Circulating fatty acids and risk of severe non-alcoholic fatty liver disease in the UK biobank: a prospective cohort of 116 223 individuals†

Fatty acid (FA) metabolism plays an important role in the development of nonalcoholic fatty liver disease (NAFLD). However, data on the relationship between circulating FAs and NAFLD risk are limited. This study aims to assess the associations between specific circulating FAs and severe NAFLD risk among the general population. Overall 116 223 participants without NAFLD and other liver diseases from the UK Biobank were enrolled between 2006 and 2010 and were followed up until the end of 2021. Plasma concentrations of saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (PUFAs) were analyzed using an NMR-based biomarker profiling platform. Hazard ratios (HRs) and 95% confidence intervals (CIs) of NAFLD risk were estimated using Cox proportional-hazard models adjusted for other potential confounders. During a mean follow-up of 12.3 years, we documented 1394 cases of severe NAFLD. After multivariate adjustment, plasma SFAs and MUFAs were associated with a higher risk of severe NAFLD, whereas plasma n-3 PUFAs, n-6 PUFAs, and linoleic acid (LA) were associated with a lower risk. As compared with the lowest quartile, HRs (95% CIs) of severe NAFLD risk in the highest quartiles were 1.85 (1.45–2.36) for SFAs, 1.74 (1.23–2.44) for MUFAs, 0.79 (0.65–0.97) for n-3 PUFAs, 0.68 (0.48–0.96) for n-6 PUFAs, and 0.73 (0.54–0.99) for LA. The significant relationships were mainly mediated by serum TG for SFAs, HDL-C for MUFAs and n-6 PUFAs, and C-reactive protein for n-3 PUFAs. Plasma SFAs were associated with a more pronounced increase in the risk of severe NAFLD among participants with fewer SFA-associated alleles (P interaction = 0.032). Dietary recommendations for reducing plasma SFAs and MUFAs while increasing n-3 and n-6 PUFAs may be protective for severe NAFLD, which could be mediated by lipid metabolism and inflammation.