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.
Original language | English |
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Article number | 1520 |
Number of pages | 16 |
Journal | International journal of molecular sciences |
Volume | 21 |
Issue number | 4 |
DOIs | |
Publication status | Published - Feb 2020 |
Keywords
- vacuolar H+-ATPase
- lipid accumulation
- insulin resistance
- contractile function
- diabetic heart
- ACTIVATED PROTEIN-KINASE
- FATTY-ACID UPTAKE
- INSULIN-RESISTANCE
- CARDIAC MYOCYTES
- GLUCOSE
- OVEREXPRESSION
- TRANSLOCATION
- METABOLISM
- CD36
- ACIDIFICATION