Overall, our data combined with previous observations suggest that although PPARα activation reduced macrovesicular steatosis and lipotoxicity via the reduction of excess free fatty acids by enhancing re-esterification and lipid droplet formation, PPARα agonists may not result in a sufficient TG reduction in diabetes-based NAFLD/NASH livers because PPARα is mainly involved in the regulation of nutrient flux to supply glucose and ketone bodies to peripheral tissues, rather than to provide an energy source in the liver. The gene discussed is PPARA; the disease is metabolic dysfunction-associated steatohepatitis.