组胺N-甲基转移酶（HNMT）是催化组胺代谢的关键酶之一，其在人体肝脏组织中的表达丰度最高。然而，有关HNMT是否可调控肝脏糖脂代谢，目前尚未阐明。申请人前期研究发现，HNMT在2型糖尿病和肥胖小鼠肝脏中表达显著上调，并且对营养状态改变和胰岛素处理的应答迅速；HNMT过表达显著增加原代肝细胞的脂质沉积、上调SREBP-1c等脂质合成基因表达，提示HNMT可能通过上调脂质合成相关基因的表达从而促进肝脏脂质沉积和胰岛素抵抗。在此基础上，本项目拟利用腺病毒载体介导HNMT过表达或敲减的方法，在动物实验和离体研究中明确HNMT对肝脏胰岛素敏感性和糖脂代谢的调控作用；通过高通量筛选、Co-IP质谱、染色质免疫共沉淀等方法，鉴定HNMT作用的下游靶分子，进而阐明HNMT调控肝脏代谢的分子机制。本研究有助于深入了解肝脏糖脂代谢的调控机制，为建立2型糖尿病、脂肪肝等代谢性疾病的治疗新策略提供理论基础。

Histamine N-methyl transferase (HNMT) is one of the key enzymes that catalyze histamine metabolism, which is most abundant in human liver tissue. However, the role of HNMT in regulating glucose and lipid metabolism in the liver has not been elucidated. The applicant's previous studies found that HNMT was significantly up-regulated in the liver of type 2 diabetic and obese mice, and was responsive to changes in nutritional status and insulin treatment. The overexpression of HNMT significantly increased the lipid deposition in primary hepatocytes and up-regulated the expression of lipid synthesis genes such as SREBP-1c, suggesting that HNMT may promote lipid deposition and insulin resistance in the liver by up-regulating the expression of genes related to lipid synthesis. On this basis, this study intends to investigate the effect of HNMT on insulin sensitivity and glucose and lipid metabolism in the liver by using adenovirus vectors to mediate HNMT overexpression or knockdown. HNMT downstream target molecules were identified by high-throughput screening, Co-IP mass spectrometry, chromatin immunoprecipitation and other methods, so as to elucidate the molecular mechanism by which HNMT regulates liver metabolism. This study helps to further understand the regulation mechanism of liver glucose and lipid metabolism, and provides a theoretical basis for the establishment of new therapeutic strategies for metabolic diseases such as type 2 diabetes and fatty liver.