TM6SF2 is a regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content
TM6SF2 is a regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content
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DOI：
10.1073/pnas.1323785111
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发表时间：
2014-06-17
影响因子：
11.1
通讯作者：
van't Hooft, Ferdinand
中科院分区：
文献类型：
--
作者：
Mahdessian, Hovsep;Taxiarchis, Apostolos;van't Hooft, Ferdinand
全基因组关联研究已经确定了19号染色体上的一个位点与血浆甘油三酯（TG）浓度和非酒精性脂肪肝疾病相关。然而，负责这些关联的基因的身份和功能作用仍然未知。在这个位点中包含的19个表达基因中，没有一个先前与脂质代谢有关。我们在206个人类肝脏样本中进行了基因表达研究和表达数量性状位点分析，以确定推定的致病基因。跨膜6超家族成员2（Transmembrane 6 superfamily member 2，TM 6SF 2）是一个功能未知的基因，主要在肝脏和肠道中表达，被认为是致病基因。TM 6SF 2编码351个氨基酸，具有7-10个预测的跨膜结构域。除此之外，没有发现其他蛋白质特征可以帮助阐明TM 6SF 2的功能。共聚焦显微镜下的蛋白质亚细胞定位研究表明，TM 6SF 2定位于内质网和ER-高尔基体的人肝细胞的中间隔室。利用共聚焦显微镜和siRNA抑制和过表达技术对人肝癌Huh 7和HepG 2细胞中富含TG的脂蛋白（TRL）的分泌和脂滴含量进行了功能研究。与全基因组关联数据一致，发现TM 6SF 2 siRNA抑制与TRL分泌减少和细胞TG浓度和脂滴含量增加相关，而TM 6SF 2过表达减少肝细胞脂肪变性。我们的结论是，TM 6SF 2是一个调节肝脏脂肪代谢的TRLs和肝脂滴含量的分泌具有相反的效果。
Genome-wide association studies have identified a locus on chromosome 19 associated with plasma triglyceride (TG) concentration and nonalcoholic fatty liver disease. However, the identity and functional role of the gene(s) responsible for these associations remain unknown. Of 19 expressed genes contained in this locus, none has previously been implicated in lipid metabolism. We performed gene expression studies and expression quantitative trait locus analysis in 206 human liver samples to identify the putative causal gene. Transmembrane 6 superfamily member 2 (TM6SF2), a gene with hitherto unknown function, expressed predominantly in liver and intestine, was identified as the putative causal gene. TM6SF2 encodes a protein of 351 amino acids with 7-10 predicted transmembrane domains. Otherwise, no other protein features were identified which could help to elucidate the function of TM6SF2. Protein subcellular localization studies with confocal microscopy demonstrated that TM6SF2 is localized in the endoplasmic reticulum and the ER-Golgi intermediate compartment of human liver cells. Functional studies for secretion of TG-rich lipoproteins (TRLs) and lipid droplet content were performed in human hepatoma Huh7 and HepG2 cells using confocal microscopy and siRNA inhibition and overexpression techniques. In agreement with the genome-wide association data, it was found that TM6SF2 siRNA inhibition was associated with reduced secretion of TRLs and increased cellular TG concentration and lipid droplet content, whereas TM6SF2 overexpression reduced liver cell steatosis. We conclude that TM6SF2 is a regulator of liver fat metabolism with opposing effects on the secretion of TRLs and hepatic lipid droplet content.