AGK2, a SIRT2 inhibitor, ameliorates D-galactose-induced liver fibrosis by inhibiting fibrogenic factors

Abstract

In our study, we aimed to investigate the effect of SIRT2 inhibition on function, fibrosis and inflammation in liver fibrosis induced by D-Galactose (D-Gal) administration. A total of 32 3-month-old Sprague Dawley rats were used in the study. Rats were divided into 4 groups as Control, d-Gal, Solvent+d-Gal, d-Gal+AGK2+Solvent. d-Gal (150 mg/kg/day), AGK-2 (10 µM/bw) as a specific SIRT2 inhibitor, 4%DMSO + PBS as a solvent was applied to the experimental groups and physiological saline was applied to the control group for 10 weeks. All applications were performed subcutaneously. Histological fibrotic changes were studied in the liver tissues by Masson's trichrome staining, hematoxylin and eosin staining and immunohistochemistry and the levels of selected factors were determined by quantitative reverse transcription-polymerase chain reaction, western blot analysis, and immunohistochemical analysis. Biochemical parameters and Paraoxonase levels were determined in the plasma. d-Galactose administration increased AST, AST-ALT Ratio, APRI, SIRT2 protein expression, IL1β, TGF β, β-catenin, Type I collagen, Type III collagen and α-SMA, collagen fiber density and histopathological score. ALT and lipid panels were not changed and paraxonase plasma level was shown to decrease. These effects were largely blocked by the SIRT2 inhibitor AGK2. These findings suggest that SIRT2 inhibition attenuates d-Gal-induced liver injury and that this protection may be due to its antifibrotic and anti-inflammatory activities.

Keywords: SIRT2 inhibition; TGFβ; d‐Galactose; liver fibrosis; β‐catenin.