肝细胞TMEM154介导的线粒体氧化呼吸链对非酒精性脂肪性肝炎进展中炎症微环境的调控作用及其具体机制研究

非酒精性脂肪性肝炎(NASH)是一种慢性肝脏代谢性炎症疾病。其病理的不可逆性一直困扰着其临床诊疗的进展。深入探索NASH进展中的关键靶标具有重要的临床意义和科研价值。本研究从肝细胞对炎症微环境的起始板机作用这一角度切入，基于高通量检测，筛选NASH进展中的关键靶点。通过临床样本及NASH模型，初步发现肝细胞TMEM154可以通过介导TNFα分泌促进NASH中炎症微环境的形成。初步机制探索提示肝细胞TMEM154通过促进线粒体氧化呼吸链进而引起ROS产生及肝细胞TNFα的分泌增加。本研究拟进一步采用体内外NASH模型、联合蛋白组学检测、深入分析肝细胞TMEM154对于氧化呼吸链的精准作用靶点，并通过阻断实验阐明肝细胞TMEM154介导氧化呼吸链对NASH中炎症微环境的调控作用。本课题旨在以肝细胞TMEM154为靶标，通过诠释其在NASH中的作用及具体机制，为未来的临床防治探索提供新的思路。

Non-alcoholic steatohepatitis (NASH) is a chronic metabolic inflammatory liver disease that can develop into cirrhosis and even liver cancer. The irresability of its pathology has been troubling the progress of its clinical diagnosis and treatment. Detailed investigation of the crucial target involving in the process of NASH present important clinical significance and scientific research value. This study is based on the pointcut that the effect of hepatocyte on inflammatory micro-environment at the initial stage of NASH, and based on a high-throughput microarray detection. Based on the expression validation in patients’ samples and the NASH model in vivo and vitro, we found hepatic TMEM154 could aggravate the inflammatory micro-environment via enhancing hepatic secretion of TNFα. Preliminary mechanism analysis suggested hepatic TMEM154 promotes ROS production via enhancing mitochondrial oxidation respiratory chain (MORC), then promoting the secretion of TNFα. In this study, we proposed to use the NASH model in vivo and vitro, and the proteomics detection and analysis, to deeply analyze the precise target of hepatic TMEM154 for MORC, and use joint blockers and truncated mutation to clarify that hepatic TMEM154-mediated MORC induces the inflammatory micro-environment during NASH. This study aims to provide a theoretical basis for the future construction of multi-cell multi-dimensional framework of NASH, and for clinical prevention and treatment of NASH by interpreting the role and specific mechanism of hepatic TMEM154 in the development of NASH.