title: 7β-Hydroxysitosterol crosses the blood-brain barrier more favored than its substrate sitosterol in ApoE-/- mice.
abstract: 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.
authors: Institute for Clinical Chemistry and Clinical Pharmacology, University Clinics, Bonn, Germany.
authors: Hans-Frieder
authors: HF
authors: Schött
authors: Institute for Clinical Chemistry and Clinical Pharmacology, University Clinics, Bonn, Germany.
authors: Constanze
authors: C
authors: Husche
authors: Institute for Clinical Chemistry and Clinical Pharmacology, University Clinics, Bonn, Germany.
authors: Silvia
authors: S
authors: Friedrichs
authors: Department of Chemistry and Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland.
authors: Charlotte M
authors: CM
authors: Miller
authors: Department of Chemistry and Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland.
authors: Florence O
authors: FO
authors: McCarthy
authors: Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Homburg/Saar, Germany.
authors: Ulrich
authors: U
authors: Laufs
authors: Department of Human Biology, Maastricht University, Maastricht, The Netherlands.
authors: Jogchum
authors: J
authors: Plat
authors: Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Homburg/Saar, Germany; Abteilung für Kardiologie, Klinikum Oldenburg, European Medical School Oldenburg-Groningen, Carl von Ossietzky Universität Oldenburg, Oldenburg, Germany.
authors: Oliver
authors: O
authors: Weingärtner
authors: Institute for Clinical Chemistry and Clinical Pharmacology, University Clinics, Bonn, Germany. Electronic address: dieter.luetjohann@ukb.uni-bonn.de.
authors: Dieter
authors: D
authors: Lütjohann
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000378:metabolism; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002784:Cholesterol / Q000096:biosynthesis; D004987:Ethers / Q000737:chemistry; D007274:Injections, Intraperitoneal; D008099:Liver / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012855:Sitosterols / Q000097:blood*; D013379:Substrate Specificity
chemical_list: D001057:Apolipoproteins E; D004987:Ethers; D012855:Sitosterols; C011486:hydroxysitosterol; D002784:Cholesterol
keywords: ApoE−/− mice; Brain oxyphytosterols; Oxysterols; Phytosterols; Plant sterols; Sitosterol