Active autophagy but not lipophagy in macrophages with defective lipolysis.
Active autophagy but not lipophagy in macrophages with defective lipolysis.
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DOI：
10.1016/j.bbalip.2015.06.005
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发表时间：
2015-10
期刊：
影响因子：
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通讯作者：
Kratky D
中科院分区：
文献类型：
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作者：
Goeritzer M;Vujic N;Schlager S;Chandak PG;Korbelius M;Gottschalk B;Leopold C;Obrowsky S;Rainer S;Doddapattar P;Aflaki E;Wegscheider M;Sachdev V;Graier WF;Kolb D;Radovic B;Kratky D
在自噬过程中，自噬体与溶酶体融合，降解受损的细胞器和错误折叠的蛋白质。分解产物被释放到细胞质中，并有助于能量和代谢的基础供应，特别是在饥饿期间。脂噬被定义为溶酶体酸性脂肪酶自噬介导的脂滴降解。脂肪甘油三酯脂肪酶（ATGL）是通过水解细胞内ldl中的甘油三酯（tg）催化脂解初始步骤的主要酶。因此，大多数器官和细胞，包括巨噬细胞，缺乏ATGL积累tg，导致细胞内游离脂肪酸浓度降低。缺乏激素敏感脂肪酶（H0）的巨噬细胞缺乏TG积累，尽管体外TG水解酶活性降低。我们假设自噬在脂肪酶缺陷的巨噬细胞中被激活以抵消它们的能量缺陷。因此，我们产生了缺乏ATGL和HSL （A0H0）的小鼠。A0H0小鼠巨噬细胞中性TG水解酶活性降低73%，导致富含TG的LD积累。组织蛋白酶B的表达增加，LC3-II的积累，p62的表达减少，DQ-BSA脱冷增加，表明A0H0巨噬细胞的自噬和功能溶酶体完好。然而，与巴菲霉素A1治疗无关的酸TG水解酶活性和脂质通量明显降低，这表明A0H0巨噬细胞中ld的溶酶体降解并不有效。我们得出结论，在A0H0巨噬细胞中，蛋白质和细胞器的自噬而非ld的自噬作为一种补偿机制是活跃的，以规避和平衡能量底物可用性的降低。
During autophagy, autophagosomes fuse with lysosomes to degrade damaged organelles and misfolded proteins. Breakdown products are released into the cytosol and contribute to energy and metabolic building block supply, especially during starvation. Lipophagy has been defined as the autophagy-mediated degradation of lipid droplets (LDs) by lysosomal acid lipase. Adipose triglyceride lipase (ATGL) is the major enzyme catalyzing the initial step of lipolysis by hydrolyzing triglycerides (TGs) in cytosolic LDs. Consequently, most organs and cells, including macrophages, lacking ATGL accumulate TGs, resulting in reduced intracellular free fatty acid concentrations. Macrophages deficient in hormone-sensitive lipase (H0) lack TG accumulation albeit reduced in vitro TG hydrolase activity. We hypothesized that autophagy is activated in lipase-deficient macrophages to counteract their energy deficit. We therefore generated mice lacking both ATGL and HSL (A0H0). Macrophages from A0H0 mice showed 73% reduced neutral TG hydrolase activity, resulting in TG-rich LD accumulation. Increased expression of cathepsin B, accumulation of LC3-II, reduced expression of p62 and increased DQ-BSA dequenching suggest intact autophagy and functional lysosomes in A0H0 macrophages. Markedly decreased acid TG hydrolase activity and lipid flux independent of bafilomycin A1 treatment, however, argue against effective lysosomal degradation of LDs in A0H0 macrophages. We conclude that autophagy of proteins and cell organelles but not of LDs is active as a compensatory mechanism to circumvent and balance the reduced availability of energy substrates in A0H0 macrophages.