Inhibition of RKIP aggravates thioacetamide‑induced acute liver failure in mice

Abstract

Accumulating evidence has indicated that Raf kinase inhibitor protein (RKIP) is involved in several intracellular signaling pathways; its abnormal expression is associated with tumor progression and metastasis in several human neoplasms. However, the role of RKIP in acute liver injury has remained elusive. In the present study, acute liver failure was induced by thioacetamide in mice, and locostatin was used to interfere with RKIP expression. It was found that RKIP expression was significantly inhibited by locostatin. Down-regulation of RKIP expression resulted in severe liver injury and extensive release of alanine aminotransferase and aspartate aminotransferase. In addition, reduced RKIP expression significantly enhanced the levels of reactive oxygen species and the content of pro-inflammatory factors such as tumor necrosis factor-α as well as interleukin-6 and −1β, and decreased the levels of nuclear factor E2-related factor-2 and heme oxygenase-1. Furthermore, down-regulation of RKIP promoted the activation of the nuclear factor-κB and extracellular signal-regulated kinase signaling pathways. In conclusion, the present study indicates an inverse correlation between RKIP level and the degree of hepatic injury, that is, a decrease in RKIP expression may exacerbate acute liver failure.

The Ameliorative Effects of Fucoidan in Thioacetaide-Induced Liver Injury in Mice

“…TAA-induced hepatic inflammation, fibrosis, and liver damage in mice, in terms of clinical features, are very close to chronic human liver disease [ 11 ]. After TAA exposure, the levels of plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are upregulated due to hepatocyte membrane damage, which causes a leakage of transaminase enzymes into the systemic circulation [ 12 ]. The advantage of using the TAA model for the hepatotoxin animal model is its unique specificity for targeting the liver [ 12 , 13 ].…”

“…After TAA exposure, the levels of plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are upregulated due to hepatocyte membrane damage, which causes a leakage of transaminase enzymes into the systemic circulation [ 12 ]. The advantage of using the TAA model for the hepatotoxin animal model is its unique specificity for targeting the liver [ 12 , 13 ]. The toxicity is because of its bioactivation led by a mixed-function oxidase system—mainly, the cytochrome P2E1 and flavin adenine dinucleotide monooxygenases [ 13 , 14 ].…”

The Ameliorative Effects of Saikosaponin in Thioacetamide-Induced Liver Injury and Non-Alcoholic Fatty Liver Disease in Mice

“…Hepatic inflammation is common in liver injury associated with liver fibrosis, cirrhosis, and HCC. Promising anti-inflammatory molecules can be considered a cornerstone of liver disease treatment [ 17 ]. Many studies have demonstrated that SSd has beneficial effects on health via anti-inflammatory, antioxidant, neuroprotective, anticancer, and cardioprotective activities [ 28 , 51 ].…”

“…The biochemical processing of TAA within the cellular milieu leads to oxidative damage of hepatocytes, which in turn causes degeneration and necrosis in liver tissue [ 16 ]. TAA-induced hepatic inflammation, fibrosis, and liver damage in mice are, in terms of clinical features, comparable to chronic liver disease in humans [ 10 , 17 ]. Accordingly, the advantage of using TAA to induce hepatoxicity in animal models is its unique specificity in targeting the liver [ 17 , 18 ].…”

“…TAA-induced hepatic inflammation, fibrosis, and liver damage in mice are, in terms of clinical features, comparable to chronic liver disease in humans [ 10 , 17 ]. Accordingly, the advantage of using TAA to induce hepatoxicity in animal models is its unique specificity in targeting the liver [ 17 , 18 ]. Animal models play an essential role in demonstrating the pathophysiological mechanisms of NAFLD [ 19 ].…”