Published online Feb 21, 2010. doi: 10.3748/wjg.v16.i7.897
Revised: December 16, 2009
Accepted: December 23, 2009
Published online: February 21, 2010
AIM: To test whether ethanol feeding could induce Toll-like receptor 4 (TLR4) responses, assess the hepatoprotective effect of betaine and its inhibitive effect on TLR4 in animal models of alcoholic liver injury.
METHODS: Forty-eight female Sprague-Dawley rats were randomly divided into four groups as control, model, low and high dose betaine groups. Except control group, all rats were fed with high fat-containing diet plus ethanol and fish oil gavages for 8 wk. Betaine was administered intragastrically after exposure of ethanol for 4 wk. The changes of liver histology were examined. The expression of TLR4 mRNA and protein was detected by RT-PCR and Western blotting, respectively. The serum aminotransferase activity [alanine transarninase (ALT), aspartate aminotransferase (AST)], serum endotoxin, and liver inflammatory factors [tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-18 (IL-18)] were also assayed.
RESULTS: Compared with control group, rats of model group developed marked liver injury, accompanied by an increase of ALT (159.41 ± 7.74 U/L vs 59.47 ± 2.34 U/L, P < 0.0001), AST (248.25 ± 1.40 U/L vs 116.89 ± 3.48 U/L, P < 0.0001), endotoxin (135.37 ± 30.17 ng/L vs 44.15 ± 7.54 ng/L, P < 0.0001), TNF-α (20.81 ± 8.58 pg/mL vs 9.34 ± 2.57 pg/mL, P = 0.0003), IFN-γ (30.18 ± 7.60 pg/mL vs 16.86 ± 9.49 pg/mL, P = 0.0039) and IL-18 (40.99 ± 8.25 pg/mL vs 19.73 ± 9.31 pg/mL, P = 0.0001). At the same time, the expression of TLR4 mRNA and protein was markedly induced in the liver after chronic ethanol consumption (1.45 ± 0.07 vs 0.44 ± 0.04, P < 0.0001; 1.83 ± 0.13 vs 0.56 ± 0.08, P < 0.0001). Compared with model group, betaine feeding resulted in significant decreases of ALT (64.93 ± 6.06 U/L vs 159.41 ± 7.74 U/L, P < 0.0001), AST (188.73 ± 1.11 U/L vs 248.25 ± 1.40 U/L, P < 0.0001), endotoxin (61.80 ± 12.56 ng/L vs 135.37 ± 30.17 ng/L, P < 0.0001), TNF-α (9.79 ± 1.32 pg/mL vs 20.81 ± 8.58 pg/mL, P = 0.0003), IFN-γ (18.02 ± 5.96 pg/mL vs 30.18 ± 7.60 pg/mL, P = 0.0008) and IL-18 (18.23 ± 7.01 pg/mL vs 40.99 ± 8.25 pg/mL, P < 0.0001). Betaine also improved liver steatosis. The expression levels of TLR4 mRNA or protein in liver tissues were significantly lowered (0.62 ± 0.04 vs 1.45 ± 0.07, P < 0.0001; and 0.65 ± 0.06 vs 1.83 ± 0.13, P < 0.0001). There was a statistical difference of TLR4 mRNA and protein expression between high- and low-dose betaine groups (0.62 ± 0.04 vs 0.73 ± 0.05, P < 0.0001, and 0.65 ± 0.06 vs 0.81 ± 0.09, P < 0.0001).
CONCLUSION: Betaine can prevent the alcohol-induced liver injury effectively and improve the liver function. The expression of TLR4 increases significantly in ethanol-fed rats and betaine administration can inhibit TLR4 expression.