Dietary Macronutrient Composition Is Associated with Distinct Hepatic Phenotypes During Post-Weaning Growth: An Integrated Biochemical, Histological, Immunohistochemical and Ultrastructural Study

Background/Objectives: The aim of this study was to compare the biochemical, histological, immunohistochemical and ultrastructural hepatic phenotypes associated with carbohydrate-, fat- and protein-enriched diets initiated during post-weaning growth. Methods: Forty 21-day-old male Wistar albino rats were divided into four groups: a control group and three experimental groups (carbohydrate, protein, and fat). The respective diets were fed for 13 weeks. Hepatic oxidant–antioxidant parameters, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP), histopathological scores; interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α) immunoreactivity and transmission electron microscopy (TEM) findings were evaluated. Results: The carbohydrate group showed higher thiobarbituric acid-reactive substances (TBARS), total oxidant status (TOS) and oxidative stress index (OSI), together with lower reduced glutathione (GSH) and total antioxidant status (TAS). Histology showed hydropic change, vacuolization and inflammatory cell infiltration, while TEM showed mitochondrial swelling, loss of cristae and nuclear alterations. The fat group showed prominent vacuolization, TEM-observed lipid droplets, inflammatory cell infiltration and TNF-α immunoreactivity. Most findings in the protein group were closer to control values. Thus, the carbohydrate-enriched diet was associated with the most pronounced redox and ultrastructural injury profile, whereas the fat-enriched diet was associated with a morphological and inflammatory injury profile compatible with lipid accumulation. Conclusions: These findings identify distinct hepatic phenotypes associated with the dietary formulations administered during post-weaning growth. The carbohydrate- and fat-enriched formulations were associated with more pronounced biochemical and morphological changes; inference is made at the level of the complete dietary formulation.