Lipotoxic Palmitate Impairs the Rate of β-Oxidation and Citric Acid Cycle Flux in Rat Neonatal Cardiomyocytes

Abstract

Background/Aims: Diabetic hearts exhibit intracellular lipid accumulation. This suggests that the degree of fatty acid oxidation (FAO) in these hearts is insufficient to handle the elevated lipid uptake. We previously showed that palmitate impaired the rate of FAO in primary rat neonatal cardiomyocytes. Here we were interested in characterizing the site of FAO impairment induced by palmitate since it may shed light on the metabolic dysfunction that leads to lipid accumulation in diabetic hearts. Methods: We measured fatty acid oxidation, acetyl-CoA oxidation, and carnitine palmitoyl transferase (Cpt1b) activity. We measured both forward and reverse aconitase activity, as well as NAD+ dependent isocitrate dehydrogenase activity. We also measured reactive oxygen species using the 2', 7'-Dichlorofluorescin Diacetate (DCFDA) assay. Finally we used thin layer chromatography to assess diacylglycerol (DAG) levels. Results: We found that palmitate significantly impaired mitochondrial β-oxidation as well as citric acid cycle flux, but not Cpt1b activity. Palmitate negatively affected net aconitase activity and isocitrate dehydrogenase activity. The impaired enzyme activities were not due to oxidative stress but may be due to DAG mediated PKC activation. Conclusion: This work demonstrates that palmitate, a highly abundant fatty acid in human diets, causes impaired β-oxidation and citric acid cycle flux in primary neonatal cardiomyocytes. This metabolic defect occurs prior to cell death suggesting that it is a cause, rather than a consequence of palmitate mediated lipotoxicity. This impaired mitochondrial metabolism can have important implications for metabolic diseases such as diabetes and obesity.

Association between Epicardial Adipose Tissue Thickness and Left Ventricular Diastolic Functions

“…16,17 Consequently, these studies suggested that EAT may lead to LV hypertrophy, left atrium (LA) dilation, diastolic and systolic dysfunction, irrespective of the presence of coronary artery disease (CAD). [16][17][18][19][20][21] Consistent with these fi ndings, CRP, an infl ammatory marker, was higher in the patient with diastolic dysfunction and was associated with increased EAT thickness in our study.…”

Oxidative and endoplasmic reticulum stresses are involved in palmitic acid-induced H9c2 cell apoptosis

“…Diets rich in high fat foods, especially saturated fats, cause obesity, leading to serious health problems, such as type 2 diabetes and lipotoxic cardiomyopathy [1]. It has been confirmed that the degree of lipid accumulation is linked to cardiac dysfunction of human diabetic hearts [2,3]. Palmitic acid (PA), the most common saturated long-chain fatty acid, triggers apoptosis in many cell types including cardiomyocytes [4].…”

Lipid Peroxidation as a Link between Unhealthy Diets and the Metabolic Syndrome

“…Palmitate also induces oxidative stress and ER stress independently of ceramide. For example, it increases diacylglycerol levels, which is associated with activation of protein kinase C (PKC), which inhibits the Kreb's cycle enzymes aconitase and isocitrate dehydrogenase [91]. Thus, the acetyl COA generated from peroxisomal and mitochondrial fatty acid beta oxidation accumulates in the cell, promoting acetylation of mammalian target of rapamycin complex (MTORC-1) and high mobility group box-1 (HMGB-1), as has been demonstrated in hepatocytes [92].…”