4.5 Article

Galectin-3 S-glutathionylation regulates its effect on adipocyte insulin signaling

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ELSEVIER
DOI: 10.1016/j.bbamcr.2022.119234

Keywords

S-glutathionylation; Galectin-3; Macrophage; Reactive oxygen species; Insulin resistance

Funding

  1. UGC, India
  2. CSIR
  3. CSIR-CDRI [10356]
  4. DBT, India

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Protein-S-glutathionylation promotes redox signaling in physiological and oxidative distress conditions. Gal-3 S-glutathionylation plays a protective role by enhancing insulin signaling and glucose uptake in adipocytes.
Protein-S-glutathionylation promotes redox signaling in physiological and oxidative distress conditions. Galectin3 (Gal-3) promotes insulin resistance by down-regulating adipocyte insulin signaling, however, its S-glutathionylation and significance is not known. In this context, we report reversible S-glutathionylation of Gal-3. Site-directed mutagenesis established Gal-3 Cys187 as the putative S-glutathionylation site. Glutathionylated Gal-3 prevents Gal-3(WT)-Insulin Receptor interaction and facilitates insulin-induced murine adipocyte p-IRS1 (tyr895) and p-AKT(ser473) signaling and glucose uptake in a Gal-3 Cys187 glutathionylation dependent manner in murine adipocytes, as assessed by Western blotting and 2-NBDG uptake assay respectively. Preglutathionylated Gal-3 at Cys187 resisted irreversible oxidation by H2O2. M2 macrophages showed enhanced Gal-3 S-glutathionylation when compared to M1 phenotype. Serum and stromal vascular fraction (SVF) isolated from control mice showed increased Gal-3 S-glutathionylation as compared to db/db mice. A significant increase in Gal-3 S-glutathionylation was observed in metformin-treated db/db mice when compared to db/db mice alone. Similar to murine, enhanced Gal-3 S-glutathionylation is observed in primary human monocyte derived M2 macrophages when compared to the M1 macrophage phenotype and Gal-3 regulates primary human adipocyte insulin signaling in a glutathionylation dependent manner. Collectively, we identified Gal-3 S-glutathionylation as a protective phenomenon, which relieves its inhibitory effect on adipocyte insulin signaling.& nbsp;

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