Nobiletin Ameliorates Hepatic Lipid Deposition, Oxidative Stress, and Inflammation by Mechanisms That Involve the Nrf2/NF-κB Axis in Nonalcoholic Fatty Liver Disease

J Agric Food Chem. 2023 Dec 20;71(50):20105-20117. doi: 10.1021/acs.jafc.3c06498. Epub 2023 Dec 10.

Abstract

Nobiletin (NOB), a flavonoid with significant antioxidant potential, holds promise for treating nonalcoholic fatty liver disease (NAFLD). In this work, we aim to assess the effects and investigate the molecular mechanisms of NOB on NAFLD. After using a methionine choline-deficient diet to induce C57BL/6J mice, as well as oleic acid to induce HepG2 and L02 cells, we administered NOB as an intervention. The results indicated that the NOB significantly ameliorated lipid deposition, oxidative stress, and inflammation in NAFLD in both models. Its mechanism may involve the Nrf2, SREBP-1c, and NF-κB signaling pathways. Furthermore, Nrf2 is not only a direct target for NOB to improve oxidative damage but also indirectly involved in lipid-lowering and anti-inflammatory processes in NAFLD. By inhibiting Nrf2, we found that the regulatory role of Nrf2 in lipid metabolism is not related to SREBP-1c but is closely associated with NF-κB in terms of inflammation. Our results suggest that Nrf2 is one of the most critical targets for NOB against NAFLD in multiple aspects.

Keywords: NAFLD; Nrf2 signaling pathway; inflammation; lipid deposition; oxidative stress.

MeSH terms

  • Animals
  • Diet, High-Fat
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Lipid Metabolism
  • Lipids
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Non-alcoholic Fatty Liver Disease* / drug therapy
  • Non-alcoholic Fatty Liver Disease* / genetics
  • Non-alcoholic Fatty Liver Disease* / metabolism
  • Oxidative Stress
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism

Substances

  • NF-kappa B
  • nobiletin
  • NF-E2-Related Factor 2
  • Sterol Regulatory Element Binding Protein 1
  • Lipids