Resveratrol suppresses cholestasis-induced liver injury and fibrosis in rats associated with the inhibition of TGFβ1-Smad3-miR21 axis and profibrogenic and hepatic injury biomarkers.

Abstract

Cholestasis caused by slowing or blockage of bile flow is a serious liver disease that can lead to liver fibrosis and cirrhosis. The link between transforming growth factor beta 1 (TGFβ1), Smad family member 3 (Smad3), and microRNA 21 (miR21) in bile duct ligation (BDL)-induced liver fibrosis in the presence and absence of the anti-inflammatory and antioxidant compound, resveratrol (RSV), has not been previously studied. Therefore, we tested whether RSV can protect against BDL-induced liver fibrosis associated with the inhibition of the TGFβ1-Smad3-miR21 axis and profibrogenic and hepatic injury biomarkers. The model group of rats had their bile duct ligated (BDL) for 3weeks before being killed, whereas, the BDL-treated rats were separated into three groups that received 10, 20, and 30mg/kg RSV daily until the end of the experiment. Using light microscopy and ultrasound examinations, we documented in the BDL group, the development of hepatic injury and fibrosis as demonstrated by hepatocytes necrosis, bile duct hyperplasia, collagen deposition, enlarged liver with increased echogenicity, irregular nodular border and dilated common bile duct, which were more effectively inhibited by the highest used RSV dosage. In addition, RSV significantly (p≤0.0027) inhibited BDL-induced hepatic TGFβ1, Smad3, miR21, the profibrogenic biomarker tissue inhibitor of metalloproteinases-1 (TIMP-1), malondialdehyde (MDA), interleukin-17a (IL-17a), and blood levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin. These findings show that RSV at 30mg/kg substantially protects against BDL-induced liver injuries, which is associated with the inhibition of TGFβ1-Smad3-miR21 axis, and biomarkers of profibrogenesis, oxidative stress, and inflammation.