基于靶标NLRP-3的miR-233探讨滋阴益气活血解毒法对2型糖尿病合并非酒精性脂肪性肝病的调控分子机制

Non-alcoholic fatty liver disease is a common chronic complications of type 2 diabetes mellitus. Inflammation is one of the most important mechanisms of the cells’ damage by pyroptosis associated with diabetes mellitus with non-alcoholic fatty liver disease. Small molecule miRNAs are participated in post-transcriptional regulation of inflammatory molecules. The abnormal expressions of miRNAs are closely related to the liver cells pyroptosis. However, at early stages, the cell injury at a moderate degree of fatty liver are reversible; thus clarify the mechanisms of liver cells’ injury of diabetes mellitus with non-alcoholic fatty liver and the effective treatments are have great significance. preliminary studies found that “Nourishing yin and invigorating qi, and promoting blood circulation and detoxication” can reduce the patients’ glucose and lipid,and improve the function of liver, to protect the liver; based on the previous study, combinating the in vivo and in vitro experiments, from the aspects of inflammatory damage, using molecular biology methods, to discuss the liver cells injury molecular mechanisms of diabetes mellitus with non-alcoholic fatty liver based on miR-233 targeted to inflammatory signaling molecules NOD-like receptor protein-3; and to explore the regulation molecular mechanisms of“Nourishing yin and invigorating qi, and promoting blood circulation and detoxication”of Zuogui Jiangtang Qingzhi Recipe; so as to find new therapeutic targets for the diabetes mellitus with non-alcoholic fatty liver.

非酒精性脂肪性肝病是2型糖尿病常见慢性并发症之一。炎症反应是2型糖尿病合并非酒精性脂肪性肝病肝细胞焦亡的重要机制之一。小分子miRNAs参与炎症信号分子的转录后调控，其异常表达与肝细胞焦亡密切相关。而早期轻中度脂肪肝，肝细胞焦亡及损伤程度具有一定可逆性，因而阐明2型糖尿病合并非酒精性脂肪性肝病肝细胞损伤机制及有效防治具有重要意义。前期研究发现滋阴益气、活血解毒的中药复方通过降低患者血脂、血糖、改善肝功能，从而保护肝脏。本课题拟进一步开展体外实验与体内实验，并运用分子生物学手段，从炎症损伤角度，探讨靶标炎症信号分子NLRP-3的miR-233介导2型糖尿病合并非酒精性脂肪性肝病肝细胞焦亡及损伤机制，并探讨滋阴益气、活血解毒的左归降糖清脂方的调控分子机制；以期为2型糖尿病合并非酒精性脂肪性肝病的治疗寻找新的靶点。

非酒精性脂肪性肝病是2型糖尿病常见慢性并发症之一。炎症反应是2型糖尿病合并非酒精性脂肪性肝病肝细胞焦亡及损伤的重要机制之一。本课题组研究认为2型糖尿病合并非酒精性脂肪性肝病中医病机主要为肝肾阴虚、脾气亏虚（虚），湿热内蕴、痰瘀互结（毒、瘀）；与“因毒致损”，“毒损肝络”的病机认识具有一致性。研究发现滋阴益气、活血解毒的中药复方左归降糖清脂方或茵陈蒿汤通过降低2型糖尿病合并非酒精性脂肪性肝病MKR鼠血脂、血糖、改善肝功能，从而保护肝脏；还可通过调控NLRP3或PI3K或TLR4或Visfatin等炎症信号通路，改善肝组织病理损伤结构。左归降糖清脂方含药血清可调控NLRP3等信号通路改善肝细胞“毒损肝络”病理状态。通过研究，阐明了滋阴益气、活血解毒的中药复方调控2型糖尿病合并非酒精性脂肪性肝病肝细胞焦亡及损伤的分子机制；丰富了2型糖尿病合并非酒精性脂肪性肝病“毒损肝络”病机，并为其治疗提供了新思路和新方法。