Brief review
Mechanisms of Lipoapoptosis: Implications for Human Heart Disease

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Abstract

Accumulation of long-chain fatty acids in the heart has been proposed to play a role in the development of heart failure and diabetic cardiomyopathy. Several animal models with increased cardiomyocyte lipid accumulation suggest a link between the accumulation of lipid, cardiomyocyte cell death and the development of cardiomyopathy. In this review, we discuss the mechanism through which fatty acid accumulation may contribute to the development or progression of heart failure by initiation of apoptotic cell death. Long-chain saturated fatty acids induce apoptosis through a mechanism involving the generation of reactive intermediates. Reactive intermediate production occurs in concert with de novo ceramide synthesis, but ceramide production is not required for cell death. Cardiomyocyte dysfunction and death from reactive intermediates generated by long-chain saturated fatty acids may contribute to the pathogenesis of human heart disease.

Section snippets

Palmitate-Induced Apoptosis Can Occur through a Ceramide-Independent Pathway

Fatty acid–induced apoptosis is specific for the long-chain saturated fatty acids palmitate and stearate de Vries et al. 1997, Paumen et al. 1997. Since the de novo synthetic pathway for ceramide exhibits marked specificity for palmitate and stearate (Riboni et al. 1997), it has been hypothesized that saturated fatty acids lead to apoptosis through the generation of ceramide (Figure 1). Consistent with this hypothesis, CHO cell supplementation with palmitate for six hours results in a 2.4-fold

Palmitate-Induced Apoptosis Leads to Generation of Reactive Intermediates

Supplementation with the saturated fatty acid palmitate, but not the unsaturated fatty acid oleate, leads to an increase in reactive intermediates. By 14 h of palmitate supplementation, reactive intermediates increase 3.5-fold. Reactive intermediate formation is inhibited by pyrrolidine dithiocarbamate and 4,5-dihydroxy-1,3-benzene-disulfonic acid, two compounds that scavenge reactive intermediates. In addition, these compounds prevent palmitate-induced caspase 3 activity and DNA laddering.

Mouse Models of Cardiomyocyte Lipotoxicity

Studies of animal models with increased cardiomyocyte lipid accumulation provide a link between the accumulation of lipid, cardiomyocyte cell death and the development of cardiomyopathy. In several of these models decreased β-oxidation leads to an imbalance of fatty acid uptake and utilization. Pharmacologic inhibition of fatty acid oxidation with chronic administration of 2-tetradecylglycidic acid (Litwin et al. 1990) or oxfenicine (Bachmann and Weber 1988) results in lipid accumulation in the

Relevance to Hyperlipidemic States

Cardiomyocyte lipotoxicity may play a role in the pathogenesis of a number of human heart diseases. Acute elevations in serum fatty acid in acute coronary syndromes Kleinfeld et al. 1996, Oliver et al. 1968 may predispose to cardiomyocyte dysfunction and cell death, leading to arrhythmias and/or contractile dysfunction. Disease states associated with chronically high serum fatty acid levels, such as type 1 (Zuniga-Guajardo and Zinman 1985) and type 2 (Lewis et al. 1972) diabetes, or congenital

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