Effects of tocotrienol on tumor necrosis factor-α/D-galactosamine-induced steatohepatitis in rats

It has been reported that a-tocopherol (alpha-Toc), a vitamin E analog, is effective for treatment of non-alcoholic steatohepatitis (NASH). However, it is unknown whether or not other vitamin E analogs are effective. Therefore we designed a new rat model of steatohepatitis induced by tumor necrosis factor-alpha (TNF-alpha) stimulation, and used it to investigate the effects of vitamin E analogs. The rat liver triglyceride content increased with the dosage of TNF-alpha/Dgalactosamine (GaIN), but was suppressed by intake of both tocotrienol (T3) and alpha-tocopherol. Moreover, lipid peroxides (thiobarbituric acid-reactive substances) level in the liver level was also lower in both groups after tocotrienol and a-Toc intake. Intake of both tocotrienol and alpha-tocopherol also tended to control the increase of liver damage marker activity. In the tocotrienol and alpha-tocopherol groups, increases of inflammatory cytokines mRNA expression in the liver were inhibited, and these effects were considered to contribute to improvement of inflammation and fibrosis. The expression of mRNAs for inflammatory cytokines in rat primary hepatocytes was increased by TNF-a stimulation, but was inhibited by addition of a-tocotrienol and gamma-tocotrienol. Transforming growth factor-beta 1 mRNA expression in particular was significantly inhibited by gamma-tocotrienol. These findings suggest that tocotrienol species are effective for amelioration of steatohepatitis, and that tocotrienol and alpha-tocopherol exert a synergistic effect.