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

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ID: 100644
2020
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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.
Reference Key
wang2020augmentinginternational Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
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
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Journal International journal of molecular sciences
Year 2020
DOI
E1520
URL
https://www.mdpi.com/1422-0067/21/4/1520
Keywords
insulin resistance lipid accumulation contractile function diabetic heart vacuolar h+-atpase

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