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

Int J Mol Sci. 2020 Feb 23;21(4):1520. doi: 10.3390/ijms21041520.

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.

Keywords: contractile function; diabetic heart; insulin resistance; lipid accumulation; vacuolar H+-ATPase.

MeSH terms

  • Animals
  • Biological Transport / drug effects
  • CD36 Antigens / metabolism
  • Endosomes / metabolism
  • Glucose / metabolism
  • Glucose Transporter Type 4 / metabolism
  • Humans
  • Induced Pluripotent Stem Cells
  • Insulin Resistance
  • Lipid Accumulation Product
  • Lipid Metabolism*
  • Lipids / adverse effects*
  • Male
  • Myocardial Contraction / drug effects
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism*
  • Phosphotransferases / metabolism
  • Rats
  • Sarcolemma / metabolism
  • Triglycerides / metabolism
  • Vacuolar Proton-Translocating ATPases / metabolism*
  • Vacuolar Proton-Translocating ATPases / pharmacology*

Substances

  • CD36 Antigens
  • Glucose Transporter Type 4
  • Lipids
  • SLC2A4 protein, human
  • Triglycerides
  • Phosphotransferases
  • Vacuolar Proton-Translocating ATPases
  • Glucose