[Protective effect of glycogen synthase kinase 3ß inhibition via peroxisome proliferator-activated receptor alpha activation in mice with acute liver failure].

ABSTRACT

Objective: To investigate the role of the glycogen synthase kinase 3ß (GSK3ß) and the peroxisome proliferator-activated receptor alpha (PPARα) signaling pathway in acute liver failure and related mechanisms in a mouse model of acute liver failure induced by D-galactosamine/lipopolysaccharide (D-GalN/LPS). Methods: C57BL/6 mice were given intraperitoneal injection of D-GalN/LPS to establish a mouse model of acute liver failure. SB216763 was used to inhibit the activity of GSK3ß and PPARα siRNA was used to inhibit the expression of PPARα. Western blotting was used to measure the expression of PPARα protein. The changes in liver pathology were observed to evaluate liver injury, and the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured to assess liver function. Quantitative real-time PCR was used to measure the mRNA expression of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-12p40 (IL-12p40), and PPARα. A one-way analysis of variance was used for comparison of means between multiple groups; the least significant difference test was used for data with homogeneity of variance, and the Games-Howell method was used for data with heterogeneity of variance. Results: In the mice with liver failure induced by D-GalN/LPS, GSK3ß inhibition promoted the mRNA and protein expression of PPARα (F = 13.18 and 301.36, P = 0.00 and 0.00). In the mice with acute liver failure induced by D-GalN/LPS, GSK3ß inhibition alleviated liver bleeding, inflammation, and necrosis and reduced the serum levels of ALT (F = 25.16, P = 0.000) and AST (F = 12.96, P = 0.001), as well as the mRNA expression of TNF-α (F = 32.17, P = 0.00), IL-1ß (F = 11.57, P = 0.005), and IL-12p40 (F = 14.17, P = 0.015) in liver tissue. The inhibition of PPARα expression reversed the liver-protecting effect of GSK3ß inhibition, which manifested as aggravation in liver bleeding, inflammation, and necrosis, increases in the serum levels of ALT (F = 25.16, P = 0.001) and AST (F = 12.96, P = 0.000), and an increase in the mRNA expression of TNF-α (F = 32.17, P = 0.00), IL-1ß (F = 11.57, P = 0.024), and IL-12p40 (F = 14.17, P = 0.001) in liver tissue. Conclusion: In mice with acute liver failure induced by D-GalN/LPS, the GSK3ß-PPARα-inflammatory factor signaling pathway may play an important role. GSK3ß inhibition has a protective effect in mice with acute liver failure possibly by activating the inhibitory inflammatory factor of PPARα.