非酒精性脂肪性肝病的特征性表现是肝脏内甘油三酯的过量堆积,其发生过程和精确机制是目前全球代谢研究领域的核心和热点。我们首次在高脂喂养及db/db小鼠肝脏中发现MafB表达上调，利用MafB腺病毒转染原代肝细胞后，ChREBP启动子活性上调，甘油三酯合成基因表达上调。表明MafB可能通过上调ChREBP参与脂肪肝发生。本项目将在这些重要发现的基础上开展以下工作:（1）采用shRNA腺病毒，沉默肥胖小鼠肝脏中MafB表达，观察脂肪肝改善情况及ChREBP基因表达变化；（2）体外细胞及分子水平研究MafB调控ChREBP表达的机制；（3）利用ChREBP基因敲除小鼠，明确MafB和ChREBP的调控关系；在小鼠肝脏干扰ChREBP表达，观察是否可逆转MafB的作用；(4)在已建立的人群队列中检验MafB基因与脂肪肝发生的遗传关联性。通过这些问题的阐释，有望为脂肪肝治疗提供新的理论依据与治疗靶点。

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of triglycerides in the liver. The study focused on the process and the precise mechanism of its occurrence is the core of the global metabolic research areas and hot spots, and the research about the key regulatory genes and signaling pathways will reveal new therapeutic approaches and targets. Here, we found that expression level of MafB was markedly increased in livers from high-fat-diet-induced obese mice and db/db mice. In addition, hepatic overexpression of MafB activated ChREBP expression and promoted triglycerides accumulation in C57 mice, indicating that MafB might promote the development of NAFLD through up-regulation of ChREBP expression. Therefore, using in vivo and in vitro models, our project will further investigate: (1) whether hepatic MafB knockdown could improve hepatosteatosis and ChREBP expression in obese mice; (2) the molecular mechanisms of MafB in the regulation of ChREBP; (3) the regulation of ChREBP by MafB using ChREBP knockout models; whether ChREBP knockout could rescue the hepatosteatosis induced by MafB; (4) the genetic relevance between MafB gene polymorphism and lipid metabolism in the established NAFLD cohort. Our project will benefit to seek new therapeutic targets for fatty liver diseases and related metabolic disorders.