Xu Wenyi, Wu Lizhen, Yu Miao, Chen Feng-Jung, Arshad Muhammad, Xia Xiayu, Ren Hao, Yu Jinhai, Xu Li, Xu Dijin, Li John Zhong, Li Peng, Zhou Linkang
From the MOE Key Laboratory of Bioinformatics and Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
the Department of Bioinformatics and Biotechnology, International Islamic University, Islamabad 44000, Pakistan.
J Biol Chem. 2016 Feb 26;291(9):4282-93. doi: 10.1074/jbc.M115.701094. Epub 2016 Jan 5.
Lipid droplets (LDs) are dynamic subcellular organelles whose growth is closely linked to obesity and hepatic steatosis. Cell death-inducing DNA fragmentation factor-α-like effector (CIDE) proteins, including Cidea, Cideb, and Cidec (also called Fsp27), play important roles in lipid metabolism. Cidea and Cidec are LD-associated proteins that promote atypical LD fusion in adipocytes. Here, we find that CIDE proteins are all localized to LD-LD contact sites (LDCSs) and promote lipid transfer, LD fusion, and growth in hepatocytes. We have identified two types of hepatocytes, one with small LDs (small LD-containing hepatocytes, SLHs) and one with large LDs (large LD-containing hepatocytes, LLHs) in the liver. Cideb is localized to LDCSs and promotes lipid exchange and LD fusion in both SLHs and LLHs, whereas Cidea and Cidec are specifically localized to the LDCSs and promote lipid exchange and LD fusion in LLHs. Cideb-deficient SLHs have reduced LD sizes and lower lipid exchange activities. Fasting dramatically induces the expression of Cidea/Cidec and increases the percentage of LLHs in the liver. The majority of the hepatocytes from the liver of obese mice are Cidea/Cidec-positive LLHs. Knocking down Cidea or Cidec significantly reduced lipid storage in the livers of obese animals. Our data reveal that CIDE proteins play differential roles in promoting LD fusion and lipid storage; Cideb promotes lipid storage under normal diet conditions, whereas Cidea and Cidec are responsible for liver steatosis under fasting and obese conditions.
脂滴（LDs）是动态的亚细胞细胞器，其生长与肥胖和肝脂肪变性密切相关。细胞死亡诱导DNA片段化因子-α样效应蛋白（CIDE），包括Cidea、Cideb和Cidec（也称为Fsp27），在脂质代谢中起重要作用。Cidea和Cidec是与脂滴相关的蛋白，可促进脂肪细胞中的非典型脂滴融合。在这里，我们发现CIDE蛋白都定位于脂滴-脂滴接触位点（LDCSs），并促进肝细胞中的脂质转移、脂滴融合和生长。我们在肝脏中鉴定出两种类型的肝细胞，一种含有小脂滴（含小脂滴肝细胞，SLHs），另一种含有大脂滴（含大脂滴肝细胞，LLHs）。Cideb定位于LDCSs，促进SLHs和LLHs中的脂质交换和脂滴融合，而Cidea和Cidec则特异性定位于LDCSs，促进LLHs中的脂质交换和脂滴融合。Cideb缺陷的SLHs脂滴尺寸减小，脂质交换活性降低。禁食显著诱导Cidea/Cidec的表达，并增加肝脏中LLHs的百分比。肥胖小鼠肝脏中的大多数肝细胞是Cidea/Cidec阳性的LLHs。敲低Cidea或Cidec可显著减少肥胖动物肝脏中的脂质储存。我们的数据表明，CIDE蛋白在促进脂滴融合和脂质储存中发挥不同作用；Cideb在正常饮食条件下促进脂质储存，而Cidea和Cidec在禁食和肥胖条件下导致肝脏脂肪变性。
