The Geriatric Research, Education and Clinical Center, Department of Medicine, School of Medicine, University of Maryland, Baltimore, Maryland 21201.
The Geriatric Research, Education and Clinical Center, Department of Medicine, School of Medicine, University of Maryland, Baltimore, Maryland 21201; Baltimore Veterans Affairs Health Care Center, Division of Endocrinology, Department of Medicine, School of Medicine, University of Maryland, Baltimore, Maryland 21201.
J Lipid Res. 2011 Dec;52(12):2159-2168. doi: 10.1194/jlr.M017939. Epub 2011 Aug 31.
Maintaining cellular lipid homeostasis is crucial to oxidative tissues, and it becomes compromised in obesity. Lipid droplets (LD) play a central role in lipid homeostasis by mediating fatty acid (FA) storage in the form of triglyceride, thereby lowering intracellular levels of lipids that mediate cellular lipotoxicity. LDs and mitochondria have interconnected functions, and anecdotal evidence suggests they physically interact. However, the mechanisms of interaction have not been identified. Perilipins are LD-scaffolding proteins and potential candidates to play a role in their interaction with mitochondria. We examined the contribution of LD perilipin composition to the physical and metabolic interactions between LD and mitochondria using multiple techniques: confocal imaging, electron microscopy (EM), and lipid storage and utilization measurements. Using neonatal cardiomyocytes, reconstituted cell culture models, and rodent heart tissues, we found that perilipin 5 (Plin5) recruits mitochondria to the LD surface through a C-terminal region. Compared with control cells, Plin5-expressing cells show decreased LD hydrolysis, decreased palmitate β-oxidation, and increased palmitate incorporation into triglycerides in basal conditions, whereas in stimulated conditions, LD hydrolysis inhibition is lifted and FA released for β-oxidation. These results suggest that Plin5 regulates oxidative LD hydrolysis and controls local FA flux to protect mitochondria against excessive exposure to FA during physiological stress.
维持细胞脂质稳态对氧化组织至关重要，而在肥胖症中则会受到损害。脂滴 (LD) 通过将脂肪酸 (FA) 以甘油三酯的形式储存来介导脂质稳态，从而降低介导细胞脂肪毒性的细胞内脂质水平，从而在脂质稳态中发挥核心作用。LD 和线粒体具有相互关联的功能，并且有证据表明它们之间存在物理相互作用。然而，相互作用的机制尚未确定。脂滴相关蛋白 ( perilipin ) 是 LD 的支架蛋白，是其与线粒体相互作用的潜在候选蛋白。我们使用多种技术：共聚焦成像、电子显微镜 (EM)、脂质储存和利用测量，研究了 LD 中 perilipin 组成对 LD 和线粒体之间的物理和代谢相互作用的贡献。使用新生心肌细胞、重建的细胞培养模型和啮齿动物心脏组织，我们发现 perilipin 5 (Plin5) 通过 C 端区域将线粒体募集到 LD 表面。与对照细胞相比，表达 Plin5 的细胞在基础条件下显示出 LD 水解减少、棕榈酸 β-氧化减少和棕榈酸掺入甘油三酯增加，而在刺激条件下，LD 水解抑制被解除，FA 释放用于 β-氧化。这些结果表明 Plin5 调节氧化 LD 水解，并控制局部 FA 通量，以在生理应激期间保护线粒体免受 FA 的过度暴露。
