We explored whether growth differentiation factor 15 (GDF15) affects the histological severity of non‐alcoholic fatty liver disease (NAFLD) independent of insulin resistance.

In a biopsy‐proven NAFLD cohort, we measured serum GDF15 levels using enzyme‐linked immunosorbent assays.

Among 190 subjects (mean age, 53 ± 14 years; men, 52.1%), 72 (men, 65.3%) and 78 (men, 44.9%) were diagnosed with biopsy‐proven non‐alcoholic fatty liver (NAFL) and non‐alcoholic steatohepatitis (NASH) respectively. GDF15 levels were significantly higher in NASH patients than in controls (P = .010) or NAFL patients (P = .001). Subjects with advanced fibrosis (≥F3) also showed higher GDF15 levels compared to the others (F0‐2; P < .001). Among NAFLD patients, the highest quartile of GDF15 levels was significantly associated with a risk of advanced fibrosis even after adjustment for age, gender, body mass index, smoking status, hypertension, diabetes, aspartate aminotransferase, platelet, albumin, insulin resistance and low skeletal muscle mass (odds ratio, 4.27; 95% confidence interval, 1.04‐17.63), but not with NASH risk. GDF15 levels showed a significant positive correlation with liver stiffness (Spearman's ρ, .525; P < .001). Palmitate treatment increased the GDF15 mRNA expression level significantly in Kupffer cells, but not in hepatocytes. In LX‐2 cells, GDF15 treatment resulted in enhanced expression of α‐smooth muscle actin and collagen I, as well as phosphorylation of SMAD2 and SMAD3.

Our findings suggest that GDF15 may serve as a novel biomarker of advanced fibrosis in NAFLD, thereby indicating the need for urgent anti‐fibrotic pharmacotherapy.