No abstract

Background Intramyocardial triglyceride (TG) turnover is reduced in pressure overloaded, failing hearts, limiting availability of this rich source of long-chain fatty acids (LCFAs) for mitochondrial β-oxidation and nuclear receptor activation. This study explored two major dietary fats, palmitate and oleate, in supporting endogenous TG dynamics and peroxisome proliferator-activated receptor-α (PPAR-α) activation in sham-operated (SHAM) and hypertrophied (transverse aortic constriction, TAC) rat hearts. Methods and Results Isolated SHAM and TAC hearts were provided media containing carbohydrate with either 13C-palmitate or 13C-oleate for dynamic 13C NMR spectroscopy and endpoint LC/MS of TG dynamics. With palmitate, TAC hearts contained 48% less TG versus SHAM (P=0.0003), while oleate maintained elevated TG in TAC, similar to SHAM. TG turnover in TAC was greatly reduced with palmitate (TAC: 46.7±12.2 nmol/g dw/min; SHAM: 84.3±4.9; P=0.0212), as was β-oxidation of TG. Oleate elevated TG turnover in both TAC (140.4±11.2) and SHAM (143.9±15.6), restoring TG oxidation in TAC. PPAR-α target gene transcripts were reduced by 70% in TAC with palmitate, while oleate induced normal transcript levels. Additionally, mRNA levels for PGC-1α and PGC-1β in TAC hearts were maintained by oleate. With these metabolic effects, oleate also supported a 25% improvement in contractility over palmitate with TAC (P=0.0202). Conclusions The findings link reduced intracellular lipid storage dynamics to impaired PPAR-α signaling and contractility in diseased hearts, consistent with a rate-dependent lipolytic activation of PPAR-α. In decompensated hearts, oleate may serve as a beneficial energy substrate versus palmitate by upregulating TG dynamics and nuclear receptor signaling.

Treatment of type 2 diabetic db/db mice with a novel PPAR␥ agonist improves cardiac metabolism but not contractile function. Am J Physiol Endocrinol Metab 286: E449-E455, 2004. First published November 4, 2003 10.1152/ajpendo.00329.2003.-Hearts from insulin-resistant type 2 diabetic db/db mice exhibit features of a diabetic cardiomyopathy with altered metabolism of exogenous substrates and reduced contractile performance. Therefore, the effect of chronic oral administration of 2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid (COOH), a novel ligand for peroxisome proliferatoractivated receptor-␥ that produces insulin sensitization, to db/db mice (30 mg/kg for 6 wk) on cardiac function was assessed. COOH treatment reduced blood glucose from 27 mM in untreated db/db mice to a normal level of 10 mM. Insulin-stimulated glucose uptake was enhanced in cardiomyocytes from COOH-treated db/db hearts. Working perfused hearts from COOH-treated db/db mice demonstrated metabolic changes with enhanced glucose oxidation and decreased palmitate oxidation. However, COOH treatment did not improve contractile performance assessed with ex vivo perfused hearts and in vivo by echocardiography. The reduced outward K ϩ currents in diabetic cardiomyocytes were still attenuated after COOH. Metabolic changes in COOH-treated db/db hearts are most likely indirect, secondary to changes in supply of exogenous substrates in vivo and insulin sensitization. diabetic cardiomyopathy; cardiac metabolism PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS (PPARs) are ligand-activated transcription factors within the nuclear receptor superfamily (11). PPARs heterodimerize with retinoid X receptors and bind to specific DNA response elements in the promoter region of target genes.Three PPAR isoforms (␣, ␤/␦, ␥) can be distinguished by expression patterns and activation by relatively selective ligands. PPAR␣ and PPAR␤/␦ are widely expressed (13, 28). PPAR␣ is activated by hypolipidemic fibrate drugs (23). PPAR␣ regulates a wide variety of target genes involved in catabolism of lipids (5). PPAR␣ is highly expressed in the heart; Barger and Kelly (5) have suggested that cardiac PPAR␣ plays a role in metabolic remodeling. In general, cardiac PPAR␣ expression correlates with capacity for fatty acid (FA) oxidation (26). Studies with cultured cardiomyocytes incubated with selective PPAR␣ ligands have revealed specific target genes that regulate FA uptake and intracellular binding and cellular FA oxidative metabolism. As a consequence, PPAR␣ activation by selective ligands enhanced rates of FA oxidation (14,24,47). Because FA are endogenous ligands for cardiac PPAR␣, oxidative capacity of the heart can be regulated according to FA delivery. Interestingly, activation of cardiac PPAR␤/␦ also stimulated expression of FA-metabolizing genes (24).PPAR␥ expression is more restrictive (11). In adipose tissue, PPAR␥ promotes differentiation and lipid storage (37). PPAR␥ agonists augment insulin sensitivity (35, 48); consequently, thiazolidinediones that activate PPAR...

The specifi c kinetic characteristics of intramyocellular triacylglycerol (TAG) turnover, involving synthesis and lipolysis in the intact beating heart, have been largely uncharacterized to date, and the mechanisms linking uptake and storage dynamics have until now remained elusive. This work examines the dynamics of the TAG pool in the intact heart, under normal conditions and in response to acute changes in in vivo, transporter protein-mediated lipid uptake, in the absence of developmental adaptations that might otherwise occur in a murine mouse model. Through the use of dynamic mode 13 CNMR and endpoint enrichment analysis via LC/MS, we have been able to quantify the turnover of LCFA in and out of the TAG pool and identify distinct exponential and linear characteristics that are associated with regulatory processes of lipid dynamics in the cell ( 1-3 ).TAG is the major source of energy stores within the heart. Traditionally viewed as an inert pool of unmetabolized long chain fatty acids, the newer, emerging realization is that TAG content in the cardiomyocyte is a dynamic metabolic pool that supports the high demand for fatty acid oxidation by the heart, as well as contributes fatty acids that serve as ligands for nuclear receptors and the induction of nuclear transcription factor activity ( 1, 2, 4, 5 ). Additionally, the rates of TAG turnover and content serve as neutral buffers implicated in limiting the formation and accumulation of physiological active and potentially toxic acyl intermediates and derivatives ( 6, 7 ). TAG turnover responds to the magnitude of lipid pool; TAG turnover increases following high-fat diet ( 1 ) in diabetes ( 3 ) or in mouse models of increased lipid mobilization, such as the peroxisome proliferator-activated receptor (PPAR) ␣ or peroxisome Abstract Cardiac triacylglycerol (TAG) stores buffer the intracellular availability of long chain fatty acid (LCFA) that act as nuclear receptor ligands, substrate for lipotoxic derivatives, and high energy-yield fuel. The kinetic characteristics of TAG turnover and homeostatic mechanisms linking uptake and storage dynamics in hearts have until now remained elusive. This work examines TAG pool dynamics in the intact beating heart, under normal conditions and in response to acute gene expression-induced changes in CD36. Dynamic mode 13 C NMR elucidated multiple kinetic processes in 13 C-palmitate incorporation into TAG: an initial, saturable exponential component and a slower linear rate. Although previous work indicates the linear component to refl ect TAG turnover, we hypothesized the saturable exponential to refl ect transport of LCFA across the sarcolemma. Thus, we overexpressed the LCFA transporter CD36 through cardiac-specifi c adenoviral infection in vivo. Within 72 h, CD36 expression was increased 40% in intact hearts, accelerating the exponential phase relative to PBS-infused hearts. TAG turnover also increased with elevations in adipose triglyceride lipase (ATGL) and a modest increase in diacylglycerol acyltransferase 1 (DGAT1), wi...

Background: Metabolic remodeling in heart failure contributes to dysfunctional lipid trafficking and lipotoxicity. Acyl coenzyme A synthetase-1 (ACSL1) facilitates long-chain fatty acid (LCFA) uptake and activation with coenzyme A (CoA), mediating the fate of LCFA. The authors tested whether cardiac ACSL1 overexpression aids LCFA oxidation and reduces lipotoxicity under pathological stress of transverse aortic constriction (TAC). Methods: Mice with cardiac restricted ACSL1 overexpression (MHC-ACSL1) underwent TAC or sham surgery followed by serial in vivo echocardiography for 14 weeks. At the decompensated stage of hypertrophy, isolated hearts were perfused with 13 C LCFA during dynamic-mode 13 C nuclear magnetic resonance followed by in vitro nuclear magnetic resonance and mass spectrometry analysis to assess intramyocardial lipid trafficking. In parallel, acyl CoA was measured in tissue obtained from heart failure patients pre- and postleft ventricular device implantation plus matched controls. Results: TAC-induced cardiac hypertrophy and dysfunction was mitigated in MHC-ACSL1 hearts compared with nontransgenic hearts. At 14 weeks, TAC increased heart weight to tibia length by 46% in nontransgenic mice, but only 26% in MHC-ACSL1 mice, whereas ACSL1 mice retained greater ejection fraction (ACSL1 TAC: 65.8±7.5%; nontransgenic TAC: 45.9±7.3) and improvement in diastolic E/E’. Functional improvements were mediated by ACSL1 changes to cardiac LCFA trafficking. ACSL1 accelerated LCFA uptake, preventing C16 acyl CoA loss post-TAC. Long-chain acyl CoA was similarly reduced in human failing myocardium and restored to control levels by mechanical unloading. ACSL1 trafficked LCFA into ceramides without normalizing the reduced triglyceride storage in TAC. ACSL1 prevented de novo synthesis of cardiotoxic C16- and C24-, and C24:1 ceramides and increased potentially cardioprotective C20- and C22-ceramides post-TAC. ACLS1 overexpression activated AMP activated protein kinase at baseline, but during TAC, prevented the reduced LCFA oxidation in hypertrophic hearts and normalized energy state (phosphocreatine:ATP) and consequently, AMP activated protein kinase activation. Conclusions: This is the first demonstration of reduced acyl CoA in failing hearts of humans and mice, and suggests possible mechanisms for maintaining mitochondrial oxidative energy metabolism by restoring long-chain acyl CoA through ASCL1 activation and mechanical unloading. By mitigating cardiac lipotoxicity, via redirected LCFA trafficking to ceramides, and restoring acyl CoA, ACSL1 delayed progressive cardiac remodeling and failure.