目的 探讨聚乙二醇洛塞那肽通过调控脂噬延缓非酒精性脂肪性肝病的机制。 方法 （1）体内实验：32只C57BL/6雄性小鼠正常喂养1周后，随机分为4组，每组8只。分为正常对照组（饲以正常饲料）、高脂组（饲以高脂饲料）、正常+GLP?IRA（腹腔注射聚乙二醇洛塞那肽0.3 mg/kg，每3天1次）、高脂+ GLP?IRA（在饲以高脂饲料基础上，腹腔注射聚乙二醇洛塞那肽0.3 mg/kg，每3天1次），造模持续16周。在16周末测量小鼠体质量、血糖和进行糖耐量实验（GTT），酶联免疫吸附试验（ELISA）检测小鼠血清中总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白（LDL）、高密度脂蛋白（HDL）等指标，苏木素-伊红（HE）、油红O染色观察肝脏病理学改变，蛋白质免疫印迹法（WB）检测肝脏中脂噬经典分子微管相关蛋白轻链3（LC3）、自噬接头蛋白（P62）及转录因子EB（TFEB）的蛋白表达量。（2）体外实验分组：正常组（BSA）、正常+聚乙二醇洛塞那肽组（BSA+100 nmol/L GLP-1RA）、高脂组（0.5 mmol/L 棕榈酸）、高脂+聚乙二醇洛塞那肽组（0.5 mmol/L PA+100 nmol/L GLP-1RA），24 h后油红O染色观察脂肪变性情况，检测细胞上清内TG水平，WB检测LC3、TFEB、P62蛋白表达，实时荧光定量PCR（RT-qPCR）检测细胞内与脂质合成相关因子的mRNA水平。 结果 （1）体内实验：与正常对照组比较，高脂组小鼠体质量和血糖明显增加（P < 0.01），糖耐量下降（P < 0.01），血清中TC、TG、LDL水平均明显增高（P < 0.01），HDL明显降低（P < 0.01）；与高脂组相比，高脂+GLP-1RA组小鼠血糖，血清中TC、TG、LDL水平及肝脏中P62水平均明显降低（P < 0.01），HDL、糖耐量及肝脏中LC3、TFEB水平均明显升高（P < 0.01）；与正常对照组相比，正常+GLP-1RA组上述指标变化不明显（P > 0.05）。（2）体外实验：0.5 mmol/L PA成功构建NAFLD HepG2细胞模型，棕榈酸（PA）作用24 h后细胞内脂滴明显增加（P < 0.01），细胞上内TG水平增加（P < 0.01），脂质合成相关因子mRNA水平明显增加（P < 0.01）；高脂+GLP-1RA组改善高脂诱导的脂肪变性，上述指标变化呈相反趋势并且脂噬经典分子LC3、TFEB表达升高（P < 0.01），P62蛋白表达量下降（P < 0.01）。 结论 聚乙二醇洛塞那肽通过调控脂噬延缓非酒精性脂肪性肝病进展。

Objective To investigate the mechanism of polyethylene glycol losenatide in improving non-alcoholic fatty liver disease by regulating lipophagy. Methods （1） 32 C57BL/6 male mice were fed normally for 1 week and randomly divided into 4 groups with 8 mice in each group. Normal control group （fed normal diet）， Normal + GLP-1RA （intraperitoneal injection of polyethylene glycol losenatide 0.3 mg/kg q3d）， High fat group （fed with high fat diet）， High-fat + GLP-1RA （on the basis of high-fat diet， intraperitoneally injected polyethylene glycol losenatide 0.3 mg/kg q3d）， The molding lasts 16 weeks. Body weight， blood glucose and glucose tolerance test （GTT） were measured at the end of 16 weeks. Serum total cholesterol （TC）， triglyceride （TG）， low density lipoprotein （LDL）， high density lipoprotein （HDL） and other indexes were detected by Enzyme-linked immunosorbent assay （ELISA）， liver pathological changes were observed by Hematoxylin-eosin （HE） and oil red O sections， and the expression of microtubule-associated protein light chain 3 （LC3）， autophagy adaptor protein （P62）， and transcription factor EB （TFEB）. in liver were detected by Western blot （Wb）. （2） The cell was divided into normal group （treated with bovine serum albumin， BSA）； Normal + polyethylene glycol losenatide group （BSA+100 nmol/L GLP-1RA）， High fat group （0.5 mmol/L PA）； High fat + polyethylene glycol losenatide group （0.5 mmol/L PA+100 nmol/L GLP-1RA）. After 24 h， the steatosis was observed by oil red O staining， the levels of TG in the supernatant were detected， Wb analysis was performed to detect protein expression levels of LC3， TFEB， and P62. Reverse transcription quantitative PCR （RT-qPCR） was used to measure mRNA levels of lipid synthesis-related factors. Results （1） Compared with normal control group， the body weight and blood glucose of mice in the high fat group increased significantly （P < 0.01）， reduced glucose tolerance （P < 0.01）， the levels of TC，TG and LDL in serum in liver of high fat group were significantly increased （P < 0.01）， while HDL was significantly decreased （P < 0.01）. Compared with high fat group，blood sugar in mice， the levels of TC， TG and LDL in serum and P62 in liver of high fat + GLP-1 group were significantly decreased （P < 0.01）； Glucose tolerance， HDL and and the protein expressions of LC3， TFEB were significantly increased （P < 0.01）. Compared with normal control group， the above indexes in normal + GLP-1 group were not significantly changed （P > 0.05）. （2） In vitro， The NAFLD HepG2 cell model was successfully constructed with 0.5 mmol/L PA. After 24 h of PA treatment， intracellular lipid drops were significantly increased （P < 0.01）， intracellular TG and the mRNA levels of lipid synthesis-related factors in the cells were increased （P < 0.01）. High fat + GLP-1 group improved the fatty degeneration induced by high fat， and the changes of the above indexes showed an opposite trend but the expression of LC3， TFEB were significantly increased （P < 0.01）， lipid regulatory factor P62 protein in liver were decreased （P < 0.01）. Conclusion Polyethylene glycol losenatide can improve non-alcoholic fatty liver disease by regulating lipophagy.