The Protective Effect of Bilirubin on MAFLD May Be Mediated by Improving Insulin Re-Sistance and Alleviating Chronic Inflammation

Mengying Yang,1,&ast; Jing Liu,1,&ast; Xiaoman Liu,1 Qianqian Li,1 Jun Liu,2 Baogui Wang1 1Department of Infectious Disease, Fuyang People’s Hospital, Fuyang, Anhui, People’s Republic of China; 2Physical Examination Center, Fuyang People’s Hospital, Fuyang, Anhui, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Baogui Wang, Department of Infectious Disease, Fuyang People’s Hospital, Fuyang, Anhui, People’s Republic of China, Tel +86-13805582057, Email [email protected]: Bilirubin, as a potent endogenous antioxidant, has demonstrated protective effects in various metabolic and inflammatory diseases. However, the precise role and underlying mechanisms of bilirubin in metabolic-associated fatty liver disease (MAFLD) remain unclear.Methods: This study involved 3000 participants, categorized into non-MAFLD and MAFLD groups. Using weighted multiple linear regression and mediation effect analysis, this study examined the protective impact of total bilirubin (TBIL), direct bilirubin (DBIL), and indirect bilirubin (IBIL) on MAFLD risk. Additionally, potential mediators-inflammation and insulin resistance (IR) through which bilirubin exerts its protective effects were explored.Results: TBIL and DBIL levels in the MAFLD group were significantly lower than those in the non-MAFLD group. Multiple linear regression analysis, adjusted for confounding variables, revealed that compared to the lowest tertile group (TBIL < 14.6), the odds ratios (ORs) for the middle tertile (TBIL 14.6– 19.2) and the highest tertile (TBIL ≥ 19.3) groups were 0.735 and 0.615. Similarly, compared to the lowest tertile group (DBIL < 3.4), the ORs for the middle tertile (DBIL 3.4– 4.4) and the highest tertile (DBIL ≥ 4.5) groups were 0.613 and 0.367. Mediation analysis revealed significant indirect effects of SIRI, PIV, TyG, TyGBMI, METS-IR, and AIP on the relationship between TBIL, DBIL, and MAFLD risk. Specifically, SIRI mediated 4.07% and 1.55% of the TBIL-MAFLD and DBIL-MAFLD associations, respectively; PIV mediated 9.56% and 4.22%; TyG mediated 69.27% and 81.91%; TyGBMI mediated 100% and 78.34%; METS-IR mediated 100% and 81.41%; and AIP mediated 100% for both TBIL-MAFLD and DBIL-MAFLD associations.Conclusion: Our findings suggest that increased serum levels of TBIL and DBIL are significantly inversely correlated with MAFLD risk, with both serving as independent protective factors against MAFLD occurrence. Further mediation analysis indicates that this protective effect is likely mediated by improvements in IR and the alleviation of systemic chronic inflammation.Keywords: bilirubin, metabolic-associated fatty liver disease, MAFLD, insulin resistance, IR, systemic chronic inflammation, mediation effect analysis