. Luiken*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

11 Citations (Web of Science)

Abstract

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.

Original languageEnglish
Article number1520
Number of pages16
JournalInternational journal of molecular sciences
Volume21
Issue number4
DOIs
Publication statusPublished - Feb 2020

Keywords

  • vacuolar H+-ATPase
  • lipid accumulation
  • insulin resistance
  • contractile function
  • diabetic heart
  • ACTIVATED PROTEIN-KINASE
  • FATTY-ACID UPTAKE
  • INSULIN-RESISTANCE
  • CARDIAC MYOCYTES
  • GLUCOSE
  • OVEREXPRESSION
  • TRANSLOCATION
  • METABOLISM
  • CD36
  • ACIDIFICATION

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