Caveolin-1 and TGF-beta crosstalk in hepatocytes in non-alcoholic fatty liver disease/ non alcoholic steatohepatitis (NAFLD/NASH)

非酒精性脂肪性肝病/非酒精性脂肪性肝炎 (NAFLD/NASH) 肝细胞中的 Caveolin-1 和 TGF-β 串扰

• 批准号: 276773423
• 负责人: Dr. Christoph Meyer
• 金额: --
• 依托单位: Medizinische Fakultät Mannheim
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/276773423?language=en
• 关键词: Caveolin; TGF; beta; crosstalk; hepatocytes

Non-alcoholic fatty liver disease (NAFLD) is a global health concern with increasing numbers especially in Western countries with an incidence of 20-30%. Frequently, inflammation and fibrotic remodeling develops in those patients (NASH) which may culminate in severe chronic liver injury with fatal prognosis. We could previously show that caveolin-1 is deregulated in chronic liver diseases. Caveolin-1 is a protein involved in endocytic processes and a potent regulator of diverse signaling pathways. Furthermore, our microarray analyses defined caveolin-1 as modulator of metabolic processes in hepatocytes. In context of chronic liver disease, abundance of TGF-beta fosters fibrogenesis. TGF-beta is a pleiotropic cytokine and fulfills a range of functions on diverse cell types. Towards hepatocytes, it can trigger epithelial to mesenchymal transition as well as control proliferation and induce apoptosis. We could previously show that caveolin-1 is a strong modulator of the TGF-beta signaling pathway in hepatocytes which determines cell fate. In the proposed project we intend to determine the influence of hepatocyte specific caveolin-1 on NASH development. In addition, we will assess the crosstalk of caveolin-1 and TGF-beta during liver disease development and progression. Finally, we will investigate how caveolin-1 is regulated during disease progression in vivo. To achieve our ambitious goals, we will make use of hepatocyte specific caveolin-1 knockout animals which will be fed a methionine/choline deficient diet to induce NAFLD/NASH. Furthermore, we will over-express caveolin-1 and/or TGF-beta (via lentiviral and adenoviral transduction in vivo) to study functional consequences on the cellular and organ level.This approach will enable us to determine the function of caveolin-1 on hepatocyte physiology and metabolism in healthy and diseased states as well as to describe in detail the regulation of TGF-beta signaling and cellular consequences in vivo. Hence, this attempt will give rational whether caveolin-1 in hepatocytes is a putative druggable target in metabolic liver disease.

非酒精性脂肪性肝病（NAFLD）是一个全球性的健康问题，其发病率越来越高，特别是在西方国家，发病率为20- 30%。通常，炎症和纤维化重塑在这些患者（NASH）中发展，这可能最终导致具有致命预后的严重慢性肝损伤。我们以前可以证明caveolin-1在慢性肝病中是失调的。Caveolin-1是一种参与内吞过程的蛋白质，是多种信号通路的有效调节剂。此外，我们的微阵列分析定义小窝蛋白-1作为肝细胞代谢过程的调节剂。在慢性肝病的背景下，TGF-β的丰富促进纤维化。TGF-β是一种多效性细胞因子，在不同的细胞类型上发挥一系列功能。对于肝细胞，它可以触发上皮向间充质转化以及控制增殖和诱导凋亡。我们先前已经证明小窝蛋白-1是肝细胞中TGF-β信号通路的强调节剂，该通路决定细胞命运。在这个项目中，我们打算确定肝细胞特异性小窝蛋白-1对NASH发展的影响。此外，我们将评估caveolin-1和TGF-β在肝脏疾病发展和进展过程中的相互作用。最后，我们将研究小窝蛋白-1在体内疾病进展过程中的调节。为了实现我们雄心勃勃的目标，我们将利用肝细胞特异性小窝蛋白-1敲除动物，这些动物将被喂食甲硫氨酸/胆碱缺乏的饮食以诱导NAFLD/NASH。此外，我们将过度表达小窝蛋白-1和/或TGF-β（通过慢病毒和腺病毒体内转导），以研究在细胞和器官水平上的功能后果。这种方法将使我们能够确定小窝蛋白-1在健康和疾病状态下对肝细胞生理和代谢的功能，以及详细描述TGF-β信号转导和细胞后果的调节。因此，这一尝试将合理地给出肝细胞中的小窝蛋白-1是否是代谢性肝病中假定的可用药靶点。