Lipotoxicity and cardiac dysfunction in mammals and Drosophila

Abstract

The lipotoxic effects of obesity are important contributing factors in cancer, diabetes, and cardiovascular disease (CVD), but the genetic mechanisms, by which lipotoxicity influences the initiation and progression of CVD are poorly understood. Hearts, of obese and diabetic individuals, exhibit several phenotypes in common, including ventricular remodeling, prolonged QT intervals, enhanced frequency of diastolic and/or systolic dysfunction, and decreased fractional shortening. High systemic lipid concentrations are thought to be the leading cause of lipid-related CVD in obese or diabetic individuals. However, an alternative possibility is that obesity leads to cardiac-specific steatosis, in which lipids and their metabolites accumulate within the myocardial cells themselves and thereby disrupt normal cardiovascular function. Drosophila has recently emerged as an excellent model to study the fundamental genetic mechanisms of metabolic control, as well as their relationship to heart function. Two recent studies of genetic and diet-induced cardiac lipotoxicity illustrate this. One study found that alterations in genes associated with membrane phospholipid metabolism may play a role in the abnormal lipid accumulation associated with cardiomyopathies. The second study showed that Drosophila fed a diet high in saturated fats, developed obesity, dysregulated insulin and glucose homeostasis, and severe cardiac dysfunction. Here, we review the current understanding of the mechanisms that contribute to the detrimental effects of dysregulated lipid metabolism on cardiovascular function. We also discuss how the Drosophila model could help elucidate the basic genetic mechanisms of lipotoxicity- and metabolic syndrome-related cardiomyopathies in mammals.

Figure 1

Schematic of the effects of lipid accumulation in non-adipose tissues. When overwhelmed with lipids, the adipose tissue will begin transporting excess free fatty acids (FFA) to non-adipose tissues such as the skeletal muscle, liver, and heart. Adipose tissue will also release adipokines (leptin, adiponectin, and inflammatory cytokines), while the liver will release inflammatory cytokines, and skeletal muscle may induce insulin resistance (IR). This may lead to heart problems, including ventricular remodeling, increased QT interval (arrhythmias), alterations in diastolic and systolic dysfunction, and lower fractional shortening.

Figure 2

Schematic representation of excess lipid accumulation and possible effects on lipolysis and lipogenesis. In an obese and/or lipotoxic state, the heart accommodates excess fat by increasing either lipid breakdown (lipolysis) or storage as TG (lipogenesis). Lipolysis involves the progressive breakdown of triaclyglycerides (TG) by adipose triglyceride lipase (ATGL), sensitive lipase (HSL), and monoacylglyceride (MAG) lipase. This breakdown generates diacylglycerides (DAG) and MAG and liberates FFA, which can then be converted by Acyl-CoA synthase (ACS) to fatty acid CoAs (FA-CoAs), which are then transported into the mitochondria to undergo β-oxidation. The heart may also reduce an excess lipid load by converting FFA to TG through lipogenesis. FFA are transported into the cell by the Fatty Acid Transport Protein 1 (FATP1) and other transport mechanisms. These FA can then be processed into ceramides, which may lead to insulin resistance. Acyl-CoA uses the FFA to produce DAG and, in combination with diacylglyceride transferase (DGAT1), to produce TG. When FFA levels in the cardiomyocyte exceed the mitochondrial capacity for oxidation, lipolysis is decreased and lipogenesis is increased. Collectively, these events can lead to cardiac steatosis and eventually, to cardiac dysfunction.