Nuclear factor interleukin 3 and metabolic dysfunction-associated fatty liver disease development

This study investigated sex-specific effects in a gain-of-function model to evaluate Nfil3 function in relation to high-fat diet (HFD)-induced metabolic dysfunction-associated steatotic liver disease (MASLD) and gut microbiota (GM)-induced alterations in the bile acid (BA) profile. MASLD was induced in both wild type and Nfil3-deficient (NKO) C57BL/6J mice through an HFD. The hepatic immune response was evaluated using flow cytometry, revealing that NKO mice exhibited lower body weight, serum triglyceride (TG) levels, tissue injury, inflammation, and fat accumulation. The Nfil3 deletion reduced macrophage counts in fibrotic liver tissues, decreased proinflammatory gene and protein expression, and diminished gut barrier function. Alpha and beta diversity analysis revealed increased GM alpha diversity across different sexes. The Nfil3 gene deletion modified the BA profile, suggesting that negative feedback through the Nfil3-FXR-FGF15 axis facilitates BA recycling from the liver via enterohepatic circulation. Therefore, inhibiting Nfil3 in the liver offers a viable treatment approach for MASLD.