Magnesium chenoursodeoxycholic acid ameliorates carbon tetrachloride-induced liver fibrosis in rats

Abstract

This study was designed to investigate the hepatoprotective effects of magnesium chenoursodeoxycholic acid (Mg-CUD), a magnesium trihydrate salt of ursodeoxycholic acid and chenodeoxycholic acid, in carbon tetrachloride (CCl(4))-induced liver fibrosis in rats. Rats were treated with CCl(4) dissolved in olive oil (0.5 mL/kg, twice a week) intraperitoneally for eight weeks. Mg-CUD was administered orally at 15.625, 31.25, 62.5 and 125 mg/kg once a day. Chronic CCl(4) administration induced increases in serum transforming growth factor-β1, hepatic hydroxyproline content and serum alanine aminotransferase activity. Mg-CUD attenuated these increases. The levels of α-smooth muscle actin protein and mRNA expression were increased by chronic CCl(4) exposure and Mg-CUD attenuated these increases. Mg-CUD suppressed increases in matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 mRNA expression and elevation of oxidative stresses by attenuating lipid peroxidation and enhancing reduced glutathione/oxidized glutathione ratio. The overexpression of toll-like receptor 4 and increased nuclear translocation of nuclear factor-κB and phosphorylated c-Jun, a component of activator protein 1, were suppressed by Mg-CUD. Furthermore, CCl(4) increased the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10 and cyclooxygenase (COX)-2. Mg-CUD attenuated the levels of TNF-α, IL-6 and COX-2, while it augmented the level of IL-10. Our results suggest that Mg-CUD may prevent liver fibrosis by modulating collagen accumulation and inflammatory signaling pathways.