Lipid metabolism and toxicity in the heart

Abstract

The heart has both the greatest caloric needs and the most robust oxidation of fatty acids (FAs). Under pathological conditions such as obesity and type 2 diabetes, cardiac uptake and oxidation are not balanced and hearts accumulate lipid potentially leading to cardiac lipotoxicity. We will first review the pathways utilized by the heart to acquire FAs from the circulation and to store triglyceride intracellularly. Then we will describe mouse models in which excess lipid accumulation causes heart dysfunction and experiments performed to alleviate this toxicity. Finally, the known relationships between heart lipid metabolism and dysfunction in humans will be summarized.

FIGURE 1. Regulation of cardiomyocyte lipid storage

A. Fatty acids esterified as triacylglycerol (TG) within lipoproteins require hydrolysis by lipoprotein lipase (LpL) associated with proteoglycans and GPIHBP1 on the luminal surface of endothelial cells. Angiopoietin like protein 4 (ANGPTL4) is an LpL inhibitor. Non-esterified fatty acids (FFA) associated with albumin likely are internalized by membrane transporters such as CD36. These lipids must cross the endothelial barrier; how this occurs is unclear. B. Within the cardiomyocytes the fatty acids are esterified to CoA and either stored in the lipid droplet (LD) or used for energy. At least 4 lipid droplet proteins (perilipins – PLINs) are expressed in the heart. The lipid droplet supplies some oxidized fatty acids via the actions of adipose triglyceride lipase (ATGL)/desnutrin and hormone sensitive lipase (HSL). CGI58 is the ATGL co-activator. ATGL and LpL actions both provide ligands for PPAR activation.

Figure 2. Lipotoxicity is created by an imbalance of lipid uptake and oxidation

Genetically modified mice have been created that have either increased lipid uptake or decreased oxidation. Uptake occurs via the cell surface molecules lipoprotein lipase (LpL) and perhaps the fatty acid transporter CD36 and/or FATPs. More fatty acids are “trapped” by complexing to CoA. Stored triglyceride accumulates with defective hydrolysis due to deletion of ATGL. Two interventions, loss of PPARδ and high fat feeding in mice overexpressing Glut1, lead to reduced lipid oxidation. Transgenic expression of PPARα and PPARγ, which induce lipid oxidation genes, also cause lipid accumulation, presumably because uptake exceeds oxidation.