Manifestations and mechanisms of myocardial lipotoxicity in obesity

Abstract

Environmental and socioeconomic changes over the past thirty years have contributed to a dramatic rise in the worldwide prevalence of obesity. Heart disease is amongst the most serious health risks of obesity, with increases in both atherosclerotic coronary heart disease and heart failure among obese individuals. In this review, we focus on primary myocardial alterations in obesity that include hypertrophic remodelling and diastolic dysfunction. Obesity-associated perturbations in myocardial and systemic lipid metabolism are important contributors to cardiovascular complications of obesity. Accumulation of excess lipid in nonadipose cells of the cardiovascular system can cause cell dysfunction and cell death, a process known as lipotoxicity. Lipotoxicity has been modelled in mice using high-fat diet feeding, inbred lines with mutations in leptin receptor signalling, and in genetically engineered mice with enhanced myocardial fatty acid uptake, altered lipid droplet homoeostasis or decreased cardiac fatty acid oxidation. These studies, along with findings in cell culture model systems, indicate that the molecular pathophysiology of lipid overload involves endoplasmic reticulum stress, alterations in autophagy, de novo ceramide synthesis, oxidative stress, inflammation and changes in gene expression. We highlight recent advances that extend our understanding of the impact of obesity and altered lipid metabolism on cardiac function.

Keywords: diabetes; heart failure; lipids; obesity.

Figure 1. Alterations in myocardial structure and function associated with obesity

Remodeling of myocardial structure and impaired diastolic and systolic function are observed in obese individuals. Contributions of altered lipid metabolism, inflammation and endothelial dysfunction are highlighted. eNOS, endothelial nitric oxide synthase; ROS, reactive oxygen species.

Figure 2. Mechanisms of myocardial lipotoxicity

Excess delivery of fatty acids to the myocardial impacts many different aspects of normal cardiomyocyte function. Effects on cellular signaling, expression of protein-coding genes and non-coding RNAs, and organelle integrity and function are depicted. ROS, reactive oxygen species; ER, endoplasmic reticulum.