Pathogenesis of liver injury and hepatic fibrosis in Non-Alcoholic SteatoHepatitis, NASH

非酒精性脂肪性肝炎(NASH)是富裕国家最常见的肝病形式。在澳大利亚，至少3%的人口和20%的肥胖者患有NASH。这种鲜为人知的疾病涵盖了一系列肝脏疾病-从相对良性的肝脏过度脂肪存在-到肝硬变和肝功能衰竭。这种肝损害模式实际上与酒精性肝炎相同，但NASH排除了饮酒。它通常与II型糖尿病、肥胖症和血脂紊乱有关。尽管脂肪肝本身被认为是无害的和可逆的，但少数患有这种轻度综合征的病例发展为更严重的NASH形式。该项目的一个目标是确定和描述在脂肪肝中引发损伤并导致肝细胞破坏的因素。作为对NASH患者最初的肝脏损伤的反应，肝脏中的细胞和免疫系统中的细胞会发生炎症反应。然而，这可能会放大最初的侮辱的影响，从而使肝脏更容易受到进一步的伤害。炎症反应由特定的肝脏和免疫细胞产生的关键信号分子控制。该项目的第二个目标是确定这些分子及其细胞来源，并确定它们是否使NASH的疾病过程永久化。肝脏损伤和随之而来的炎症反应的一个结果是，肝脏通过在类似于伤口愈合的过程中形成疤痕组织纤维来修复损伤。如果不加以控制，这个纤维化过程会导致肝硬变和严重的肝脏并发症。最终目的是对肝细胞损伤、炎症反应和纤维化之间的联系获得新的见解，最终将导致预防这种疾病的初始触发因素的治疗，并阻止NASH进展到更严重的纤维化阶段。

Nonalcoholic steatohepatitis (NASH) is the most common form of liver disease in affluent countries. In Australia at least 3% of the population and 20% of those with obesity have NASH. This poorly understood disease covers a spectrum of liver disorders - from relatively benign presence of excess fat in the liver - to cirrhosis and liver failure. This pattern of liver damage is virtually identical to alcoholic hepatitis, however alcohol consumption is excluded in NASH. It is often associated with type II diabetes , obesity and lipid disorders. Although fatty liver by itself is thought to be innocuous and reversible, a small number of cases with this mild syndrome progress to a more severe form of NASH. One aim of this project is to identify and characterise the factors which trigger injury in a fatty liver and lead to the destruction of liver cells. In response to the initial liver injury in NASH, cells in the liver and from the immune system mount an inflammatory reaction. However this may make the liver even more susceptible to further injury by amplifying the effect of the initial insult. The inflammatory response is controlled by key signalling molecules produced by specific liver and immune cells. The second aim of this project is to identify such molecules and their cellular source and to determine whether they perpetuate the disease processes of NASH. One outcome of liver injury and the consequent inflammatory reaction is that the liver repairs the damage by forming fibres of scar tissue in a process similar to wound healing. When unchecked this process of fibrosis leads to cirrhosis and the development of severe liver complications. The final aim is to gain new insights into the links between liver cell injury, the inflammatory response and fibrosis which will eventually lead to treatments to prevent the initial triggers of this disease and also to interrupt the progression of NASH to more serious fibrotic stage.