Sterol 27-hydroxylase gene dosage and the antiatherosclerotic effect of Rifampicin in mice.

Zurkinden, Line; Sviridov, Dmitri; Vogt, Bruno; Escher, Geneviève (2018). Sterol 27-hydroxylase gene dosage and the antiatherosclerotic effect of Rifampicin in mice. Bioscience reports, 38(1) Portland Press 10.1042/BSR20171162

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Sterol 27-hydroxylase (CYP27A1) catalyzes the hydroxylation of cholesterol to 27-hydroxycholesterol (27-OHC) and regulates cholesterol homeostasis. In Cyp27a1/ Apolipoprotein E (ApoE) double knockout (KO) mice fed with Western diet (WD), the atherosclerotic phenotype found in ApoE KO mice was reversed. As protective mechanism, up-regulation of Cyp3a11 and Cyp7a1 was proposed. Cyp27a1 heterozygote/ApoE KO (het) mice, with reduced Cyp27a1 expression and normal levels of Cyp7a1 and Cyp3a11, developed more severe lesions than ApoE KO mice. To analyze the contribution of Cyp3a11 to the protection of atherosclerosis development, Cyp3a11 was induced by Rifampicin (RIF) in ApoE KO and het mice. Males were fed with WD and treated daily with RIF (10 mg/kg ip) or vehicle for 4 weeks. Atherosclerosis was quantified in the aortic valve. Plasma lipids and 27-hydroxycholesterol (27-OHC), expression of cytochromes P450 and genes involved in cholesterol transport and bile acids (BAs) signaling in liver and intestine, and intestinal cholesterol absorption were analyzed. RIF increased expression of hepatic but not intestinal Cyp3a11 4-fold in both genotypes. In ApoE KO mice treated with RIF, we found a 2-fold decrease in plasma cholesterol, and a 2-fold increase in high-density lipoprotein/low-density lipoprotein ratio and CY27A1 activity. Intestinal cholesterol absorption remained unchanged and atherosclerotic lesions decreased approximately 3-fold. In het mice, RIF had no effect on plasma lipids composition, CYP27A1 activity, and atherosclerotic plaque development, despite a reduction in cholesterol absorption. In conclusion, the antiatherogenic effect of Cyp3a11 induction by RIF was also dependent on Cyp27a1 expression.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Nephrologie / Hypertonie

UniBE Contributor:

Vogt, Bruno and Escher, Geneviève

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1573-4935

Publisher:

Portland Press

Language:

English

Submitter:

Geneviève Escher

Date Deposited:

27 Feb 2018 10:32

Last Modified:

27 Feb 2018 10:36

Publisher DOI:

10.1042/BSR20171162

PubMed ID:

29191818

Uncontrolled Keywords:

27-hydroxycholesterol ApoE knock out mice Western diet

BORIS DOI:

10.7892/boris.110416

URI:

https://boris.unibe.ch/id/eprint/110416

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