To explore the effects of glucagon-like peptide-1 (GLP-1) therapy on the expression of growth different factor 15(GDF15) in hepatocytes of non-alcoholic fatty liver disease (NAFLD).

A total of 25 patients with NAFLD and type 2 diabetes mellitus were analyzed (liraglutide group, 9; insulin glargine group, 8 and sitagliptin group, 8). The level of serum GDF15, intrahepatic lipid (IHL), body weight, and body mass index (BMI) were collected at baseline and week 26. IHL of patients was quantified by magnetic resonance imaging-estimated proton density fat fraction. Male C57BL/6 mice challenged with a high-fat diet for 12 weeks were treated with exenatide (GLP-1 group, n=6) or normal saline (HFD group, n=6) by intraperitoneal injection. Another group with a chow diet was designed as normal control (n=6). Liver tissue were collected after 8 weeks of intervention. Human HepG2 cells were incubated in medium containing 300 μmol/L sodium palmitate (PA) and treated with Exendin-4 (0 nmol/L, 1 nmol/L, 20 nmol/L, 100 nmol/L, respectively). 10% bovine serum albumin was set as the control group. GDF15 knockout stable cell line constructed by using CRISPR/Cas9 system, and empty vector served as a negative control. Transfected cells were incubated in medium containing 300 μmol/L PA and treated with or without 100 nmol/L Exendin-4. The levels of GDF15 released into serum or cell supernatant and relative mRNA levels of GDF15 in hepatic tissue or HepG2 cells were detected. Statistical analysis was mainly performed using one-way analysis of variance (ANOVA), covariance analysis, Pearson correlation coefficients.

No significant changes in the level of serum GDF15 was observed in the sitagliptin and insulin glargine groups after 26-week therapy. However, the level of serum GDF15 increased significantly in the liraglutide group [(742.2±279.0)vs. (920.3±265.4) pg/ml, P=0.015], and weight, BMI and IHL decreased statistically significant [(80.4±6.3) vs. (76.9±7.2) kg; (29.0±2.2) vs. (27.8±1.9) kg/m²; (18.3±7.4)% vs. (12.2±5.5) %; respectively] (all P<0.05). Furthermore, negative correlation was found between the change in serum GDF15 and IHL in the liraglutide group (r=-0.676, P=0.045). We found that 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. In addition, GLP-1 alleviated lipid deposition in HepG2 cells, which induced by PA, and elevated the expression and secretion of GDF15 in a dose-dependent manner. Compared with the negative control, GDF15 knockout abolished the effect of GLP-1 on alleviation of triglyceride accumulation and inflammation.

GLP-1 could up-regulate the expression and secretion of GDF15 and alleviatehepatic steatosis and inflammation of NAFLD.

Diabetes mellitas; Glucagon-like peptide-1; Non-alcoholic fatty liver disease; Growth differentiation factor 15