AI Article Synopsis

  • Nonalcoholic fatty liver disease (NAFLD) is linked to an increase in M1 macrophages compared to M2 macrophages, which contributes to its progression.
  • A study found that a high-fat and high-fructose diet in mice led to more M1 macrophages and decreased autophagy, along with hypermethylation of autophagy-related genes.
  • Using DNA hypomethylating agents restored autophagy, rebalanced macrophage polarization, and helped prevent NAFLD progression, highlighting the role of epigenetics in macrophage behavior.

Article Abstract

Nonalcoholic fatty liver disease (NAFLD) is associated with an increased ratio of classically activated M1 macrophages/Kupffer cells to alternatively activated M2 macrophages, which plays an imperative role in the development and progression of NAFLD. However, little is known about the precise mechanism behind macrophage polarization shift. Here, we provide evidence regarding the relationship between the polarization shift in Kupffer cells and autophagy resulting from lipid exposure. High-fat and high-fructose diet supplementation for 10 weeks significantly increased the abundance of Kupffer cells with an M1-predominant phenotype in mice. Interestingly, at the molecular level, we also observed a concomitant increase in expression of DNA methyltransferases DNMT1 and reduced autophagy in the NAFLD mice. We also observed hypermethylation at the promotor regions of autophagy genes (LC3B, ATG-5, and ATG-7). Furthermore, the pharmacological inhibition of DNMT1 by using DNA hypomethylating agents (azacitidine and zebularine) restored Kupffer cell autophagy, M1/M2 polarization, and therefore prevented the progression of NAFLD. We report the presence of a link between epigenetic regulation of autophagy gene and macrophage polarization switch. We provide the evidence that epigenetic modulators restore the lipid-induced imbalance in macrophage polarization, therefore preventing the development and progression of NAFLD.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10248527PMC
http://dx.doi.org/10.1016/j.jbc.2023.104779DOI Listing

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