Review
Lipoprotein lipase mediated fatty acid delivery and its impact in diabetic cardiomyopathy

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Abstract

Although cardiovascular disease is the leading cause of diabetes-related death, its etiology is still not understood. The immediate change that occurs in the diabetic heart is altered energy metabolism where in the presence of impaired glucose uptake, glycolysis, and pyruvate oxidation, the heart switches to exclusively using fatty acids (FA) for energy supply. It does this by rapidly amplifying its lipoprotein lipase (LPL—a key enzyme, which hydrolyzes circulating lipoprotein-triglyceride to release FA) activity at the coronary lumen. An abnormally high capillary LPL could provide excess fats to the heart, leading to a number of metabolic, morphological, and mechanical changes, and eventually to cardiac disease. Unlike the initial response, chronic severe diabetes “turns off” LPL, this is also detrimental to cardiac function. In this review, we describe a number of post-translational mechanisms that influence LPL vesicle formation, actin cytoskeleton rearrangement, and transfer of LPL from cardiomyocytes to the vascular lumen to hydrolyze lipoprotein-triglyceride following diabetes. Appreciating the mechanism of how the heart regulates its LPL following diabetes should allow the identification of novel targets for therapeutic intervention, to prevent heart failure. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.

Highlights

► LPL is a key provider of fatty acids to the heart following diabetes. ► We describe mechanisms by which vascular LPL is regulated following diabetes. ► Perturbations in LPL contribute to the pathology of diabetic cardiomyopathy.

Introduction

During diabetes, when cardiac glucose utilization is impaired, the heart switches to exclusively using FA for energy supply [1]. This metabolic switching could lead to cardiomyocyte cell death, and eventually heart disease [1]. One mechanism for providing the heart with FA is LPL. LPL, synthesized in cardiomyocytes, is transferred to endothelial cells lining the vascular lumen, where it catalyzes the breakdown of lipoprotein-triglyceride (TG) to provide FA to the heart [2]. Following diabetes, LPL activity at the coronary lumen increases by mechanisms that have yet to be completely elucidated. This review discusses how, following diabetes, the heart adapts to reduced glucose uptake and oxidation by increasing FA delivery (from LPL-catalyzed degradation of TG-rich lipoproteins), and hence utilization. Specifically, we will focus on the mechanisms that alter LPL, and the consequences of this augmented LPL-derived FA on cardiac function. Understanding the regulation of cardiac LPL will allow to us lower FA delivery to the heart, and develop strategies to overcome contractile dysfunction following diabetes.

Section snippets

Heart disease in diabetes

Heart disease is a leading cause of death in diabetic patients, with coronary vessel disease and atherosclerosis being primary reasons for the increased incidence of cardiovascular dysfunction [3], [4]. However, a predisposition to heart failure might also reflect the effects of underlying abnormalities in diastolic function that can be detected in asymptomatic patients with Type 1 (T1D) and Type 2 (T2D) diabetes alone [5], [6]. These observations suggest a specific impairment of heart muscle

Cardiac metabolism

As uninterrupted contraction is a unique feature of the heart, cardiac muscle has a high demand for provision of energy in the form of ATP [22]. Under normal physiological conditions, this energy is obtained via the oxidation of an assortment of different substrates including lactate, ketone bodies, glucose and FA [23], [24]. Interestingly, the heart can rapidly switch its substrate selection to accommodate different physiological and pathophysiological conditions involving altered

Substrate availability during diabetes

Glucose and lipids are the major substrates affected by diabetes. Hyperglycemia is a consequence of decreased glucose clearance and augmented hepatic glucose production, whereas enhanced lipolysis in adipose tissue and higher lipoprotein synthesis in the liver dramatically increases circulating free FA and TG [35], [36]. These fuels are made available to the cardiomyocyte through a wide array of mechanisms.

Heart LPL in human diabetes

In vascular tissue, LPL is bound to heparan sulfate proteoglycans (HSPG) and glycosylphosphatidylinositol-anchored high density lipoprotein binding protein 1 (GPIHBP1) through ionic linkage (Fig. 1); LPL has abundant positively charged domains [48]. HSPG are ubiquitous macromolecules present on cell membranes and extracellular matrix, and consist of a core protein to which several linear heparan sulfate (HS) side chains are covalently linked [49], [50]. They serve, not only as structural

Enzyme dimerization

Catalytically active LPL is a homodimer, with two inactive monomers attached non-covalently in a head-to-tail fashion [84]. Thus, after LPL mRNA is translated as an inactive polypeptide, the monomeric enzyme requires processing to attain activity, an event that occurs in the endoplasmic reticulum (ER) and involves multiple steps [85], [86]. This includes glycosylation, subsequent trimming of glucose residues in the oligosaccharides, and binding to chaperones like calreticulin/calnexin and

LPL and cardiomyopathy

A number of studies have shown that excessive FA induces lipotoxicity and contributes to the development of cardiomyopathy through over production of reactive oxygen species (as a consequence of high rate of FA oxidation) [132], accumulation of TG (when FA uptake supersedes its oxidation) [133], [134], [135], and generation of ceramide (an intracellular messenger known to trigger apoptosis) [133], [136], [137]. Thus, cardiac-specific overexpression of FA transport protein 1 significantly

Conclusion

In patients with diabetes, an increased risk of symptomatic heart failure usually develops in the presence of hypertension or ischemic heart disease [146]. However, a predisposition to heart failure might also reflect the effects of underlying abnormalities in diastolic function that can occur in asymptomatic patients with diabetes alone (termed diabetic cardiomyopathy). We suggest that following diabetes and compromised glucose utilization, recruitment of LPL to the cardiomyocyte cell surface

Acknowledgements

This study was supported by an operating grant from the Canadian Diabetes Association and the CIHR. Minsuk Kim was a recipient of a doctoral research award from Heart and Stroke Foundation of Canada and the Canadian Diabetes Association and more recently, a PDF from the Heart and Stroke Foundation of Canada.

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