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Article

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

1
Department of Genetics & Cell Biology, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200-MD Maastricht, The Netherlands
2
Department of Clinical Genetics, Maastricht University Medical Center+, 6200-MD Maastricht, The Netherlands
3
Departments of Pathology, CARIM School for Cardiovascular Diseases, Maastricht University, 6200-MD Maastricht, The Netherlands
4
Departments of Physiology, CARIM School for Cardiovascular Diseases, Maastricht University, 6200-MD Maastricht, The Netherlands
*
Author to whom correspondence should be addressed.
This author shares last author.
Int. J. Mol. Sci. 2020, 21(4), 1520; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041520
Received: 16 January 2020 / Revised: 17 February 2020 / Accepted: 21 February 2020 / Published: 23 February 2020
(This article belongs to the Collection Feature Papers in Molecular Biology)
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. View Full-Text
Keywords: vacuolar H+-ATPase; lipid accumulation; insulin resistance; contractile function; diabetic heart vacuolar H+-ATPase; lipid accumulation; insulin resistance; contractile function; diabetic heart
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MDPI and ACS Style

Wang, S.; Wong, L.-Y.; Neumann, D.; Liu, Y.; Sun, A.; Antoons, G.; Strzelecka, A.; Glatz, J.F.C.; Nabben, M.; Luiken, J.J.F.P. Augmenting Vacuolar H+-ATPase Function Prevents Cardiomyocytes from Lipid-Overload Induced Dysfunction. Int. J. Mol. Sci. 2020, 21, 1520. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041520

AMA Style

Wang S, Wong L-Y, Neumann D, Liu Y, Sun A, Antoons G, Strzelecka A, Glatz JFC, Nabben M, Luiken JJFP. Augmenting Vacuolar H+-ATPase Function Prevents Cardiomyocytes from Lipid-Overload Induced Dysfunction. International Journal of Molecular Sciences. 2020; 21(4):1520. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041520

Chicago/Turabian Style

Wang, Shujin, Li-Yen Wong, Dietbert Neumann, Yilin Liu, Aomin Sun, Gudrun Antoons, Agnieszka Strzelecka, Jan F.C. Glatz, Miranda Nabben, and Joost J.F.P. Luiken 2020. "Augmenting Vacuolar H+-ATPase Function Prevents Cardiomyocytes from Lipid-Overload Induced Dysfunction" International Journal of Molecular Sciences 21, no. 4: 1520. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041520

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