Deciperhing inter-organelle cross talk in epithelial architecture

肝脏主要由称为肝细胞的特化细胞组成。肝细胞执行重要的功能，包括胆汁分泌，从血液中摄取营养物质如葡萄糖和脂质，以及从血液中清除毒素。为了执行这些不同的任务，在肝细胞之间形成细胞-细胞连接以维持胆汁-血液屏障。肝细胞之间的连接缺陷是包括脂肪肝疾病和肝癌在内的肝病的标志。因此，了解细胞间连接是如何在肝细胞中建立和维持的是至关重要的。最近，使用电子显微镜，我们观察到细胞膜（称为质膜，PM）中的连接复合物经常被发现靠近称为内质网（ER）的细胞内膜区室。因此，细胞内ER膜隔室广泛位于PM中形成肝细胞之间连接的区域。ER和PM之间的接触（ER-PM接触）是新合成的膜脂质从ER转移到PM的重要位点。我们正在进行的研究揭示了ER-PM接触如何维持肝细胞之间连接稳定所需的PM脂质的精确供应。肝细胞在血液中脂质慢性过载时易受损伤，称为脂毒性。非酒精相关性脂肪肝（NAFLD）是由肝脏中脂肪积累引起的一种疾病，在英国和西方世界越来越受到健康问题的关注。据英国肝脏信托基金会估计，三分之一的人患有早期NAFLD，20%的NAFLD患者可能会发展为更严重的肝脏疾病，包括肝癌。转移性癌细胞的标志是细胞-细胞连接的丧失，其允许随后的癌细胞迁移。因此，我们的研究，以揭示细胞内的ER如何维持正常的肝细胞的结构和功能，可能会导致新的见解的膜脂和细胞连接的改变引起的肝脏疾病的进展。

The liver is composed mostly of specialised cells known as hepatocytes. Hepatocytes perform vital functions including bile secretion, uptake of nutrients such as glucose and lipids from the blood, as well as the removal of toxins from the blood. To perform these distinct tasks, cell-cell junctions form between hepatocytes to maintain the bile-blood barrier. Defects in junctions between hepatocytes are a hallmark of liver disease including fatty liver disease and liver cancer. It is therefore crucial to understand how cell-cell junctions are established and maintained in hepatocytes.Recently, using electron microscopy, we have observed that junctional complexes in the cell membrane (termed the plasma membrane, PM) are often found in close proximity to an intracellular membrane compartment termed the endoplasmic reticulum (ER). Thus, intracellular ER membrane compartments are extensively localised at regions in the PM that form junctions between hepatocytes. Contacts between the ER and PM (ER-PM contacts) are important sites for the transfer of newly synthesised membrane lipids from the ER to the PM. Our ongoing studies are revealing how ER-PM contacts maintain the precise supply of lipids to the PM needed for the stability of junctions between hepatocytes. Hepatocytes are susceptible to damage upon chronic overload of lipids from the blood, termed lipotoxicity. Non-alcohol related fatty liver disease (NAFLD), a condition caused by the accumulation of fat in the liver, is a growing health concern in the UK and the western world. According to the British Liver Trust, it is estimated that one in three people have early-stage NAFLD and that 20% of patients with NAFLD may develop more severe liver disorders including liver cancer. A hallmark of metastatic cancer cells is the loss of cell-cell junctions that allows subsequent cancer cell migration. Consequently, our studies to reveal how the intracellular ER maintains normal hepatocyte architecture and function may lead to new insight into the progression of liver diseases caused by alterations in membrane lipids and cell-cell junctions.