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甜菜碱抑制乙醇诱导肝损伤大鼠 Toll 样受体 4 的表达。

Betaine inhibits toll-like receptor 4 expression in rats with ethanol-induced liver injury.

机构信息

Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China.

出版信息

World J Gastroenterol. 2010 Feb 21;16(7):897-903. doi: 10.3748/wjg.v16.i7.897.

Abstract

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 blot, respectively. The serum aminotransferase activity [alanine transarninase (ALT), aspartate aminotransferase (AST)], serum endotoxin, and liver inflammatory factors [tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), 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-alpha (20.81 +/- 8.58 pg/mL vs 9.34 +/- 2.57 pg/mL, P = 0.0003), IFN-gamma (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-alpha (9.79 +/- 1.32 pg/mL vs 20.81 +/- 8.58 pg/mL, P = 0.0003), IFN-gamma (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.

摘要

目的

检测乙醇喂养是否能诱导 Toll 样受体 4(TLR4)反应,评估甜菜碱在酒精性肝损伤动物模型中的肝保护作用及其对 TLR4 的抑制作用。

方法

48 只雌性 Sprague-Dawley 大鼠随机分为对照组、模型组、低剂量甜菜碱组和高剂量甜菜碱组。除对照组外,所有大鼠均给予高脂肪饮食加乙醇和鱼油灌胃 8 周。在暴露于乙醇 4 周后,通过胃内给予甜菜碱。检查肝组织学变化。通过 RT-PCR 和 Western blot 分别检测 TLR4 mRNA 和蛋白的表达。测定血清转氨酶活性[丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)]、血清内毒素和肝炎症因子[肿瘤坏死因子-α(TNF-α)、干扰素-γ(IFN-γ)、白细胞介素-18(IL-18)]。

结果

与对照组相比,模型组大鼠发生明显肝损伤,伴有 ALT(159.41 ± 7.74 U/L 比 59.47 ± 2.34 U/L,P < 0.0001)、AST(248.25 ± 1.40 U/L 比 116.89 ± 3.48 U/L,P < 0.0001)、内毒素(135.37 ± 30.17 ng/L 比 44.15 ± 7.54 ng/L,P < 0.0001)、TNF-α(20.81 ± 8.58 pg/mL 比 9.34 ± 2.57 pg/mL,P = 0.0003)、IFN-γ(30.18 ± 7.60 pg/mL 比 16.86 ± 9.49 pg/mL,P = 0.0039)和 IL-18(40.99 ± 8.25 pg/mL 比 19.73 ± 9.31 pg/mL,P = 0.0001)显著增加。同时,慢性乙醇摄入后肝脏 TLR4 mRNA 和蛋白表达明显增加(1.45 ± 0.07 比 0.44 ± 0.04,P < 0.0001;1.83 ± 0.13 比 0.56 ± 0.08,P < 0.0001)。与模型组相比,甜菜碱喂养使 ALT(64.93 ± 6.06 U/L 比 159.41 ± 7.74 U/L,P < 0.0001)、AST(188.73 ± 1.11 U/L 比 248.25 ± 1.40 U/L,P < 0.0001)、内毒素(61.80 ± 12.56 ng/L 比 135.37 ± 30.17 ng/L,P < 0.0001)、TNF-α(9.79 ± 1.32 pg/mL 比 20.81 ± 8.58 pg/mL,P = 0.0003)、IFN-γ(18.02 ± 5.96 pg/mL 比 30.18 ± 7.60 pg/mL,P = 0.0008)和 IL-18(18.23 ± 7.01 pg/mL 比 40.99 ± 8.25 pg/mL,P < 0.0001)显著降低。甜菜碱还改善了肝脂肪变性。肝组织 TLR4 mRNA 或蛋白表达水平明显降低(0.62 ± 0.04 比 1.45 ± 0.07,P < 0.0001;和 0.65 ± 0.06 比 1.83 ± 0.13,P < 0.0001)。高、低剂量甜菜碱组 TLR4 mRNA 和蛋白表达存在统计学差异(0.62 ± 0.04 比 0.73 ± 0.05,P < 0.0001,和 0.65 ± 0.06 比 0.81 ± 0.09,P < 0.0001)。

结论

甜菜碱能有效预防乙醇诱导的肝损伤,改善肝功能。乙醇喂养大鼠 TLR4 表达明显增加,甜菜碱给药可抑制 TLR4 表达。

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