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      Pharmacological inhibition of DNMT1 restores macrophage autophagy and M2 polarization in Western diet–induced nonalcoholic fatty liver disease

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          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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          Most cited references30

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          Obesity induces a phenotypic switch in adipose tissue macrophage polarization.

          Adipose tissue macrophages (ATMs) infiltrate adipose tissue during obesity and contribute to insulin resistance. We hypothesized that macrophages migrating to adipose tissue upon high-fat feeding may differ from those that reside there under normal diet conditions. To this end, we found a novel F4/80(+)CD11c(+) population of ATMs in adipose tissue of obese mice that was not seen in lean mice. ATMs from lean mice expressed many genes characteristic of M2 or "alternatively activated" macrophages, including Ym1, arginase 1, and Il10. Diet-induced obesity decreased expression of these genes in ATMs while increasing expression of genes such as those encoding TNF-alpha and iNOS that are characteristic of M1 or "classically activated" macrophages. Interestingly, ATMs from obese C-C motif chemokine receptor 2-KO (Ccr2-KO) mice express M2 markers at levels similar to those from lean mice. The antiinflammatory cytokine IL-10, which was overexpressed in ATMs from lean mice, protected adipocytes from TNF-alpha-induced insulin resistance. Thus, diet-induced obesity leads to a shift in the activation state of ATMs from an M2-polarized state in lean animals that may protect adipocytes from inflammation to an M1 proinflammatory state that contributes to insulin resistance.
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            5-Azacytidine and 5-aza-2'-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy.

            5-Azacytidine was first synthesized almost 40 years ago. It was demonstrated to have a wide range of anti-metabolic activities when tested against cultured cancer cells and to be an effective chemotherapeutic agent for acute myelogenous leukemia. However, because of 5-azacytidine's general toxicity, other nucleoside analogs were favored as therapeutics. The finding that 5-azacytidine was incorporated into DNA and that, when present in DNA, it inhibited DNA methylation, led to widespread use of 5-azacytidine and 5-aza-2'-deoxycytidine (Decitabine) to demonstrate the correlation between loss of methylation in specific gene regions and activation of the associated genes. There is now a revived interest in the use of Decitabine as a therapeutic agent for cancers in which epigenetic silencing of critical regulatory genes has occurred. Here, the current status of our understanding of the mechanism(s) by which 5-azacytosine residues in DNA inhibit DNA methylation is reviewed with an emphasis on the interactions of these residues with bacterial and mammalian DNA (cytosine-C5) methyltransferases. The implications of these mechanistic studies for development of less toxic inhibitors of DNA methylation are discussed.
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              DNA methylation landscapes: provocative insights from epigenomics.

              The genomes of many animals, plants and fungi are tagged by methylation of DNA cytosine. To understand the biological significance of this epigenetic mark it is essential to know where in the genome it is located. New techniques are making it easier to map DNA methylation patterns on a large scale and the results have already provided surprises. In particular, the conventional view that DNA methylation functions predominantly to irreversibly silence transcription is being challenged. Not only is promoter methylation often highly dynamic during development, but many organisms also seem to target DNA methylation specifically to the bodies of active genes.
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                Author and article information

                Contributors
                Journal
                J Biol Chem
                J Biol Chem
                The Journal of Biological Chemistry
                American Society for Biochemistry and Molecular Biology
                0021-9258
                1083-351X
                02 May 2023
                June 2023
                02 May 2023
                : 299
                : 6
                : 104779
                Affiliations
                [1 ]Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S Nagar (Mohali), Punjab, India
                [2 ]Department for Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar, Punjab, India
                Author notes
                []For correspondence: Kulbhushan Tikoo tikoo.k@ 123456gmail.com tikoo@ 123456niper.ac.in
                Article
                S0021-9258(23)01807-0 104779
                10.1016/j.jbc.2023.104779
                10248527
                37142224
                f6c5d743-6977-4c3c-b3ae-f7ad9ca19e3a
                © 2023 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 9 December 2022
                : 16 April 2023
                Categories
                Research Article

                Biochemistry
                macrophage polarization,autophagy,dna hypomethylating agents,epigenetic reprogramming,nafld

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