Knockout of mouse Cyp3a gene enhances synthesis of cholesterol and bile acid in the liver
Knockout of mouse Cyp3a gene enhances synthesis of cholesterol and bile acid in the liver
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DOI：
10.1194/jlr.m033464
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发表时间：
2013-08-01
影响因子：
6.5
通讯作者：
Chiba, Kan
中科院分区：
文献类型：
--
作者：
Hashimoto, Mari;Kobayashi, Kaoru;Chiba, Kan
在这里，我们使用Cyp3a敲除（Cyp3a(-/-)）小鼠研究了细胞色素P450 (CYP)3A缺乏对肝脏胆固醇水平调控基因mRNA表达的影响。Cyp3a（-/-）小鼠肝脏中胆固醇生物合成相关酶基因mRNA表达水平高于野生型（WT）小鼠。促进胆固醇生物合成的固醇调节元件结合蛋白2 （SREBP-2）的核水平在Cyp3a（-/-）小鼠的肝脏中也较高。在Cyp3a（-/-）小鼠的肝脏中，SREBP-2与Hmgcs1基因启动子的结合更为丰富。这些结果表明，缺乏CYP3A酶可以通过激活SREBP-2来增强胆固醇生物合成相关酶的基因转录。另一方面，Cyp3a（-/-）小鼠的肝脏胆固醇水平比WT小鼠低20%。Cyp3a（-/-）小鼠胆汁酸合成相关酶基因mRNA表达水平、血浆7 α -羟基-4-胆甾醇-3- 1水平和肝脏总胆汁酸水平均显著高于WT小鼠。这些发现表明，Cyp3a（-/-）小鼠肝脏总胆固醇的降低可能是胆汁酸合成增强的结果。因此，CYP3A酶似乎在体内胆固醇和胆汁酸的合成中发挥作用。
Here, we studied the effects of cytochrome P450 (CYP)3A deficiency on the mRNA expression of genes encoding regulators of hepatic cholesterol levels using Cyp3a-knockout (Cyp3a(-/-)) mice. The mRNA expression levels of genes encoding enzymes involved in cholesterol biosynthesis in the livers of Cyp3a(-/-) mice were higher than those of wild-type (WT) mice. Nuclear levels of sterol regulatory element-binding protein-2 (SREBP-2), which enhances cholesterol biosynthesis, were also higher in the livers of Cyp3a(-/-) mice. Binding of SREBP-2 to the Hmgcs1 gene promoter was more abundant in the livers of Cyp3a(-/-) mice. These results suggest that deficiency of CYP3A enzymes enhances transcription of genes encoding enzymes involved in cholesterol biosynthesis via activation of SREBP-2. On the other hand, hepatic cholesterol levels in Cyp3a(-/-) mice were 20% lower than those in WT mice. The mRNA expression levels of genes encoding enzymes involved in bile acid synthesis, plasma levels of 7 alpha-hydroxy-4-cholesten-3-one and hepatic levels of total bile acid were significantly higher in Cyp3a(-/-) mice than in WT mice. These findings suggest that reduction of hepatic total cholesterol in Cyp3a(-/-) mice would be the consequence of enhanced bile acid synthesis. Therefore, CYP3A enzymes appear to play roles in the synthesis of cholesterol and bile acid in vivo.