Lipid-induced NOX2 activation inhibits autophagic flux by impairing lysosomal enzyme activity
Lipid-induced NOX2 activation inhibits autophagic flux by impairing lysosomal enzyme activity
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DOI：
10.1194/jlr.m055152
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发表时间：
2015-03-01
影响因子：
6.5
通讯作者：
Abel, E. Dale
中科院分区：
文献类型：
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作者：
Jaishy, Bharat;Zhang, Quanjiang;Abel, E. Dale
自噬是一种参与维持能量和细胞器稳态的分解代谢过程。肥胖与自噬调节之间的关系是细胞类型特异性的。尽管肥胖对心脏结构和功能产生不利影响，但心脏自噬改变对脂肪酸超载的影响尚不完全清楚。在这里，我们报告了高脂肪喂养的小鼠心脏和棕榈酸处理的 H9C2 心肌细胞 (CM) 中自噬体清除的抑制和 NADPH 氧化酶 (Nox) 2 的激活。在棕榈酸酯处理的 CM 中，自噬体清除缺陷是继发于超氧化物依赖性溶酶体酸化和酶活性损伤的原因。抑制 Nox2 可以防止超氧化物过量产生，恢复溶酶体酸化和酶活性，并减少棕榈酸酯处理的 CM 中自噬体的积累。棕榈酸酯诱导的 Nox2 激活依赖于经典蛋白激酶 Cs (PKC)，特别是 PKC beta II 的激活。这些发现揭示了一种新机制，该机制将脂毒性与 PKC beta-Nox2 介导的 pH 依赖性溶酶体酶活性损害联系起来，从而减少 CM 中的自噬周转。
Autophagy is a catabolic process involved in maintaining energy and organelle homeostasis. The relationship between obesity and the regulation of autophagy is cell type specific. Despite adverse consequences of obesity on cardiac structure and function, the contribution of altered cardiac autophagy in response to fatty acid overload is incompletely understood. Here, we report the suppression of autophagosome clearance and the activation of NADPH oxidase (Nox) 2 in both high fat-fed murine hearts and palmitate-treated H9C2 cardiomyocytes (CMs). Defective autophagosome clearance is secondary to superoxide-dependent impairment of lysosomal acidification and enzyme activity in palmitate-treated CMs. Inhibition of Nox2 prevented superoxide overproduction, restored lysosome acidification and enzyme activity, and reduced autophagosome accumulation in palmitate-treated CMs. Palmitate-induced Nox2 activation was dependent on the activation of classical protein kinase Cs (PKCs), specifically PKC beta II. These findings reveal a novel mechanism linking lipotoxicity with a PKC beta-Nox2-mediated impairment in pH-dependent lysosomal enzyme activity that diminishes autophagic turnover in CMs.