In conclusion, we have demonstrated that the function loss of Lrp6, either likely via a germline variant in human subjects or through genetic manipulation in rodents or cell models, can result in a less severity of NAFLD, This may be explained by the consequent downregulation of the Wnt/β-catenin-Cyp2e1 signaling activity. This evidence concerns the gene LRP6 and metabolic dysfunction-associated steatotic liver disease.