课题组前期研究发现，脾阳虚证是NAFLD疾病慢性化复杂化的“拐点”，初步明确其特征性代谢谱和表观遗传学特点。在“病痰饮者，当以温药和之，苓桂术甘汤主之”治疗原则的指导下，从方证效应角度发现苓桂术甘汤影响线粒体损伤/内质网应激的证据，提出NAFLD“脾阳虚—线粒体损伤/内质网应激—代谢性炎症”相关假说。本课题与加拿大渥太华大学合作，在病证结合、方证相应理论指导下，通过前瞻性队列研究设计，结合体内外实验研究，以分子生物学技术为主要手段，研究脾阳虚在NAFLD已病和未病人群流行规律、易感基因和表观遗传学特征；研究肝脏SCD1、UCPS表达与线粒体能量储备的关系及PRR信号通路介导的脂肪肝肝细胞损伤敏感性的病理基础，阐明内质网应激和代谢性炎症在NAFLD发生发展过程中的作用规律，从苓桂术甘汤方证效应角度揭示NAFL脾阳虚证的现代生命科学内涵，提高中医药治疗脂肪肝的临床疗效提供依据。

Previous work from our Lab suggested that a symptom termed "Spleen Yang Vacuity" represents a "turning point" during the pathologic progression of non-alcoholic fatty liver disease (NAFLD). Our preliminary clinical studies have identified several key metabolic abnormalities associated with NAFLD, including mitochondrial damage, endoplasmic reticulum stress, and hepatic inflammation. Accodingly, this research proposal aims to test the “Spleen Yang Vacuity-mitochondrial damage/endoplasmic reticulum stress-metabolic inflammation” hypothesis, attempting to elucidate cellular/molecular mechanism underlying the efficacy of Ling-Gui-Shu-Gan Decoction in the treatment of NAFLD. Ling-Gui-Shu-Gan Decoction is used in traditional Chinese medicine (TCM) as a principle treatment for "Spleen Yang Vacuity," which is known as "of phlegm retention syndrome, Ling-Gui-Shu-Gan Decoction being the main choice, coupled with Warm Yang reagents." The project will be conducted in collaboration with Yao Lab at University of Ottawa in Canada. The guiding principles of this Ji-Yao joint research are the “disease and symptom combination” and “sympton in corresponding to formula” theories. Specifically, we will design perspective cohorts to study epidemic feature, susceptibility genes, and epigenetic characteristics of "Spleen Yang Vacuity" in patients with NAFLD. These studies will be peroformed both in vitro and in vivo using molecular biology techniques. For instance, through monitoring the experession of hepatic SCD1and UCPs, we will determine hepatic lipogenesis status and mitochondrial energy homeostasis. By exploring the pathological basis of susceptibility to hepatic injury in NAFLD, we will define mechanisms under NAFLD and inflammation conditions. It is hoped that from the TCM angle of “formula-symptom” pattern, the scientific connotation of "Spleen Yang Vacuity" in NAFLD can be further elucidated, and the efficacy of Ling-Gui-Shu-Gan Decoction in the treatment of NAFLD demonstrated at cellular/molecular levels.