Background and aims : Metabolic-Associated Fatty Liver Disease (MAFLD) represents a common cause of liver disease leading to increased cardiovascular disease (CVD) morbidity and mortality. Autoantibodies against apolipoprotein A-1 (AAA-1) are a possible novel CVD risk factor promoting inflammation and disrupting intracellular lipid homeostasis, two prominent pathogenic features of MAFLD. We aimed to evaluate the possible role of AAA-1 in MAFLD and their association with CVD risk.

Methods : HepaRG cells and liver sections from ApoE-/- mice exposed to AAA-1 were used for lipid quantification and conditional protein expression. Randomly selected sera from 312 subjects of a general population cohort were used to measure AAA-1. A Fatty Liver Index (FLI) ≥60 and a 10-year Framingham Risk Score (FRS) ≥20% were used as proxy of MAFLD and high CVD risk, respectively.

Results : In-vitro and mouse models showed tha-t AAA-1 interfered with triglyceride synthesis leading to steatosis. AAA-1 generated pro-inflammatory and pro-fibrotic responses. In the 112 participants with FLI≥60, AAA-1 were associated with higher FRS, alkaline phosphatase levels, lower HDL cholesterol and tended to display higher FLI values. Univariate linear and logistic regression analyses (LR) confirmed significant associations between AAA-1, FLI and FRS≥20%, while in adjusted LR, FLI was the sole independent predictor of FRS≥20% (OR:1.05,95%CI:1.01-1.09, P=0.003) and AAA-1 was not found to be an independent FLI predictor.

Conclusion : Despite inducing a MAFLD-compatible phenotype on in vitro and in mouse models and being associated with an increased CVD risk according to FRS, the present results suggest that the AAA-1 association with CVD risk in the general population is dependent on hepatic steatosis.