Increased hepatic expression is a major determinant of serum alanine aminotransferase elevation in mice with nonalcoholic steatohepatitis
Increased hepatic expression is a major determinant of serum alanine aminotransferase elevation in mice with nonalcoholic steatohepatitis
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DOI：
10.1111/j.1478-3231.2008.01862.x
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发表时间：
2009-03-01
影响因子：
6.7
通讯作者：
Whitington, Peter F.
中科院分区：
文献类型：
--
作者：
Liu, Rui;Pan, Xiaomin;Whitington, Peter F.
血清丙氨酸转氨酶（ALT）是包括脂肪肝在内的各种病因肝炎的生物标志物。血清ALT升高被认为与死亡肝细胞释放ALT增加有关。我们试图了解在肝细胞死亡最小的实验性脂肪肝小鼠模型中血清ALT升高的机制。为了诱导脂肪肝，雌性A/J小鼠被喂食蛋氨酸-胆碱缺乏（MCD）饮食长达12周。比较对照组小鼠血清和肝脏ALT的表达以及肝脏炎症、坏死和凋亡的表达。给小鼠喂食MCD饮食会导致肝脏脂肪变性，并伴有轻微的肝脏炎症或坏死。MCD饮食对肝细胞凋亡无显著影响。相反，12周时血清ALT活性增加了约4倍，血清ALT蛋白表达量相应增加：12周时ALT1增加1.7倍，ALT2增加1.9倍。MCD治疗2-12周后，肝脏中ALT1和ALT2蛋白表达升高。12周时，与蛋氨酸和胆碱组相比，肝脏ALT1蛋白表达量增加了2.27 +/- 0.31倍，ALT2蛋白表达量增加了4.72 +/- 0.48倍。肝脏ALT mRNA表达量相应增加：12周时ALT1 mRNA表达量为2.58倍，ALT2 mRNA表达量为4.97倍。线性回归分析显示，血清和肝组织中ALT1和ALT2的表达均有较强的相关性。这些发现表明，在这种实验性脂肪肝疾病模型中，诱导肝脏表达显著有助于血清ALT升高，而细胞死亡似乎没有。
Serum alanine aminotransferase (ALT) is a biomarker for hepatitis of various aetiologies including fatty liver disease. Increased serum ALT is thought to be related to its increased release from dying hepatocytes.We sought to understand the mechanisms by which serum ALT is elevated in a mouse model of experimental fatty liver disease where hepatocyte death is minimal.To induce fatty liver disease, female A/J mice were fed a methionine-choline deficient (MCD) diet for up to 12 weeks. Serum and liver ALT expression and hepatic inflammation, necrosis and apoptosis were assessed and expressed relative to their expressions in control-diet-fed mice.Feeding mice the MCD diet produced hepatic steatosis with minimal hepatic inflammation or necrosis. Liver cell apoptosis was not significantly increased by MCD diet treatment. Conversely, serum ALT activity was approximately four-fold increased at 12 weeks of diet treatment, and ALT protein expressions in serum were correspondingly increased: ALT1 1.7-fold and ALT2 1.9-fold at 12 weeks. The expressions of ALT1 and ALT2 protein in liver increased over 2-12 weeks of MCD treatment. At 12 weeks, liver ALT1 protein was 2.27 +/- 0.31-fold increased and ALT2 protein 4.72 +/- 0.48-fold increased relative to their expressions in the mice fed a diet replete with methionine and choline. Liver ALT mRNA expressions were correspondingly increased: ALT1 mRNA 2.58-fold and ALT2 mRNA 4.97-fold at 12 weeks. Linear regression analysis showed a strong correlation between serum and liver tissue expressions for both ALT1 and ALT2.These findings suggest that induction of hepatic expression significantly contributes to increased serum ALT in this model of experimental fatty liver disease, whereas cell death appears not to.