The constitutive lipid droplet protein PLIN2 regulates autophagy in liver
The constitutive lipid droplet protein PLIN2 regulates autophagy in liver
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DOI：
10.1080/15548627.2017.1319544
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发表时间：
2017-01-01
期刊：
影响因子：
13.3
通讯作者：
Chang, Benny Hung-Junn
中科院分区：
文献类型：
--
作者：
Tsai, Tsung-Huang;Chen, Elaine;Chang, Benny Hung-Junn
肝脏中过量的甘油三酯 (TG) 积聚是脂肪肝疾病（一种非常普遍的疾病）的基础。 TG 存在于肝脏中，存在于脂滴中，脂滴是主要的脂质储存细胞器。脂滴是脂滴蛋白的所在地，其中最丰富的是周脂蛋白 (PLIN)，由 5 个不同的基因（Plin1 至 Plin5）编码。在相应的基因产物中，PLIN2是唯一组成型且普遍表达的脂滴蛋白，已被用作脂滴的蛋白标记。我们和其他人报道 plin2(-/-) 小鼠的 TG 含量减少了 60%，并且可以预防脂肪肝。在这里，我们发现 PLIN2 过表达可以保护脂滴免受巨自噬/自噬的影响，而 PLIN2 缺陷会增强自噬并消耗肝脏 TG。 plin2(-/-) 小鼠中增强的自噬可防止严重内质网应激诱导的肝脂肪变性和肝细胞凋亡。相比之下，其他遗传和药理学操作导致的肝脏 TG 消耗对自噬没有影响。重要的是，PLIN2缺陷通过增强自噬降低野生型小鼠胚胎成纤维细胞（MEF）中的细胞TG含量，但不影响缺乏自噬功能的atg7（-/-）MEF中的细胞TG含量。相反，腺病毒-shAtg7介导的肝脏Atg7敲低本身并不会改变肝脏TG水平，表明体内的调节更为复杂。总而言之，PLIN2 守护着自己的家园，即脂滴。 PLIN2 过表达可防止自噬，其下调可通过自噬刺激 TG 分解代谢。
Excess triglyceride (TG) accumulation in the liver underlies fatty liver disease, a highly prevalent ailment. TG occurs in the liver sequestered in lipid droplets, the major lipid storage organelle. Lipid droplets are home to the lipid droplet proteins, the most abundant of which are the perilipins (PLINs), encoded by 5 different genes, Plin1 to Plin5. Of the corresponding gene products, PLIN2 is the only constitutive and ubiquitously expressed lipid droplet protein that has been used as a protein marker for lipid droplets. We and others reported that plin2(-/-) mice have an similar to 60% reduction in TG content, and are protected against fatty liver disease. Here we show that PLIN2 overexpression protects lipid droplets against macroautophagy/autophagy, whereas PLIN2 deficiency enhances autophagy and depletes hepatic TG. The enhanced autophagy in plin2(-/-) mice protects against severe ER stress-induced hepatosteatosis and hepatocyte apoptosis. In contrast, hepatic TG depletion resulting from other genetic and pharmacological manipulations has no effect on autophagy. Importantly, PLIN2 deficiency lowers cellular TG content in wild-type mouse embryonic fibroblasts (MEFs) via enhanced autophagy, but does not affect cellular TG content in atg7(-/-) MEFs that are devoid of autophagic function. Conversely, adenovirus-shAtg7-mediated hepatic Atg7 knockdown per se does not alter the hepatic TG level, suggesting a more complex regulation in vivo. In sum, PLIN2 guards its own house, the lipid droplet. PLIN2 overexpression protects against autophagy, and its downregulation stimulates TG catabolism via autophagy.