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

• Main Authors: 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
• Format: Article
• Language: English
• Published: MDPI AG 2020-02-01
• Series: International Journal of Molecular Sciences
• Subjects: vacuolar h⁺-atpase; lipid accumulation; insulin resistance; contractile function; diabetic heart
• Online Access: https://www.mdpi.com/1422-0067/21/4/1520

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.