Cholic acid as key regulator of cholesterol synthesis, intestinal absorption and hepatic storage in mice
Cholic acid as key regulator of cholesterol synthesis, intestinal absorption and hepatic storage in mice
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DOI：
10.1016/j.bbalip.2005.06.001
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发表时间：
2005-08-15
影响因子：
4.8
通讯作者：
Gåfvels, M
中科院分区：
文献类型：
--
作者：
Murphy, C;Parini, P;Gåfvels, M
为了研究饲喂胆酸(CA)对肝脏胆固醇代谢的影响，雄性12α-羟基酶基因敲除(-/-)小鼠和野生型对照(+/+)小鼠分别饲喂对照饲料和添加胆酸(0.1%或0.5%w/w)或胆固醇(1%w/w)的饲料。在饲喂对照饲料期间，与+/+小鼠相比，CYP8B1-/-小鼠的胆固醇合成增加。胆固醇和CA都下调了胆固醇生成基因的mRNA表达和肝脏新生胆固醇的合成，这也反映在伴随着核因子SREBP-2前体蛋白的减少和肝脏游离胆固醇水平的增加。具有完整CYP8B1基因的小鼠(CYP8B1+/+和C57B1/6小鼠)在肝脏中积累的胆固醇酯浓度(分别是CYP8B1+/+和C57B1/6小鼠的24倍和25倍)比CYP8B1-/-小鼠(8倍)高。饲喂CA可使CyP8B1+/+小鼠的肠道胆固醇吸收增加23%，使CyP8B1-/-小鼠的肠道胆固醇吸收增加50%。虽然在对照组和胆固醇喂养条件下，CYP8B1+/+和-/-小鼠的血浆胆固醇水平没有差异，但在喂饲CA的CYP8B1-/-小鼠中，可以看到胆固醇的降低。本研究表明CA是肠道胆固醇吸收的重要决定因素，肝脏中转录因子SREBP-2的水平依赖于CA对肠道胆固醇吸收和细胞色素P7A1的联合作用。本文讨论了抑制细胞色素P8B1的合成从而抑制CA的合成对治疗高脂血症的可能性。(C)2005 Elsevier B.V.保留所有权利。
To study the effects of cholic acid (CA) feeding on hepatic cholesterol metabolism, male sterol 12 alpha-hydroxylase(CYP8B1) knockout(-/-) mice and wildtype controls(+/+) were fed either a control diet or the same diet supplemented with CA (0.1% or 0.5% w/w) or cholesterol (1% w/w). During feeding of the control diet, cholesterol synthesis was increased in CYP8B1-/- compared to +/+ mice. Both cholesterol and CA feeding down regulated mRNA expression of cholesterogenic genes and hepatic de novo cholesterol synthesis as also reflected by a concomitant decrease in the nuclear factor SREBP-2 precursor protein and increased hepatic free cholesterol levels. Mice with an intact CYP8B1 gene (CYP8B1+/+ and C57B1/6 mice) accumulated higher concentrations of cholesteryl esters (24- and 25-fold, respectively) in their livers compared to CYP8B1-/- mice (8-fold). Feeding of CA increased intestinal cholesterol absorption in CYP8B1+/+ mice by 23% and in CYP8B1-/- mice by 50%. While plasma cholesterol did not differ between CYP8B1+/+ and -/- mice under control conditions and cholesterol feeding a decrease was seen in CYP8B1-/- but not CYP8B1+/+ mice fed CA. This study indicates that CA is an important determinant for intestinal cholesterol absorption and that the levels of the transcription factor SREBP-2 in the liver are dependent upon the combined effect of CA on intestinal cholesterol absorption and CYP7A1. The possibility is discussed that inhibition of CYP8B1 and thus CA synthesis may be beneficial for the treatment of hyperlipidemic disorders. (c) 2005 Elsevier B.V. All rights reserved.