Mechanisms of lipotoxicity in the cardiovascular system

Abstract

Cardiovascular diseases account for approximately one third of all deaths globally. Obese and diabetic patients have a high likelihood of dying from complications associated with cardiovascular dysfunction. Obesity and diabetes increase circulating lipids that upon tissue uptake, may be stored as triglyceride, or may be metabolized in other pathways, leading to the generation of toxic intermediates. Excess lipid utilization or activation of signaling pathways by lipid metabolites may disrupt cellular homeostasis and contribute to cell death, defining the concept of lipotoxicity. Lipotoxicity occurs in multiple organs, including cardiac and vascular tissues, and a number of specific mechanisms have been proposed to explain lipotoxic tissue injury. In addition, recent data suggests that increased tissue lipids may also be protective in certain contexts. This review will highlight recent progress toward elucidating the relationship between nutrient oversupply, lipotoxicity, and cardiovascular dysfunction. The review will focus in two sections on the vasculature and cardiomyocytes respectively.

Fig. 1

Multiple mechanisms contribute to endothelial dysfunction that exists in subjects with diet-induced obesity, insulin resistance, and type 2 diabetes mellitus. Of these, lipotoxicity can decrease endothelial function by: (i) impairing agonist-induced signaling to eNOS in endothelial cells and blood vessels; (ii) increasing inflammation; (iii) stimulating accrual of toxic sphingolipids e.g., ceramide; (iv) promoting oxidative stress to an extent that overwhelms the antioxidant environment; and/or by (v) potentially precipitating mitochondrial dysfunction. Cross talk between these pathways is likely. Definition of abbreviations: FFA—Free fatty acids; PKCα—Protein kinase C alpha; IRS-1—Insulin receptor substrate-1; IRS-2—Insulin receptor substrate-2; PI3K—Phosphoinositide 3-kinase; MAPK—Mitogen activated protein kinase; IKK—Inhibitor of kappa B kinase; p—phosphorylated; NFκB—Nuclear factor kappa-beta; IL-6—Interleukin-6; TNFα—Tumor necrosis factor-alpha; ICAM—Intercellular adhesion molecule; PAI-1—Plasminogen activator inhibitor-1; I2PP2A—Inhibitor 2 of protein phosphatase 2A; PP2A—Protein phosphatase 2A; eNOS—Endothelial nitric oxide synthase; BMP4—Bone morphogenetic protein 4; NOX4—NADPH oxidase 4. For lipid metabolites, the arrows represent the interactions between ceramide, I2PP2A, PP2A, and eNOS

Fig. 2

Schematic representation of pathways and mechanisms of lipotoxicity. Nutrient excess, from diet, increased de novo synthesis of lipids, and reduced energy expenditure, eventually overwhelms storage and oxidation. This leads to lipid accumulation that will impair cardiac contractile function, nitric oxide signaling in the vasculature, and the function of cellular organelles. Changes in intracellular signaling result in ER stress, mitochondrial dysfunction and reactive oxygen species generation, as well as persistent modifications of DNA and histones. The overall result is dysregulation of various pathways (discussed in the text) that have far reaching consequences. Figure was produced using Servier Medical Art (www.servier.com)