Empagliflozin ameliorates ethanol-induced liver injury by modulating NF-cB/Nrf-2/PPAR-γ interplay in mice

Background: Excessive alcohol intake contributes to severe liver damage involving oxidative stress and inflammatory responses, which make them promising therapeutic targets. Previous studies have demonstrated that empagliflozin (EMPA) showed cardiovascular, renal, and cerebral benefits potentially mediated through its antioxidant and anti-inflammatory actions. Aims: This experiment aimed to evaluate the hepatoprotective effect of EMPA on alcoholic liver disease (ALD) and the possible underlying mechanisms. Materials and methods: Serum biochemical parameters and the liver contents of malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), and superoxide dismutase (SOD) were measured. Real-time qPCR was conducted to determine the gene expression of peroxisome proliferator-alpha ctivated receptor gamma (PPAR-gamma), nuclear factor erythroid 2-related factor 2 (Nrf-2), and heme oxygenase-1 (Hmox-1). In addition, ELISA was performed to measure tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 beta, IL-6, Nrf-2, and PPAR-gamma. Nuclear factor-kappa B (NF-kappa B) was detected by immunohistochemical staining using an anti-NF-kappa B p65 antibody. Key findings: Our results revealed that the serum levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase were significantly reduced by EMPA. EMPA also decreased the content of MDA and NO and increased the activities of SOD and GSH in liver homogenates. Moreover, EMPA inhibited the release of proinflammatory cytokines, including TNF-alpha, IL-1 beta, and IL-6, via the downregulation of NF-kappa B. These changes were associated with an improvement in histopathological deterioration. The protective effect of EMPA against oxidative stress and inflammation was associated with the upregulation of PPAR-gamma, Nrf-2, and their target gene Hmox-1. Significance: EMPA showed protective activities against ethanol-induced liver injury by suppressing inflammation and oxidative stress via modulation of the NF-kappa B/Nrf-2/PPAR-gamma axis.