Lipotoxicity in the heart

Abstract

Obesity and insulin resistance are associated with ectopic lipid deposition in multiple tissues, including the heart. Excess lipid may be stored as triglycerides, but are also shunted into non-oxidative pathways that disrupt normal cellular signaling leading to organ dysfunction and in some cases apoptosis, a process termed lipotoxicity. Various pathophysiological mechanisms have been proposed to lead to lipotoxic tissue injury, which might vary by cell type. Specific mechanisms by which lipotoxicity alter cardiac structure and function are incompletely understood, but are beginning to be elucidated. This review will focus on mechanisms that have been proposed to lead to lipotoxic injury in the heart and will review the state of knowledge regarding potential causes and correlates of increased myocardial lipid content in animal models and humans. We will seek to highlight those areas where additional research is warranted.

Fig. 1

Pathophysiological mechanisms leading to cardiac lipotoxicity. (A) Increased dietary fat intake, hepatic lipogenesis, and lipolysis lead to increased levels of circulating free-fatty acids (FFA) and triglycerides (TG). Obesity and insulin resistance also alter adipokine signaling. (B) Changes in circulating FFA and signaling molecules lead to increased FA uptake, decreased FA oxidation, and increased synthesis of toxic lipid intermediates within the heart. (C) These molecular changes ultimately contribute to cardiac steatosis, contractile dysfunction, mitochondrial dysfunction, endoplasmic reticulum (ER) dysfunction and apoptosis.

Fig. 2

Schematic summary of mechanisms for lipotoxicity. (A) Transgenic models of increased lipid uptake and delivery as well as dietary studies have provided insight into a number of candidate molecular pathways that mediate cardiac lipotoxicity. (B) These include: decreased mitochondrial coupling and oxidative capacity, ER stress, altered membrane composition and function, and altered gene expression through enhanced ligand delivery to transcription factors (e.g. PPARs). However, the specific sequences with which these changes occur and the requirement for each of these pathways is not yet clearly defined. (C) Nevertheless, accumulation of toxic intermediates results in cell death. ACS, acyl-CoA synthase; FATP, fatty acid transport protein; LpL, lipoprotein lipase; DIO, diet-induced obesity; ROS, reactive oxygen species; DAG, diacylglyerol; IMTG, intramyocellular triglycerides; ER, endoplasmic reticulum; FA, fatty acid; PPAR, peroxisome proliferator-activated receptors. Figure was produced using Servier Medical Art (www.servier.com).