Abstract
—Hepatic fibrosis (HF) is the typical response to chronic liver disease and is characterized by deposition of abundant extracellular matrix. The aim of the present study was to investigate the protective effect of resveratrol (RSV) in a CCl4-induced rat model of HF. We demonstrate that the administration of RSV effectively improves liver function and ameliorates liver fibrosis by reducing collagen deposition and reversing the expression of COL1A1 and PPAR-γ. Treatment efficacy of RSV could be attributed to reversed epithelial-mesenchymal transition progress with upregulated expression of E-cadherin and downregulated N-cadherin, vimentin, and α-SMA. Moreover, RSV significantly decreased the levels of endoplasmic reticulum stress (ERS)-related proteins CHOP; Bip; cleaved caspase-3, caspase-7, and caspase-12; Bax; and Bak while promotes the expression of anti-apoptosis protein Bcl2. The important role of ERS in HF was confirmed by using 4-PBA, an ERS inhibitor, which markedly ameliorated CCl4-induced HF. Further, mechanistic studies demonstrated that RSV significantly decreased CCl4-induced transforming growth factor-β synthesis and inflammatory factor (tumor necrosis factor-α and interleukin-6) expression and reduced the inflammation of hepatic stellate cells by inhibiting the NF-κB pathway in vivo and in vitro. In conclusion, the results suggested that RSV ameliorated HF in associated with decreased ERS-induced apoptosis and inflammation in rats.
Highlights
Hepatic fibrosis (HF) is a serious health problem all over the world, contributing to the pathological progression of chronic liver disease to cirrhosis and cancer
The structure of hepatic lobules was disordered in the C Cl4 group, which was indicated by hepatocyte steatosis, necrosis, inflammatory cell infiltration, hepatic lobule separation by collagen fibers, and a large amount of collagen fiber deposition in the portal area
To further study role of RSV on liver fibrosis, we evaluated the levels of COL1A1 and PPAR-γ in livers
Summary
Hepatic fibrosis (HF) is a serious health problem all over the world, contributing to the pathological progression of chronic liver disease to cirrhosis and cancer. The liver synthesizes a large number of proteins and lipids, and hepatocytes have well-functioning ERs with appropriate adaptive capability. Pathological stimuli, including inflammation and oxidative stress, can disrupt the function of the ER, resulting in the aggregation of misfolded proteins in the ER cavity, which causes cell homeostasis imbalance and hepatic dysfunction [5]. A number of studies have reported that ERS promotes HF progression by activating HSCs [9, 10]. In a C Cl4-induced rat model of HF, the protein and mRNA expression levels of Tribbles homolog 3 (TRB3) and CHOP were upregulated, which suggested that ERS may induce hepatocytes apoptosis via TRB3 and CHOP [11]
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