清肝活血方通过LXR-LPCAT3信号通路抑制内质网应激改善酒精性肝病的机制研究

酒精性肝病（ALD）将成为未来肝脏疾病的主要病因之一。课题组基于其“湿热瘀血”病机研制的中药复方清肝活血方在临床和动物试验中均有效改善ALD。新近研究表明肝脏X受体（LXR）激活磷脂酰胆碱酰基转移酶3（LPCAT3）抑制内质网应激（ERS），但在ALD中的作用并不清楚。前期研究发现LXR、LPCAT3mRNA在ALD模型大鼠肝脏表达有所下调，而清肝活血方干预使其上调。因此我们提出LXR-LPCAT3信号通路调控ALD的发病进程，清肝活血方通过激活LXR-LPCAT3抑制ERS从而改善ALD这一假说。基于此，本项目拟通过临床、动物和细胞试验，应用CRISPR/CAS9、分子生物学、靶向代谢组学等实验技术，探讨LXR-LPCAT3信号通路在ALD中的作用，为ALD的治疗提供新靶点和新策略，以及清肝活血方治疗ALD的作用机制，以阐明中药复方治疗ALD的药效机理，为其在临床应用和推广提供科学依据。

Alcoholic liver disease (ALD) will become one of major cause of chronic liver diseases in the future. Based on “damp heat and blood stasis” as the core pathogenesis of ALD, the herb formula “Qinggan Huoxue Recipe(QGHXR)” developed by our study group has been proved effective in improving ALD in clinical or animal experiments. Recent studies have shown that liver X receptor (LXR) inhibit endoplasmic reticulum stress through activating lysophosphatidylcholine acyltransferase (LPCAT3), but it is unclear about its role in ALD. Our preliminary experiments indicated that the expression of LXR, LPCAT3 mRNA was obviously decreased in ALD, and QGHXR could increase its expression. Therefore, we put forward the hypothesis: LXR-LPCAT3 signal pathway is involved in the progress of ALD, and QGHXR improves ALD through suppressing ERS by activating LXR-LPCAT3. In order to verify the hypothesis, we would apply the experimental techniques such as CRISPR/CAS9, molecular biology, targeted metabolomics through clinical, animal model and cell models to explore the role of LXR-LPCAT3 signaling pathway in ALD in order to providing new targets and new strategies for the treatment of ALD, as well as the QGHXR mechanism on treating ALD with the aim to elucidate the effect mechanism of Chinese herbal compound in the treatment of ALD and provide scientific basis for its widespread clinical application.