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

Abstract

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...

Fatty Acid Chain Elongation in Palmitate-perfused Working Rat Heart

“…The potential metabolic significance of this pathway is highlighted by the fact that the content of stearate, relative to palmitic acid, is nearly double in heart what it is in plasma (5). Consistent with the high cardiac stearate content reported previously (5), oleyl-CoA and stearoylCoA are the dominant long-chain acyl-CoAs in rat heart, independent of diet (47). Stearic acid is an important component of phospholipids, which in turn are important structural and functional components of membranes.…”

“…Enzymes known to catalyze the synthesis of malonyl-CoA from acetyl-CoA are ACC1, confined to the cytosol, and ACC2, localized on the cytosolic surface of outer mitochondrial membrane (22), whereas enzymes catalyzing fatty acid chain elongation, known as Elovl1-7, are localized in endoplasmic reticulum (7,45). It has been shown that of the seven Elovl enzymes, rat heart expresses Elovl1, Elovl3, and Elovl6 mRNAs (46), and in rat heart, the presence of Elovl6 also has been documented at the protein level (47). Thus, fatty acid chain elongation using intramitochondrial generated acetyl-CoA requires the export of acetyl-CoA into the cytosol and carboxylation of acetyl-CoA to malonyl-CoA, which serves as the chain extender for fatty acid chain elongation.…”

“…Of the seven Elovls, the heart expresses Elovl1, Elovl5, and Elovl6 (7,8,46,47). From the known substrate specificity of the three Elovls expressed in heart Elovl6, is most likely responsible for the observed chain elongation of palmitate to stearate (8,16).…”

Redox regulation of insulin sensitivity due to enhanced fatty acid utilization in the mitochondria

“…Based on this scenario, the appropriate therapeutic strategy for preserving insulin sensitivity is to increase mitochondrial fatty acid oxidation to prevent the accumulation of intramuscular triacylglycerol (16,97). However, recent evidence indicates that ␤-oxidation rapidly increases in response to high dietary fat (41,58,88,100) and that inhibition rather than activation of fat consumption is cardioprotective (52,57,58,65,93). Long-chain acyl-CoA molecules are converted to acylcarnitines by carnitine palmitoyltransferase 1 before mitochondrial import.…”

The Partial Replacement of Lard by Caryocar brasiliense Oil in a Western Diet improves Cardiovascular Risk Factors in Rats

“…Upon western diet, lysogenic pathways are stimulated, using as substrates SFA and simple carbohydrates to produce endogenous SFA or MUFA. However, synthesis of desaturases does not follow the fatty acid generation, leading to an imbalance into SFA/MUFA ratio and stimulating the replacement of MUFA by SFA in cardiomyocytes, which is also associated with contractile dysfunction of the cardiac muscle [54]. We believe that the high supply of MUFA in the pequi oil diet could have favored their incorporation into the cardiomyocyte membranes, ameliorating the dysfunction cause by SFA/MUFA impairment.…”