Increased production of apolipoprotein B-containing lipoproteins in the absence of hyperlipidemia in transgenic mice expressing cholesterol 7α-hydroxylase
Increased production of apolipoprotein B-containing lipoproteins in the absence of hyperlipidemia in transgenic mice expressing cholesterol 7α-hydroxylase
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DOI：
10.1074/jbc.m101853200
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发表时间：
2001-06-29
影响因子：
4.8
通讯作者：
Davis, RA
中科院分区：
文献类型：
--
作者：
Miyake, JH;Doung, XDT;Davis, RA
培养的大鼠肝癌细胞中胆固醇 7 α-羟化酶 (CYP7A1) 转基因的表达引起脂肪生成和含 apoB 脂蛋白分泌的协调增加，这一发现导致了这样的假设：含 apoB 脂蛋白的肝脏产生可能与 CYP7A1 的表达有关（Wang, S.-L.、Du, E.、Martin, T. D. 和 Davis, R. A） (1997) 化学杂志 272, 19351-19358)。为了在体内检验这一假设，在 C56BL/6 小鼠中表达了由人 apoE 基因的组成型肝脏特异性增强子驱动的编码 CYP7A1 的转基因。与非转基因同窝小鼠相比，转基因小鼠的CYP7A1 mRNA表达（20倍）、蛋白质（接近10倍）和酶活性（5倍）显着增加，CYP7A1转基因小鼠的胆汁酸库增加了一倍，主要是由于疏水性二羟基胆汁酸增加。在 CYP7A1 转基因小鼠中，肝脏含有类似 3 倍多的甾醇反应元件结合蛋白 2 mRNA。在转基因小鼠中，编码脂肪生成酶（即脂肪酸合酶、乙酰辅酶A羧化酶、硬脂酰辅酶A去饱和酶、角鲨烯合酶、法尼基焦磷酸合酶、3-羟基-3-甲基戊二酰辅酶A还原酶和低密度脂蛋白受体）以及微粒体甘油三酯转移蛋白的mRNA的肝表达仅仅升高了3-5倍。 CYP7A1 转基因小鼠的肝脏生成和富含甘油三酯的脂蛋白的分泌也显示出 2 倍以上的增加。尽管 CYP7A1 小鼠肝脏含 apoB 脂蛋白的分泌增加，但血浆甘油三酯和胆固醇水平并未显着增加。这些数据表明，CYP7A1转基因小鼠肝脏中低密度脂蛋白受体表达增加5倍，足以补偿含apoB脂蛋白产量增加2倍。这些发现强调了 CYP7A1 在平衡合成代谢脂蛋白组装/分泌途径与胆固醇分解代谢胆汁酸合成途径中发挥的重要稳态作用。
The finding that expression of a cholesterol 7 alpha -hydroxylase (CYP7A1) transgene in cultured rat hepatoma cells caused a coordinate increase in lipogenesis and secretion of apoB-containing lipoproteins led to the hypothesis that hepatic production of apoB-containing lipoproteins may be linked to the expression of CYP7A1 (Wang, S.-L., Du, E., Martin, T. D., and Davis, R. A (1997) J. Biol. Chem. 272, 19351-19358). To examine this hypothesis in vivo, a transgene encoding CYP7A1 driven by the constitutive liver-specific enhancer of the human apoE gene was expressed in C56BL/6 mice. The expression of CYP7A1 mRNA (20-fold), protein (similar to 10-fold), and enzyme activity (5-fold) was markedly increased in transgenic mice compared with non-transgenic littermates, The bile acid pool of CYP7A1 transgenic mice was doubled mainly due to increased hydrophobic dihydroxy bile acids. In CYP7A1 transgenic mice, livers contained similar to3-fold more sterol response element-binding protein-2 mRNA. Hepatic expression of mRNAs encoding lipogenic enzymes (i.e. fatty-acid synthase, acetyl-CoA carboxylase, stearoyl-CoA desaturase, squalene synthase, farnesyl-pyrophosphate synthase, 3-hydroxy-3-methylglutaryl-CoA reductase, and low density lipoprotein receptor) as well as microsomal triglyceride transfer protein mere elevated similar to3-5-fold in transgenic mice. CYP7A1 transgenic mice also displayed a >2-fold increase in hepatic production and secretion of triglyceride-rich apoB-containing lipoproteins. Despite the increased hepatic secretion of apoB-containing lipoproteins in CYP7A1 mice, plasma levels of triglycerides and cholesterol were not significantly increased. These data suggest that the 5-fold increased expression of the low density lipoprotein receptor displayed by the livers of CYP7A1 transgenic mice was sufficient to compensate for the 2-fold increase production of apoB-containing lipoproteins. These findings emphasize the important homeostatic role that CYP7A1 plays in balancing the anabolic lipoprotein assembly/secretion pathway with the cholesterol catabolic bile acid synthetic pathway.