title: On the regulatory importance of 27-hydroxycholesterol in mouse liver.
abstract: 27-Hydroxycholesterol (27OH) is a strong suppressor of cholesterol synthesis and a weak activator of LXR in vitro. The regulatory importance of 27OH in vivo is controversial. Here we utilized male mice with increased levels of 27OH either due to increased production (CYP27A1 transgenic mice) or reduced metabolism (Cyp7b1-/- mice). We also used mice lacking 27OH due to a knockout of Cyp27a1. The latter mice were treated with cholic acid to compensate for reduced bile acid synthesis. The effects of the different levels of 27OH on Srebp- and other LXR-regulated genes in the liver were investigated. In the liver of CYP27tg mice we found a modest increase of the mRNA levels corresponding to the LXR target genes Cyp7b1 and Abca1. A number of other LXR-regulated genes were not affected. The effect on Abca1 mRNA was not seen in the liver of Cyp7b1-/- mice. There were little or no effects on cholesterol synthesis. In the liver of the Cyp27-/- mice treated with 0.025% cholic acid there was no significant effect of the knockout on the LXR target genes. In a previous work triple-knockout mice deficient in the biosynthesis of 24S-hydroxycholesterol, 25-hydroxycholesterol and 27OH were shown to have impaired response to dietary cholesterol, suggesting side-chain oxidized oxysterols to be mediators in cholesterol-induced effects on LXR target genes at a transcriptional level (Chen W. et al., Cell Metab. 5 (2007) 73-79). The hydroxylated oxysterol responsible for the effect was not defined. We show here that treatment of wildtype mice with dietary cholesterol under the same conditions as in the above study induced the LXR target genes Lpl, Abcg8 and Srebp1c in wild type mice but failed to activate the same genes in mice lacking 27-hydroxycholesterol due to a knockout of Cyp27. We failed to demonstrate the above effects at the protein level (Abcg8) or at the activity level (Lpl). The results suggest that 27OH is not an important regulator of Srebp- or LXR regulated genes under basal conditions in mouse liver. On the other hand 27OH appears to mediate cholesterol-induced effects on some LXR target genes at a transcriptional level under some in vivo conditions.
authors: Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden.
authors: Maura
authors: M
authors: Heverin
authors: Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden.
authors: Zeina
authors: Z
authors: Ali
authors: Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden.
authors: Maria
authors: M
authors: Olin
authors: Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden.
authors: Veronika
authors: V
authors: Tillander
authors: Department of Medical Biosciences/Physiological Chemistry, Umeå University, Umeå, Sweden.
authors: Masoumeh Motamedi
authors: MM
authors: Joibari
authors: Department of Medical Biosciences/Physiological Chemistry, Umeå University, Umeå, Sweden.
authors: Elena
authors: E
authors: Makoveichuk
authors: Department of Medicine B, Hadassah-Hebrew University Hospital, Israel.
authors: Eran
authors: E
authors: Leitersdorf
authors: Center for Nuclear Receptors and Cell Signaling, University of Houston, TX, USA.
authors: Margret
authors: M
authors: Warner
authors: Department of Medical Biosciences/Physiological Chemistry, Umeå University, Umeå, Sweden.
authors: Gunilla
authors: G
authors: Olivercrona
authors: Center for Nuclear Receptors and Cell Signaling, University of Houston, TX, USA.
authors: Jan-Åke
authors: JÅ
authors: Gustafsson
authors: Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden. Electronic address: ingemar.bjorkhem@karolinska.se.
authors: Ingemar
authors: I
authors: Björkhem
mesh_terms: D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8 / Q000378:metabolism; D000818:Animals; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics; D000072474:Cytochrome P450 Family 7 / Q000235:genetics; D020869:Gene Expression Profiling; D006888:Hydroxycholesterols / Q000378:metabolism*; D008071:Lipoprotein Lipase / Q000378:metabolism; D008074:Lipoproteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C462601:ABCG8 protein, mouse; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D006888:Hydroxycholesterols; D008074:Lipoproteins; D000071518:Liver X Receptors; D018160:Receptors, Cytoplasmic and Nuclear; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; C076996:27-hydroxycholesterol; D013250:Steroid Hydroxylases; D000072474:Cytochrome P450 Family 7; C097207:Cyp7b1 protein, mouse; D053493:Cholestanetriol 26-Monooxygenase; C506832:Cyp27a1 protein, mouse; D008071:Lipoprotein Lipase
keywords: Abcg8; Cholesterol metabolism; Cyp27-/- mice; Cytochrome P-450; Gene expression; Lipoprotein lipase; Lxr; Nuclear receptor; Oxysterols; Srebp1c