High susceptibility to fatty liver disease in two-pore channel 2-deficient mice
High susceptibility to fatty liver disease in two-pore channel 2-deficient mice
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DOI：
10.1038/ncomms5699
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发表时间：
2014-08-01
影响因子：
16.6
通讯作者：
Wahl-Schott, Christian
中科院分区：
文献类型：
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作者：
Grimm, Christian;Holdt, Lesca M.;Wahl-Schott, Christian
内溶酶体细胞器在低密度脂蛋白（LDL）胆固醇、上皮生长因子（EGF）或转铁蛋白等不同大分子的运输、分解和受体介导的回收中发挥着关键作用。在这里，我们研究了双孔通道 (TPC) 2（一种内溶酶体阳离子通道）在这些过程中的作用。缺乏 TPC2 的胚胎小鼠成纤维细胞和肝细胞显示出 LDL 胆固醇和 EGF/EGF 受体运输的严重损害。从机制上讲，这两种缺陷均可归因于内溶酶体降解途径的功能障碍，最有可能是在晚期内体与溶酶体融合的水平上。重要的是，TPC2 缺陷细胞中的内溶酶体酸化或溶酶体酶功能是正常的。 TPC2缺陷的小鼠非常容易出现与非酒精性脂肪肝一致的肝脏胆固醇超载和肝损伤。这些发现表明肝脏胆固醇处理的代谢储备减少。我们的结果表明，TPC2 在内溶酶体降解途径的运输中发挥着至关重要的作用，因此，可能参与许多大分子和细胞代谢物的稳态控制。
Endolysosomal organelles play a key role in trafficking, breakdown and receptor-mediated recycling of different macromolecules such as low-density lipoprotein (LDL)-cholesterol, epithelial growth factor (EGF) or transferrin. Here we examine the role of two-pore channel (TPC) 2, an endolysosomal cation channel, in these processes. Embryonic mouse fibroblasts and hepatocytes lacking TPC2 display a profound impairment of LDL-cholesterol and EGF/EGF-receptor trafficking. Mechanistically, both defects can be attributed to a dysfunction of the endolysosomal degradation pathway most likely on the level of late endosome to lysosome fusion. Importantly, endolysosomal acidification or lysosomal enzyme function are normal in TPC2-deficient cells. TPC2-deficient mice are highly susceptible to hepatic cholesterol overload and liver damage consistent with non-alcoholic fatty liver hepatitis. These findings indicate reduced metabolic reserve of hepatic cholesterol handling. Our results suggest that TPC2 plays a crucial role in trafficking in the endolysosomal degradation pathway and, thus, is potentially involved in the homoeostatic control of many macromolecules and cell metabolites.