Cardiac lipid metabolism, mitochondrial function, and heart failure

Abstract

A fine balance between uptake, storage, and the use of high energy fuels, like lipids, is crucial in the homeostasis of different metabolic tissues. Nowhere is this balance more important and more precarious than in the heart. This highly energy-demanding muscle normally oxidizes almost all the available substrates to generate energy, with fatty acids being the preferred source under physiological conditions. In patients with cardiomyopathies and heart failure, changes in the main energetic substrate are observed; these hearts often prefer to utilize glucose rather than oxidizing fatty acids. An imbalance between uptake and oxidation of fatty acid can result in cellular lipid accumulation and cytotoxicity. In this review, we will focus on the sources and uptake pathways used to direct fatty acids to cardiomyocytes. We will then discuss the intracellular machinery used to either store or oxidize these lipids and explain how disruptions in homeostasis can lead to mitochondrial dysfunction and heart failure. Moreover, we will also discuss the role of cholesterol accumulation in cardiomyocytes. Our discussion will attempt to weave in vitro experiments and in vivo data from mice and humans and use several human diseases to illustrate metabolism gone haywire as a cause of or accomplice to cardiac dysfunction.

Keywords: Cholesterol; Heart failure; Lipids; Lipoprotein.

Figure 1

Uptake of circulating lipids. The heart obtains fatty acids (FAs) from circulating triglyceride-rich lipoproteins (chylomicrons and VLDL) and albumin-bound non-esterified FAs. Lipoprotein lipase (LpL) catalyses hydrolysis of triglyceride-rich lipoproteins at the endothelial cell surface. FA uptake by the heart requires transport across the endothelial cell barrier, which is mediated by the scavenger receptor CD36. Genetic deletion of CD36 or LpL or overexpression of the LpL inhibitor angiopoietin-like protein 4 (Angptl4) leads to defective lipid uptake and heart dysfunction.

Figure 2

Cardiac lipid droplet hydrolysis. Cardiac lipid droplets provide a pool of fatty acids (FAs) to meet the varying energy requirements of the heart. Their hydrolysis is mediated by cytosolic triglyceride (TG) lipases—adipose TG lipase (ATGL) and hormone sensitive lipase (HSL) (left)—or acidic lysosomal lipases (lipophagy, right). Both processes are tightly regulated by members of the perilipin (Plin) family of lipid droplet proteins. Plin5 inhibits lipolysis by binding and sequestering ATGL co-activator CGI-58. Plin5 phosphorylation by PKA results in the release of CGI-58 and recruitment of ATGL, which catalyses the rate-limiting step of lipid droplet TG hydrolysis. Knockout of Plin5 results in lipid droplet depletion, whereas its overexpression induces severe lipid accumulation similar to that found in ATGL-deficient hearts. In addition, Plin2 has been reported to regulate cardiac lipophagy. Plin2 knockout results in heart lipid accumulation and reduced LC3-II, phosphorylated AMPK, and lipid droplet co-localization with lysosomes, all indicative of impaired lipophagy.

Figure 3

Metabolic impact of cardiac sterols. A normal/healthy heart mainly relies on fatty acid oxidation and mitochondrial oxidative phosphorylation (OXPHOs) for energy production. Failing heart has reduced OXPHOs and mitochondrial antioxidant pathways (mGSH) and greater reliance on glycolysis for ATP production. If lipid uptake is not reduced, sterols and other potentially toxic lipids can accumulate and trigger greater reactive oxygen species (ROS) production.

Figure 4

Cardiac lipoprotein production. The heart has the capacity to alleviate its burden of excess toxic lipids by oxidation, storage in lipid droplets, or secretion in lipoproteins. Akin to the liver and the intestine, the heart expresses both apolipoprotein B (ApoB) and microsomal triglyceride (TG) transfer protein (MTTP). This allows the packaging of intracellular cholesterol ester and TG in the endoplasmic reticulum into nascent lipoproteins. The nascent lipoprotein is then released into the bloodstream; cardiac lipotoxicity is reduced by this ‘reverse lipid transport’ process.