Sidt2 regulates hepatocellular lipid metabolism through autophagy
Sidt2 regulates hepatocellular lipid metabolism through autophagy
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Sidt2通过自噬调节肝细胞脂质代谢
DOI：
10.1194/jlr.m073817
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发表时间：
2018-03-01
影响因子：
6.5
通讯作者：
Zhang, Huiwen
中科院分区：
文献类型：
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作者：
Chen, Xueru;Gu, Xuefan;Zhang, Huiwen
SID1跨膜家族成员2（Sidt2）是一种完整的溶酶体膜蛋白。为了研究其明确的功能，我们构建了一种全身性Sidt2基因敲除小鼠模型（Sidt2^{-/-}）。与同窝对照小鼠相比，Sidt2^{-/-}小鼠肝脏中出现显著的脂滴蓄积。首先，观察到Sidt2^{-/-}小鼠和野生型（WT）小鼠在食物摄取、肝细胞脂肪酸摄取和从头脂肪生成、肝细胞脂解以及以极低密度脂蛋白形式的甘油三酯分泌方面具有可比性。然而，Sidt2^{-/-}小鼠血清β - 羟基丁酸水平较低，同时脂肪酸氧化相关基因的mRNA表达正常，这表明脂肪酸的肝脏β - 氧化显著降低。此外，经典的自噬途径标记蛋白p62和LC3 - II在肝脏中增加，并且原代肝细胞中的自噬通量受损，这表明由于Sidt2缺失导致自噬体成熟受阻，这也得到了来自Sidt2^{-/-}小鼠肝脏和原代肝细胞的电子显微镜图像分析的支持。结论是，Sidt2通过在终末阶段调节自噬在小鼠肝脏脂质稳态中发挥重要作用。
SID1 transmembrane family member 2 (Sidt2) is an integral lysosomal membrane protein. To investigate its explicit function, we generated a global Sidt2 knockout mouse model (Sidt2(-/-)). Compared with the littermate controls, Sidt2(-/-) mice exhibited a remarkable accumulation of lipid droplets in liver. First, it was observed that food consumption, hepatocyte fatty acid uptake and de novo lipogenesis, hepatocyte lipolysis, and TG secretion in the form of very low density lipoprotein were comparable between Sidt2(-/-) and WT mice. However, the hepatic beta-oxidation of fatty acids decreased significantly as revealed by a low level of serum beta-hydroxybutyrate in the Sidt2(-/-) mice along with normal mRNA expression of genes involved in fatty acid oxidation. In addition, the classical autophagy pathway marker proteins, p62 and LC3-II, increased in liver, along with compromised autophagic flux in primary hepatocytes, indicating a block of autophagosome maturation due to Sidt2 deficiency, which was also supported by electron microscopy image analysis both in livers and in primary hepatocytes from Sidt2(-/-) mice. It was concluded that Sidt2 plays an important role in mouse hepatic lipid homeostasis by regulating autophagy at the terminal stage.