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

Life Sci. 2020 Sep 1:256:117908. doi: 10.1016/j.lfs.2020.117908. Epub 2020 Jun 5.

Abstract

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-activated receptor gamma (PPAR-γ), 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-α (TNF-α), interleukin (IL)-1β, IL-6, Nrf-2, and PPAR-γ. Nuclear factor-kappa B (NF-κB) was detected by immunohistochemical staining using an anti-NF-κB 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-α, IL-1β, and IL-6, via the downregulation of NF-κB. 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-γ, 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-κB/Nrf-2/PPAR-γ axis.

Keywords: Empagliflozin; Ethanol; Liver injury; NF-κB; Nrf-2; PPAR-γ.

MeSH terms

  • Alanine Transaminase / metabolism
  • Alkaline Phosphatase / metabolism
  • Animals
  • Anti-Inflammatory Agents* / metabolism
  • Anti-Inflammatory Agents* / pharmacology
  • Antioxidants* / metabolism
  • Antioxidants* / pharmacology
  • Aspartate Aminotransferases / metabolism
  • Benzhydryl Compounds* / metabolism
  • Benzhydryl Compounds* / pharmacology
  • Chemical and Drug Induced Liver Injury, Chronic* / metabolism
  • Chemical and Drug Induced Liver Injury, Chronic* / prevention & control
  • Drug Discovery
  • Ethanol / adverse effects
  • Gene Expression Regulation / drug effects
  • Glucosides* / metabolism
  • Glucosides* / pharmacology
  • Glutathione / metabolism
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism
  • Interleukins / metabolism
  • Liver / metabolism
  • Male
  • Malondialdehyde / metabolism
  • Mice
  • Mice, Inbred BALB C
  • NF-E2-Related Factor 2* / genetics
  • NF-E2-Related Factor 2* / metabolism
  • NF-kappa B* / metabolism
  • Nitric Oxide / metabolism
  • Oxidative Stress / drug effects
  • PPAR gamma* / genetics
  • PPAR gamma* / metabolism
  • Superoxide Dismutase / metabolism

Substances

  • Alanine Transaminase
  • Alkaline Phosphatase
  • Anti-Inflammatory Agents
  • Antioxidants
  • Aspartate Aminotransferases
  • Benzhydryl Compounds
  • empagliflozin
  • Ethanol
  • Glucosides
  • Glutathione
  • Heme Oxygenase-1
  • Interleukins
  • Malondialdehyde
  • NF-E2-Related Factor 2
  • NF-kappa B
  • Nitric Oxide
  • PPAR gamma
  • Superoxide Dismutase