Metabolic Modulation to Treat Cardiac Diseases: Role for Membrane Substrate Transporters

Jan Glatz,Miranda Nabben,Joost Luiken

doi:10.29245/2578-3025/2020/1.1187

Abstract

There is growing recognition of the importance and multiple roles of substrate energy metabolism in both cardiac health and disease. Cardiac diseases are frequently accompanied by altered myocardial metabolism, while chronic changes in the type of myocardial substrate utilization are found to elicit cardiac contractile dysfunction. Examples are the increased glucose utilization, at the expense of fatty acids, in cardiac hypertrophy and ischemic heart failure, and the increased fatty acid utilization, at the expense of glucose, in obesity and diabetes-related cardiac dysfunction. Modulation of cardiac metabolism has emerged as a suitable therapeutic intervention in cardiac disease. Insights obtained during the past decade have revealed sarcolemmal substrate transport, facilitated by CD36 for fatty acids and by GLUT4 for glucose, to represent the main rate-governing kinetic step of substrate utilization, over-ruling intracellular sites of flux regulation. This suggests that manipulating the presence of substrate transporters in the sarcolemma may be an effective approach for metabolic modulation therapy. The present mini-review provides a short summary of the functioning of substrate transporters CD36 and GLUT4 in the heart, and discusses their application as targets for metabolic intervention.

Highlights

Cardiac energy metabolism is increasingly being recognized to play multiple roles in the cardiovascular system
The utilization of longchain fatty acids, which form the predominant substrate for myocardial energy provision, is primarily determined by the rate of myocellular fatty acid uptake as facilitated by the presence of the fatty acid transporter cluster-ofdifferentiation 36 (CD36) (SR-B2) in the sarcolemma, and overrules the regulation of mitochondrial oxidation of fatty acids by the enzyme carnitine palmitoyltransferase-1 (CPT-1)[12]
Some VesicleAssociated Membrane Protein (VAMP) isoforms are required for both CD36 and Glucose Transporter-4 (GLUT4) translocation, others are involved in only CD36 or GLUT4 trafficking[36]. These findings suggest the possibility of using VAMPs to manipulate CD36-mediated fatty acid uptake without affecting GLUT4-mediated glucose uptake[36]

Summary

Introduction

Cardiac energy metabolism is increasingly being recognized to play multiple roles in the cardiovascular system. Insights obtained during the past decade have revealed sarcolemmal substrate transport, facilitated by CD36 for fatty acids and by GLUT4 for glucose, to represent the main rate-governing kinetic step of substrate utilization, over-ruling intracellular sites of flux regulation. This suggests that manipulating the presence of substrate transporters in the sarcolemma may be an effective approach for metabolic modulation therapy.

Results

Conclusion