Role of cardiac steatosis and lipotoxicity in obesity cardiomyopathy.

The pandemic of obesity is a devastating health problem and contributes to premature morbidity and mortality. Results from clinical and experimental studies have identified a variety of unfavorable consequences of obesity including cardiovascular diseases, pulmonary diseases, cancer, and sleep disorders. An obesity-triggered parallel increase in the prevalence of type 2 diabetes mellitus is also expected to add to the overall cardiovascular burden of obesity. Components of metabolic syndrome such as dyslipidemia, hyperglycemia, insulin resistance, and hypertension are thought to play pivotal roles in obesity-associated sequelae responsible for atherosclerosis, cardiac hypertrophy, and ventricular dysfunction. The presence of 1 or more of these metabolic syndrome components can adversely affect multiple metabolic pathways resulting in alterations in glucose and lipid metabolism, fatty acid (FA) transport/storage/oxidation, oxygen consumption, redox status, and high-energy phosphate metabolism. Although the precise mechanism(s) of action responsible for metabolic derangement-induced cardiac abnormalities in obesity remains poorly understood, 1 theory that has received increasing attention focuses on lipid transport and storage, excessive FA oxidation (FAO), and lipotoxic injury to the heart.1,2 When energy intake exceeds expenditure, fat is stored as triacylglycerol (TG) in adipose tissue. In turn, once fat levels exceed the storage capacity of adipocytes, a variety of neutral lipids are released and accumulated in other cells and tissues including the heart. The presence of lipid inclusions within cardiomyocytes, a condition referred to as cardiac steatosis, has been confirmed in obesity and diabetes.3,4 Although recent evidence indicates that cardiac steatosis, increased availability of FA and excess FAO contribute to cardiac anomalies associated with obesity and type 2 diabetes, it has also been suggested that cardiac steatosis may be a compensatory mechanism used to neutralize FAs and their metabolites through esterification to neutral lipids. Generation of ATP for normal cardiac contractile function depends on a fine balance in the use of FA and carbohydrate as substrates. However, onset and development of obesity and type 2 diabetes result in an increased availability of FA, a concomitant overreliance on FA as an energy source, and accelerated FAO. In consequence, cardiomyocyte FA uptake often exceeds mitochondrial oxidative capacity, and cardiac steatosis ensues, leading to a build-up of lipotoxic intermediates such as ceramide and acylcarnitine. Collectively these events favor oxidative stress and apoptosis, and, mitochondria become damaged further compromising ATP production and cardiac contractile function. FA uptake exceeding FAO results in increased FA storage as TG and the accompanied cardiac contractile dysfunction. Myocardial TG accumulation may either protect the heart by “storing away” the detrimental lipid intermediates (eg, diacylglycerol, long-chain fatty acylCoA esters, and ceramide), or elicit severe lipotoxicity thereby compromising cardiac function.2 Meanwhile, the insulin-resistant heart in obesity and type 2 diabetes is unable to fully use glucose, forcing the heart to rely on FA for energy demand and thus prompting a vicious cycle of increased cardiomyocyte FA uptake, oxidation, and TG accumulation, all of which are hallmarks of lipotoxic cardiomyopathy. Whereas the pathophysiology of lipid accumulation on cardiac function has been defined, the clinical value of cardiac steatosis remains elusive in obesity and type 2 diabetes. Impaired glucose tolerance is accompanied by cardiac steatosis in humans and precedes the onset of type 2 diabetes and systolic dysfunction.5 Evidence from genetically modified mice with overexpression or targeted gene deletion of FA uptake protein (eg, cardiac-specific lipoprotein lipase [LpL],6 acyl-CoA synthetase,7 and FA transport protein [FATP]18) or that prevent lipid turnover (deletion of adipose triglyceride lipase gene [ATGL]) has revealed cardiomyocyte lipid deposition associated with cardiac dysfunction (Figure). For example, hearts from mice overexpressing LpL, the principal enzyme that hydrolyzes circulating TG and liberates free FAs to be used as energy, were dilated and exhibited systolic dysfunction. Increased free FA uptake with FATP1 overexpression contributes to early cardiomyocyte FA accumulation and subsequently increased cardiac FA metabolism. In this model, perturbation of cardiomyocyte lipid homeostasis leads to cardiac dysfunction with pathophysiological findings reminiscent of those seen in diabetes in the absence of systemic metabolic disturbances.8 These findings support the concept that cardiac-restricted steatosis may directly prompt cardiac anomalies independent of systemic obesity. In addition, overexpression of peroxisome proliferator-activated receptor (PPAR) and PPAR using the -myosin heavy chain (MHC) promoter led to overt cardiac lipid accumulation and cardiomyopathy.9,10 The pathophysiology behind cardiomyopathy with PPAR and PPAR overexpression is unclear The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Cardiology (Y.Z.), Xijing Hospital, Fourth Military Medical University, Xi’an, China; and Center for Cardiovascular Research and Alternative Medicine (Y.Z., J.R.), University of Wyoming, Laramie, WY. Correspondence to Jun Ren, Center for Cardiovascular Research and Alternative Medicine University of Wyoming College of Health Sciences, Laramie, WY 82071. E-mail [email protected] (Hypertension. 2011;57:148-150.) © 2011 American Heart Association, Inc.