Myocardial lipid accumulation in patients with pressure-overloaded heart and metabolic syndrome

Marfella, Raffaele; Filippo, Clara Di; Portoghese, Michele; Barbieri, Michelangela; Ferraraccio, Franca; Siniscalchi, Mario; Cacciapuoti, Federico; Rossi, Francesco; D’Amico, Michele; Paolisso, Giuseppe

doi:10.1194/jlr.p900032-jlr200

Cited by 129 publications

(109 citation statements)

References 30 publications

(27 reference statements)

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“…However, the fact that plasma insulin and plasma lipid levels dramatically increased with the long-term Western feeding might indicate that the rats were suffering from selective insulin resistance, a state known to stimulate lipogenesis and to predispose to cardiovascular diseases and diabetes ( 53 ). It is noteworthy that the failing heart of patients with metabolic syndrome, but free of diabetes, displays increased lipid deposition and higher levels of SREBP-1c ( 54 ).…”

Section: Discussionmentioning

confidence: 99%

Western diet changes cardiac acyl-CoA composition in obese rats: a potential role for hepatic lipogenesis

Harmancey¹,

Wilson²,

Wright³

et al. 2010

Journal of Lipid Research

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This article is available online at http://www.jlr.org coronary artery disease ( 3,4 ). An imbalance between myocardial substrate uptake and fatty acid oxidative capacity of the heart is thought to induce lipotoxicity, namely, an accumulation of lipid byproducts that give rise to noxious intermediates in the cardiomyocytes. However, the exact mechanism for lipotoxicity is still not known. A consistent fi nding is that myocardial triglycerides are increased in hearts of obese or type 2 diabetic patients ( 5, 6 ), which is associated with impaired left-ventricular diastolic function ( 7 ).Genetically modifi ed rodent models have been used extensively to investigate the pathophysiology of "lipotoxic cardiomyopathy" ( 8 ). Increased lipid infl ux in the heart ( 9, 10 ), decreased mobilization of triacylglycerol reserves ( 11 ), or increased fatty acid metabolism (12)(13)(14) all are associated with metabolic alterations that mimic those of diabetes, including hypertrophy of the heart and contractile dysfunction. These animal studies have led to the identifi cation of the lipid molecules that are potential culprits for impaired cardiac function. Increased reliance of the heart on ␤ -oxidation of fatty acids leads to increased reactive oxygen species generation, which promotes lipid peroxidation and alters mitochondrial function ( 15,16 ). In addition, intracellular saturated acyl-CoA species, ceramide and diacylglycerol, are linked to changes in membrane composition, endoplasmic reticulum stress, altered lipid signaling, and ultimately, apoptosis ( 17,18 ). These lipid species may also impair insulin signaling through increased serine phosphorylation of the insulin receptor and insulin receptor substrate 1 and/or reduced serine phosphorylation of PKB/Akt ( 19,20 ).However, there is controversy over whether myocardial lipids contribute to contractile dysfunction and heart Abstract The "lipotoxic footprint" of cardiac maladaptation in diet-induced obesity is poorly defi ned. We investigated how manipulation of dietary lipid and carbohydrate infl uenced potential lipotoxic species in the failing heart. In Wistar rats, contractile dysfunction develops at 48 weeks on a high-fat/high-carbohydrate "Western" diet, but not on low-fat/high-carbohydrate or high-fat diets. Cardiac content of the lipotoxic candidates-diacylglycerol, ceramide, lipid peroxide, and long-chain acyl-CoA species-was measured at different time points by high-performance liquid chromatography and biochemical assays, as was lipogenic capacity in the heart and liver by qRT-PCR and radiometric assays. Changes in membranes fl uidity were also monitored using fl uorescence polarization. We report that Western feeding induced a 40% decrease in myocardial palmitoleoyl-CoA content and a similar decrease in the unsaturated-to-saturated fatty acid ratio. These changes were associated with impaired cardiac mitochondrial membrane fl uidity. At the same time, hepatic lipogenic capacity was increased in animals fed Western diet (+270% fatty acid elongase activity comp...

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Section: Discussionmentioning

confidence: 99%

Western diet changes cardiac acyl-CoA composition in obese rats: a potential role for hepatic lipogenesis

Harmancey¹,

Wilson²,

Wright³

et al. 2010

Journal of Lipid Research

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“…On the other hand, myocardial TG accumulation is often associated with impaired cardiac function. Intracellular TG accumulation was observed in stressed hearts and this was regarded as a hallmark of cardiac lipotoxicity that eventually led to heart failure (122,123). It is of note that specific cardiac conditions, such as pressure overload (124) or ischemia (125), cause ER stress that likely contributes to cardiomyocyte dysfunction upon stress-mediated lipid accumulation (Fig.…”

Section: Heartmentioning

confidence: 99%

The role of ER stress in lipid metabolism and lipotoxicity

Han

Kaufman

2016

Journal of Lipid Research

482

372

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extremely high Ca 2+ concentration (1), which is maintained by the active transport function of the sarco/ER calcium ATPase (SERCA) (2). Many ER chaperone proteins and enzymes depend on higher Ca 2+ levels to facilitate protein folding and maturation (3). Therefore, maintaining ER homeostasis is essential for proper protein production and cell function. Homeostasis in the ER is disrupted by a number of insults, including pharmacological perturbation, genetic mutation of ER chaperones or their client proteins, elevated expression of proteins that transit the endomembrane system, viral infection, alterations in Ca 2+ or redox status, and limited or excessive available nutrients such as lipids. The accumulation of unfolded or misfolded proteins in the ER lumen activates a set of intracellular signaling pathways known as the unfolded protein response (UPR) (4, 5). The UPR regulates the quantity of ER driven by synthesis of lipids (6) and protein components of the ER to accommodate fluctuating demands on protein folding and other ER functions in response to different physiological and pathological conditions.The ER is also the major site for the synthesis of sterols and phospholipids that constitute the bulk of the lipid components of all biological membranes. In addition, many enzymes and regulatory proteins involved in lipid metabolism reside in the ER. The ER, therefore, plays an essential role in controlling membrane lipid composition (7) and membrane lipid homeostasis in all cell types. Fat The endoplasmic reticulum (ER) is a central organelle where proteins destined for the cell surface and the endomembrane system enter the secretory pathway. Once inside the ER lumen, newly synthesized polypeptides fold into their three-dimensional structures, assemble into higher order multimeric complexes, and are subject to posttranslational modifications such as glycosylation, hydroxylation, lipidation, and disulfide formation. The ER contains an Abbreviations: ACC, acetyl-CoA carboxylase; ATF4, activating transcription factor 4; ATF6, activating transcription factor 6; BiP, immunoglobulin heavy-chain binding protein; CHOP, C/EBP homologous protein; eIF2, eukaryotic translation initiation factor 2; ER, endoplasmic reticulum; ERAD, ER-associated degradation; FXR, farnesoid X receptor; GADD34, growth arrest and DNA damage-inducible protein 34; HFD, high-fat diet; HFrD, high-fructose diet; IRE1, inositol-requiring enzyme 1; 4-PBA, 4-phenylbutyric acid; PERK, the double-stranded RNAactivated protein kinase-like eukaryotic initiation factor 2 kinase; ROS, reactive oxygen species; SCD1, stearoyl-CoA desaturase 1; SERCA, sarco/ endoplasmic reticulum calcium ATPase; SFA, saturated fatty acid; S1P, serine protease site-1; S2P, metalloprotease site-2; SREBP, sterol regulatory element-binding protein; TUDCA, tauroursodeoxycholic acid; UPR, unfolded protein response; VLDLR, VLDL receptor; XBP1, X-box binding protein 1; Xbp1s, transcriptionally active form of X-box binding protein 1.

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“…In the current study by Marfella et al ( 11 ), a group of patients with and without evidence of the metabolic syndrome was selected from a large cohort of patients undergoing aortic valve replacement. All patients underwent echocardiographic assessment of their cardiac function.…”

mentioning

confidence: 99%

Myocardial lipid accumulation and lipotoxicity in heart failure

Schulze

2009

Journal of Lipid Research

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Myocardial lipid accumulation in patients with pressure-overloaded heart and metabolic syndrome

Cited by 129 publications

References 30 publications

Western diet changes cardiac acyl-CoA composition in obese rats: a potential role for hepatic lipogenesis

Western diet changes cardiac acyl-CoA composition in obese rats: a potential role for hepatic lipogenesis

The role of ER stress in lipid metabolism and lipotoxicity

Myocardial lipid accumulation and lipotoxicity in heart failure

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