The in vivo PPARα challenge further demonstrates the dysregulation of PPARα signalling in the presence of NAFLD, which results in a stochastically increasing hepatic expression of Fgf21. In conclusion, Fgf21 plasma levels reflect liver fat accumulation and dysregulation of metabolic pathways at a transcriptional level in the liver of C57BL/6J mice. Here, PPARA is linked to metabolic dysfunction-associated steatotic liver disease.