Analysis of the role of Four and a half LIM domains protein 2 (FHL2) in hepatic lipid metabolisms in non-alcoholic fatty liver disease (NAFLD)

非酒精性脂肪性肝病(NAFLD)是全球最常见的肝病。肝脏脂肪变性是NAFLD发病的第一步，也是发病的原动力。因此，全面了解导致肝内脂质积聚的分子机制是非常必要的，以支持开发治疗NAFLD的有效形式，这些治疗方法到目前为止还缺乏，但非常需要。FHL2是“四个半LIM结构域”蛋白家族的第二个成员。FHL2广泛表达，参与调节健康和疾病的各种生物学机制。FHL2缺乏直接的DNA结合活性，但可与包括转录因子在内的多种蛋白质相互作用，从而起到转录辅助激活或辅助抑制的作用。我们的初步工作表明，FHL2在肝细胞中的表达增强促进了NAFLD的肝脏脂肪变性。本项目的目的是在临床前模型中表征FHL2影响肝脏脂肪变性的分子机制，并在NAFLD患者的临床样本中验证这一发现。总体目标是确定新的治疗靶点，以抑制NAFLD的发展和进展。

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Hepatic steatosis is the first step and driving force of the NAFLD-pathology. Therefore, a comprehensive understanding of the molecular mechanisms leading to the accumulation of intrahepatic lipids is critically needed to support the development of effective forms of treatments for NAFLD, which are so far missing but highly needed. FHL2 is the second member of the "four-and-a-half LIM-domain" protein-family. FHL2 is ubiquitously expressed and is involved in the regulation of various biological mechanisms in health and disease. FHL2 lacks direct DNA binding activities but interacts with numerous proteins including transcription factors, and herewith, acts as transcriptional coactivator or corepressor. Our preliminary work indicates that enhanced FHL2 expression in hepatocytes promotes liver steatosis in NAFLD. The aims of this project are to characterize the molecular mechanisms by which FHL2 affects hepatic steatosis in preclinical models and to validate the findings in clinical samples of NAFLD-patients. The overall goal is the identification of new therapeutic targets for the inhibition of the development and progression of NAFLD.