Role of triacylglycerol-rich lipoproteins in substrate supply and metabolic signalling
We investigate the role of the triacylglycerol-rich lipoprotein very-low-density lipoprotein (VLDL) in both energy provision and metabolic signallling in a variety of tissues, including heart, and in metabolic disease states such as diabetes.
Lipids are energy-dense, and constitute an important energy source for oxidative tissues. However, their utilisation has disavantages compared to carbohydrates, and dysregulation of lipid supply can lead to severe tissue dysfunction; hence, their provision is highly regulated.
Tissue function critically depends on optimal energy metabolism, and appropriate substrate selection is vital to function, especially in tissues such as heart which have a high energetic requirement.
Changes in substrate selection are associated with clinically important disease states, such as cardiac failure, as well as metabolic diseases such as diabetes mellitus.
The role of triacylglycerols, provided in the form of plasma lipoproteins, has now been defined, and in the case of the heart has been shown to be vital for optimal cardiac function.
Endogenous triacylglycerols are synthesised and secreted by the liver as very-low-density lipoproteins (VLDL); these particles have complex structural motifs which change in metabolic disease states associated with impaired tissue function (e.g. diabetic cardiomyopathy).
We have also shown VLDL to be capable of acting as metabolic signals, modulating target tissue metabolic profile; their signalling alters with changes in their structure in pathological states associated with dyslipidaemia. This effect places VLDL with other metabolic substrates known to act as pathophysiological signals of energetic status.
Besides changes in substrate determining tissue metabolism, we are investigating the effects of altered tissue status in substrate selection - in particular, examining the effects of altered ventricular loading as a determinant of triacylglycerol utilisation, using heart failure (myocardial infarction) and heterotopic heart transplant as clinically-relevant models.