Accordantly, we observed that loss of Fbxw7 in hepatocytes downregulates the entire fat degradation network without affecting the lipogenic program, which is pivotal for NAFLD initiation but is unlikely to be the main contributor to NASH progression, suggesting that the accumulated TG in Fbxw7-null livers is predominantly caused by their massive defects in fat clearance associated with attenuated PPARα expression. Here, FBXW7 is linked to metabolic dysfunction-associated steatohepatitis.