Impaired fatty acid oxidation as a cause for lipotoxicity in cardiomyocytes

脂毒性 肉碱 内分泌学 肉碱O-棕榈酰转移酶 脂肪酸 β氧化 内科学 生物 化学 饱和脂肪酸 糖尿病性心肌病 脂滴 生物化学 心肌病 糖尿病 医学 心力衰竭 胰岛素抵抗
作者
Taha Haffar,Félix‐Antoine Bérubé‐Simard,Nicolas Bousette
出处
期刊:Biochemical and Biophysical Research Communications [Elsevier BV]
卷期号:468 (1-2): 73-78 被引量:33
标识
DOI:10.1016/j.bbrc.2015.10.162
摘要

A major cause for diabetic cardiomyopathy is excess lipid accumulation. To elucidate mechanisms of lipotoxicity mediated diabetic heart disease we need to further our understanding of how lipid metabolism is altered in the diabetic heart. Here we investigated the role of lipid clearance by oxidation as a regulator of lipid-mediated toxicity (lipotoxicity). We evaluated the effect of pre-treating rat neonatal cardiomyocytes (NCMs) with either oleate (mono-unsaturated fatty acid) or palmitate (saturated fatty acid) on fatty acid oxidation (FAO) by measuring (14)C-CO2 production. We evaluated carnitine palmitoyltransferase (Cpt1b) expression by western blotting and mitochondrial membrane potential by quantitative and qualitative fluorescence analyses using the JC-1 dye. We inhibited the Cpt1b pharmacologically using etomoxir and genetically by knocking down its expression using LentiVector mediated transduction of siRNAs targeting the Cpt1b gene. We found that palmitate had a slower clearance rate from NCMs than oleate, and this was associated with a significant decrease in FAO. This impairment in FAO was not the result of either loss of Cpt1b protein or mitochondrial integrity. Enhancing FAO with either oleate or carnitine was associated with a significant attenuation of palmitate mediated lipotoxicity. In contrast impairing FAO in oleate treated NCMs caused lipotoxicity. Here we demonstrate that a major difference between non-toxic unsaturated fatty acids and toxic saturated fatty acids is there ability to stimulate or inhibit fatty acid oxidation, respectively. This has important implications for diabetic cardiomyopathy since diabetic hearts consistently exhibit elevated lipid accumulation.
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