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

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

doi:10.3390/ijms21041520

Shujin Wang, Miranda Nabben + Show 8 more

Open Access

https://doi.org/10.3390/ijms21041520

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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.

Highlights

The healthy myocardium maintains a balance between glucose and lipids as a nutrient source
The diabetic heart is characterized by a shift in substrate utilization from glucose to lipids, resulting in insulin resistance and impaired cardiac contractile function [1,2]
Studies in high-fat diet fed rats demonstrated that increased myocellular CD36 abundance at the sarcolemma of cardiomyocytes, as well as increased long chain fatty acid (LCFA) uptake and decreased insulin signaling was due to loss of endosomal acidification, thereby providing a novel link between v-ATPase inhibition and decreased cardiac function in the lipid-overloaded diabetic heart [6]

Summary

Introduction

The healthy myocardium maintains a balance between glucose and lipids as a nutrient source. At the level of cardiomyocytes, this is accompanied by increased abundance of CD36, the predominant cardiac lipid transporter, at the sarcolemma [3]. CD36 stimulates long chain fatty acid (LCFA) uptake via reversible translocation from the endosomes to the sarcolemma upon hormonal or mechanical stimuli [1]. Upon long-term overexposure of the heart to lipids, CD36 chronically translocates to the sarcolemma, initiating a vicious cycle of increased lipid uptake and lipid-induced insulin resistance, leading to cardiac dysfunction [4]. Studies in high-fat diet fed rats demonstrated that increased myocellular CD36 abundance at the sarcolemma of cardiomyocytes, as well as increased LCFA uptake and decreased insulin signaling was due to loss of endosomal acidification, thereby providing a novel link between v-ATPase inhibition and decreased cardiac function in the lipid-overloaded diabetic heart [6]. V-ATPase inhibition underlies increased CD36 translocation to the sarcolemma and subsequent development of lipid-induced cardiomyopathy

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