Several lines of evidence have demonstrated that hepatocellular fat accumulation in NAFLD is linked to an imbalance in fatty acid uptake, de novo lipogenesis, fatty acid oxidation and lipid export58, which is caused by dysregulation of mediators for inter-organ metabolic communication such as FGF21, adiponectin, and irisin, as well as their key regulator SIRT120–22,28. This evidence concerns the gene FNDC5 and metabolic dysfunction-associated steatotic liver disease.