Intermittent Fasting Attenuates Adriamycin-induced Hepatoxicity in Rats: Possible Role for Nrf2/HO-1 and LC3/Sirt1 Pathways

Background: The current study was designed to examine, whether intermittent fasting can ameliorate the liver damage induced by adriamycin (ADR) in rats, as well as its possible underlying mechanisms. Methods: Forty male Sprague Dawley rats were allocated into 4 equal groups, control, fasting, ADR and ADR+ Fasting groups. At the end of the experiment (eight weeks after ADR administration), blood samples were collected for the measurement of ALT, AST, and albumin, and liver tissues were harvested for biochemical analyses of oxidative stress markers (AMD, GSH and Catalase). Real-time PCR was performed for NRF2 and HO-1, as well as histopathological examination and immunostaining for caspase-3, LC3, and Sirt-1 expression. Results: Administration of ADR caused significant elevation in liver enzymes (ALT, AST), lipid peroxidation (MDA), histopathological damage score and caspase-3 in liver tissues (p< 0.05) with a notable decrease in GSH, catalase, Nrf2, HO-1, LC3, and Sirt-1 genes expression (p< 0.05). Conversely, the application of intermittent fasting (IF) to ADR-treated rats caused significant attenuation of the raised liver enzymes (ALT, AST), lipid peroxidation (MDA), histopathological damage score and caspase-3 in liver tissues and significant improvement in the attenuated GSH, catalase, Nrf2, HO-1, Lc3 and Sirt-1 gene expression (p< 0.05). Conclusion: Intermittent fasting could potentially offer protection against ADR-induced hepatotoxicity in rats by reducing oxidative stress and apoptosis and modifying the expression of Nrf2/HO-1, LC3, and Sirt-1.