Effects of GLP-1 Therapy on GDF15 Expression in Hepatocytes of MAFLD

To explore the effects of glucagon-like peptide-1 therapy (GLP-1) on the expression of growth different factor 15 (GDF15) in hepatocytes of metabolic dysfunction-associated fatty liver disease (MAFLD). Patients with MAFLD and type 2 diabetes mellitus received a 26-week therapy of liraglutide, sitagliptin, or insulin glargine, respectively. The level of serum GDF15, intrahepatic lipid (IHL) and body mass index (BMI) were collected at baseline and week 26. C57BL/6J mice challenged with a high-fat diet (HFD) for 12 weeks were treated with GLP-1 receptor agonist exenatide (GLP-1 group) or normal saline by intraperitoneal injection for 8 weeks (HFD group). Another group with a chow diet was designed as normal control. Human HepG2 cells were incubated in medium containing 300 μM sodium palmitate (PA) and treated with Exendin-4 0nM, 1 nM, 20 nM, 100 nM, respectively. A total of 25 patients were analyzed (liraglutide group, 9; insulin glargine group, 8 and sitagliptin group, 8). The level of serum GDF15 increased significantly in the liraglutide group (742±279pg/mL vs. 920±265pg/mL, P=0.015), and IHL and BMI decreased significantly (18.3±7.4% vs. 12.2±5.5%, P=0.004; 29.0±2.2kg/m2 vs. 27.8±1.9 kg/m2, P= 0.01, respectively). No significant changes in the level of serum GDF15 were observed in the sitagliptin and insulin glargine groups after 26-week therapy. Furthermore, negative correlation was found between the change in serum GDF15 and IHL by in the liraglutide group (r=-0.676, P=0.045). Hepatic steatosis and inflammation in the liver, which were improved markedly in the HFD group, reduced in GLP-1 group. Relative mRNA levels of GDF15 in liver tissue of mice were remarkably higher in the GLP-1 group than those in HFD group and control group (P<0.05). In addition, Exendin-4 alleviated lipid deposition in HepG2 cells, which induced by PA, and elevate the expression and secretion of GDF15 in a dose-dependent manner (P<0.05). GLP-1 can alleviates hepatic steatosis of MAFLD and up-regulate the expression and secretion of GDF15. Disclosure L. Gan: None. B. Lin: None. W. Xu: None. J. Yan: None. Y. Su: None. Y. Chen: None. D. Yang: None. H. Liang: None. F. Xu: None.