Epigallocatechin gallate attenuates fibrosis, oxidative stress, and inflammation in non-alcoholic fatty liver disease rat model through TGF/SMAD, PI3 K/Akt/FoxO1, and NF-kappa B pathways

Abstract

To investigate the protective mechanisms of an 85 % pure extract of (-) epigallocatechin gallate (EGCG) in the development of fibrosis, oxidative stress and inflammation in a recently developed dietary-induced animal model of non-alcoholic fatty liver disease (NAFLD). Female Sprague-Dawley rats were fed with either normal rat diet or high-fat diet for 8 weeks to develop NAFLD. For both treatments, rats were treated with or without EGCG (50 mg/kg, i.p. injection, 3 times per week). At the end, blood and liver tissue samples were obtained for histology, molecular, and biochemical analyses. Non-alcoholic fatty liver disease (NAFLD) rats showed significant amount of fatty infiltration, necrosis, fibrosis, and inflammation. This was accompanied by a significant expressional increase in markers for fibrosis, oxidative stress, and inflammation. TGF/SMAD, PI3 K/Akt/FoxO1, and NF-κB pathways were also activated. Treatment with EGCG improved hepatic histology (decreased number of fatty score, necrosis, and inflammatory foci), reduced liver injury (from ~0.5 to ~0.3 of ALT/AST ratio), attenuated hepatic changes including fibrosis (reduction in Sirius Red and synaptophysin-positive stain) with down-regulation in the expressions of key pathological oxidative (e.g. nitrotyrosine formation) and pro-inflammatory markers (e.g. iNOS, COX-2, and TNF-α). EGCG treatment also counteracted the activity of TGF/SMAD, PI3 K/Akt/FoxO1, and NF-κB pathways. Treatment with EGCG did not affect the healthy rats. Epigallocatechin gallate (EGCG) reduced the severity of liver injury in an experimental model of NAFLD associated with lower concentration of pro-fibrogenic, oxidative stress, and pro-inflammatory mediators partly through modulating the activities of TGF/SMAD, PI3 K/Akt/FoxO1, and NF-κB pathways. Therefore, green tea polyphenols and EGCG are useful supplements in the prevention of NAFLD.