Schött Hans-Frieder, Husche Constanze, Friedrichs Silvia, Miller Charlotte M, McCarthy Florence O, Laufs Ulrich, Plat Jogchum, Weingärtner Oliver, Lütjohann Dieter
Institute for Clinical Chemistry and Clinical Pharmacology, University Clinics, Bonn, Germany.
Department of Chemistry and Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland.
Steroids. 2015 Jul;99(Pt B):178-82. doi: 10.1016/j.steroids.2015.03.006. Epub 2015 Mar 17.
In this study, we compare the distribution of intraperitoneally injected sitosterol, 7β-hydroxysitosterol or vehicle only (control) for 28days in male ApoE-/- mice. Furthermore we examine its impact on surrogate markers of cholesterol biosynthesis and sterol absorption rate in plasma, brain and liver tissues from these animals. Injection of sitosterol revealed a 32.1% (P=0.013) lower plasma total cholesterol compared with control. Cholesterol corrected plasma and absolute brain and liver levels of sitosterol are 4.1-, 1.7-, and 7.2-fold (P<0.001 for all) higher, respectively. This is in accordance with a reduced plasma campesterol to cholesterol ratio (-16.2%; P=0.018) together with a 24.1% (P=0.047) lower concentration of hepatic lathosterol. After injection of 7β-hydroxysitosterol the concentrations of 7β-hydroxysitosterol in plasma, brain and liver are 21.0-, 65.8- and 42.7-fold (P<0.001 for all) higher, respectively, compared with control. Injection of 7β-hydroxysitosterol revealed significantly lower plasma cholesterol corrected cholestanol and campesterol (-44.2%; P=0.001 and -24.5; P=0.004) as well as lower absolute liver cholestanol levels (-31.9%; P<0.001) compared with control. Intraperitoneally injected sitosterol and 7β-hydroxysitosterol differently influence cholesterol metabolism in plasma and liver. We conclude that the polar 7β-hydroxysitosterol compound can pass the blood brain barrier with higher efficacy than its substrate, sitosterol. Though present in higher amounts in the brain, both, sitosterol and 7β-hydroxysitosterol do not influence cholesterol metabolism in the brain as proven by our surrogate markers.
在本研究中，我们比较了雄性ApoE - / - 小鼠腹腔注射谷甾醇、7β - 羟基谷甾醇或仅注射溶媒（对照）28天的分布情况。此外，我们还研究了其对这些动物血浆、脑和肝组织中胆固醇生物合成替代标志物以及甾醇吸收率的影响。与对照组相比，注射谷甾醇后血浆总胆固醇降低了32.1%（P = 0.013）。胆固醇校正后的血浆以及脑中谷甾醇的绝对水平和肝中谷甾醇的绝对水平分别高出4.1倍、1.7倍和7.2倍（所有P < 0.001）。这与血浆中菜油甾醇与胆固醇的比例降低（-16.2%；P = 0.018）以及肝中羊毛甾醇浓度降低24.1%（P = 0.047）一致。注射7β - 羟基谷甾醇后，与对照组相比，血浆、脑和肝中7β - 羟基谷甾醇的浓度分别高出21.0倍、65.8倍和42.7倍（所有P < 0.001）。注射7β - 羟基谷甾醇后，与对照组相比，血浆中胆固醇校正后的胆甾烷醇和菜油甾醇显著降低（-44.2%；P = 0.001和-24.5；P = 0.004），肝中胆甾烷醇的绝对水平也降低（-31.9%；P < 0.001）。腹腔注射谷甾醇和7β - 羟基谷甾醇对血浆和肝脏中的胆固醇代谢有不同影响。我们得出结论，极性7β - 羟基谷甾醇化合物穿过血脑屏障的效率高于其底物谷甾醇。尽管脑中谷甾醇和7β - 羟基谷甾醇的含量较高，但如我们的替代标志物所证实，它们均不影响脑中的胆固醇代谢。
