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.