非酒精性肝炎（NASH）流行日益严峻，防治刻不容缓。近报，NASH与内质网（ER）应激有关，而ER应激又与ER膜钙泵（SERCA）失活相关。我们发现，肝刺激因子（HSS）能抑制自由基致肝线粒体损伤。HSS是否可保护内质网SERCA，抑制ER应激，治疗NASH值得关注。本课题复制NASH动物-细胞模型，研究1）HSS可否减轻ER应激；减轻应激导致肝损害？2）线粒体-内质网重叠区域（称之MAMs）Ca2+失稳态乃触发ER应激之关键，故研究NASH发病时MAMs内Ca2+稳态改变，观察HSS保护SERCA活性，探讨其阻断ER应激发生的机制；3）本室已制备HSS基因敲除（KO）动物，本课题将使用HSS-KO动物验证HSS抑制ER应激效果。本计划旨在阐述SERCA失活-ER应激-NASH发病之关系，并首次利用HSS对SERCA失活这一关键靶点进行干预，为HSS作为保肝药物而应用，提供科学依据。

Nonalcoholic steatohepatitits (NASH) is a chronic liver metabolic disorder. The prevalence of NASH is increasing extremely fast, suggesting that it is an important priority to understanding its pathogenesis. It is reported that the endoplasmic reticulum (ER) stress may contibute to the pathogenesis of NASH. While, the inactivation of sarco/endoplasmic reticulum Ca2+-dependent APTase (SERCA) is highly linked to ER stress. Recnently, we found that HSS (hepatic stimulator substane), a novel liver-specific growth factor, could alleivate ROS-induced liver damage, therefore,we attempt to investigate whether inhibition of ROS attack to SERCA by, could reduce ER stress and alleviate cell injury as well. Based upon this aim, NASH model will be reproduced in cell culture and high-fat-diet fed mice and the experimental approaches are carried out on these points. 1).Whether HSS can effectivly remove ROS and consequencely protect SERCA activity, thereby alleviating ER stress; 2). Ca2+ homostatsis, particularly in the compartment of ER-mitochondria overlap (namely MAMs), is investigated together with alternation of SERCA activity during ER stress; 3). HSS, as an antioxidant, could preserve SERCA activity at basis of recombinant HSS and HSS-transfected cells; 4). Contribution of HSS gene in prevention of NASH is going to be studied in the HSS-knockdown cells or even HSS-knockout animals. Based upon these investigations, we are hoping to illuciadate the fundemental role of HSS against ER stress and referring SERCA as a potential targeting site of NASH therapy.