CCl4‐induced hepatic injury in mice fed a Western diet is associated with blunted healing

Background and Aims: Feeding a Western diet (WD) enriched in saturated fat protects against chronic alcoholic hepatitis. However, saturated fat induces lipotoxicity in cultured hepatocytes. The purpose of the present study was to elucidate the influence of WD on acute hepatic injury and healing. Methods: Male C57BL/6 mice were fed a purified control diet (CD) or WD enriched in palmitate and cholesterol. After 3 weeks, carbon tetrachloride (CCl₄) was administered (0.1 µL/g, intraperitoneally). Hepatic inflammation and proliferation were assessed by immunostaining for neutrophils and intracellular adhesion molecule‐1, and Ki67, respectively. Cytokine expression was analyzed by real‐time polymerase chain reaction. Protein levels of peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) were assessed by western blotting. Results: Feeding a WD resulted in markedly greater histological evidence of necrosis and enhanced alanine aminotransferase activity (188 ± 6.2 U/L) compared to CD‐fed mice (99.1 ± 6.3 U/L) by day 2 post‐CCl₄. In contrast, WD blunted leukocyte accumulation in necrotic areas and the expression of cytokines (tumor necrosis factor‐α and interleukin‐6) involved in tissue regeneration. Diminished repair was further indexed by lower collagen‐αI and Ki67 expression in the mice fed a WD. Finally, feeding a WD, as well as the treatment of cultured hepatocytes with palmitic acid, upregulated the expression of PPAR‐γ, which has been previously shown to prevent hepatic repair following CCl₄ exposure. Conclusions: These findings suggest that impaired healing in WD‐fed mice blunted recovery from acute injury and underscored the complex relationship between diet and hepatic injury.