Studies on the cholesterol-free mouse -: Strong activation of LXR-regulated hepatic genes when replacing cholesterol with desmosterol
Studies on the cholesterol-free mouse -: Strong activation of LXR-regulated hepatic genes when replacing cholesterol with desmosterol
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DOI：
10.1161/atvbaha.107.149823
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发表时间：
2007-10-01
影响因子：
8.7
通讯作者：
Bjoerkhem, Ingemar
中科院分区：
文献类型：
--
作者：
Heverin, Maura;Meaney, Steve;Bjoerkhem, Ingemar
3 β-羟基类固醇-δ（24）-还原酶基因失活的雄性小鼠胆固醇体内平衡的特征，导致几乎所有的胆固醇被链甾醇取代。方法和结果-肝甾醇合成增加，中性甾醇的粪便损失显著增加。胆汁酸的粪便排泄在基因敲除小鼠和对照组中相似。胆汁酸的组成发生了变化，胆酸的形成减少。结果表明，Cyp 7a 1和Cyp 27 a1都对桥甾醇有活性，与这种类固醇形成正常胆汁酸一致。植物甾醇的水平明显降低。肝脏3-羟基-3-甲基戊二酰（HMG）辅酶A（CoA）还原酶、Srebp-1c、Srebp-2、Cyp 7a 1、Abcg 5、Abcg 8和Fas的mRNA水平均显著增加。与LXR靶向基因的强烈激活一致。中性固醇的粪便损失显著增加可以解释Dhcr 24（-/-）小鼠不积累膳食胆固醇的事实。这项研究说明了胆固醇结构完整性的重要性类固醇侧链中双键的存在与生命相容，但与固醇体内平衡的严重紊乱有关。
Objective-Characterization of cholesterol homeostasis in male mice with a genetic inactivation of 3 beta-hydroxysteroid-Delta(24)-reductase, causing replacement of almost all cholesterol with desmosterol.Methods and Results-There was an increase in hepatic sterol synthesis and markedly increased fecal loss of neutral sterols. Fecal excretion of bile acids was similar in knockout mice and in controls. The composition of bile acids was changed, with reduced formation of cholic acid. It was shown that both Cyp7a1 and Cyp27a1 are active toward desmosterol, consistent with the formation of normal bile acids from this steroid. The levels of plant sterols were markedly reduced. Hepatic mRNA levels of 3-hydroxy- 3-methylglutaryl (HMG) coenzyme A (CoA) reductase, Srebp-1c, Srebp-2, Cyp7a1, Abcg5, Abcg8, and Fas were all significantly increased.Conclusions-The changes in hepatic mRNA levels in combination with increased biliary and fecal excretion of neutral steroids, reduced tissue levels of plant sterols, increased plasma levels of triglyceride-rich VLDL, are consistent with a strong activation of LXR-targeted genes. The markedly increased fecal loss of neutral sterols may explain the fact that the Dhcr24(-/-) mice do not accumulate dietary cholesterol. The study illustrates the importance of the integrity of the cholesterol structure-presence of a double bond in the steroid side-chain is compatible with life but is associated with serious disturbances in sterol homeostasis.