Non-alcoholic fatty liver disease (NAFLD) is a great health burden. Neuregulin 4 (Nrg4) is a recently identified secret factor that may be associated with NAFLD.

To investigate the association between serum Nrg4 level and NAFLD by conducting a case–control study.

A total of 174 subjects were included. 87 NAFLD subjects and 87 age- and sex-matched non-NAFLD controls were identified by hepatic ultrasound examination. Anthropometric and biochemical data were measured and recorded. Serum Nrg4 level was evaluated by using enzyme-linked immunosorbent assay. SPSS software was used for statistical analyses.

Compared to the controls, subjects with NAFLD presented with reduced level of serum Nrg4 (0.40 (0.27, 0.55) vs. 0.50 (0.30, 0.81) ng/mL (median (interquartile range)), P = 0.029). By multivariate logistic regression analysis, reduced serum levels of Nrg4 were associated with higher NAFLD odds (OR = 0.251, 95% confidence interval = 0.081–0.779, P = 0.017). By dividing the distribution of serum Nrg4 level into quartiles, there was borderline statistical difference of NAFLD prevalence among the four groups (P = 0.058). There was no significant difference of serum Nrg4 levels in subjects according to the grades of fatty liver by ultrasound (P = 0.080). No statistical difference of serum Nrg4 level was observed between obese and non-obese subjects (P = 0.932).

Decreased serum Nrg4 level is prevalent in NAFLD subjects compared to non-NAFLD controls, and is an independent risk factor associated with NAFLD, indicating that Nrg4 might have a protective role in the development of NAFLD.