Long-Term Fructose Intake Induces Moderate Liver Inflammation but Does not Overlap with the Detrimental Effects of the Ketogenic Diet on Hepatic Steatosis in Rats

An excess of fat and carbohydrate exerts a negative role on liver metabolism, favouring the development of metabolic dysfunction-associated steatotic liver disease (MASLD). However, it is not clear which component of the diet is more detrimental to liver homeostasis. We assessed the long-term effect of high fructose and the ketogenic diet on hepatic steatosis. For this purpose, 18 adult male Wistar rats were randomized into three groups: Control Diet (CD), consisting of commercial chow; Fructose Diet (FD), which included commercial chow and water with 30% fructose; and Ketogenic Diet (KD), comprising high-fat chow (90% fat). Chow and water intake were provided ad libitum during the 100-day follow-up period. Despite the differences in calorie intake, animals exhibited similar weight gain and body length, except for the KD group at T5. Ketosis was achieved in the KD group, while glucose and fructose remained unchanged in all groups. KD promoted increases in liver enzymes (AST, ALT, GGT, and ALP) and simultaneous lipid infiltration, characterized by high TC, TG, and NEFA levels. Advanced oxidized lipids (TBARS) were reduced. Long-term FD intake stimulated inflammatory pathways, as indicated by elevated levels of IL-1β, IL-6, IL-10, and TNF-α, compared to the CD and KD groups. Although relative liver weight was high in FD, the direct evaluation of total fat confirmed the high lipid infiltration in the KD group. Histological analysis of the liver tissue revealed a marked inflammatory infiltrate of macrophages and hepatic steatosis in the KD group. In conclusion, long-term KD intervention promoted hepatic steatosis through dysfunction in lipid metabolism and inflammation, while FD induced a more pronounced inflammatory response.