Uncoupling protein 2 ‐ UCP2 ‐ regulates mitochondrial lipid fluxes and reactive oxygen species production by the respiratory chain. The −866 G>A UCP2 promoter region polymorphism has been linked to insulin resistance and lipid metabolism. The aim of this study was to assess whether the −866 G>A UCP2 polymorphism predisposes to nonalcoholic steatohepatitis in patients at risk, and the relationship with lipid metabolism and hepatic UCP2 expression.

We considered 688 Italian patients who underwent liver biopsy for suspected NASH, and 232 healthy controls. The UCP2 −866 G>A polymorphism was determined by allele specific oligonucleotide probes, hepatic UCP2 mRNA levels by quantitative real‐time PCR.

UCP2 A/A genotype was associated with a reduced risk of nonalcoholic steatohepatitis (Odds Ratio 0.49, 95% C.I. 0.26–0.90; P = 0.02; adjusted for age, sex, BMI, impaired fasting glucose or diabetes, PNPLA3 I148M alleles and recruitment centre). The A/A genotype was associated with reduced risk of steatosis grade G2–G3 and nonalcoholic steatohepatitis in patients without (P = 0.003 and P = 0.01 respectively), but not in those with (P = NS) impaired fasting glucose/diabetes. The UCP2 A/A genotype was associated with higher hepatic UCP2 mRNA levels (adjusted P = 0.008). Concerning the metabolic traits, the UCP2 A/A genotype was associated with higher total serum cholesterol levels (adjusted P = 0.03), but not with serum HDL, triglycerides or impaired fasting glucose/diabetes.

UCP2 −866 A/A genotype is associated with increased hepatic UCP2 expression and reduced risk of nonalcoholic steatohepatitis, particularly in subjects with normal fasting glucose.