University of Oulu

Salonurmi T, Nabil H, Ronkainen J, Hyötyläinen T, Hautajärvi H, Savolainen MJ, Tolonen A, Orešič M, Känsäkoski P, Rysä J, Hakkola J and Hukkanen J (2020) 4β-Hydroxycholesterol Signals From the Liver to Regulate Peripheral Cholesterol Transporters. Front. Pharmacol. 11:361. doi: 10.3389/fphar.2020.00361

4β-hydroxycholesterol signals from the liver to regulate peripheral cholesterol transporters

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Author: Salonurmi, Tuire1,2; Nabil, Heba2,3,4; Ronkainen, Justiina2,5;
Organizations: 1Research Unit of Internal Medicine, University of Oulu, Oulu, Finland
2Biocenter Oulu, Oulu, Finland
3Research Unit of Biomedicine, University of Oulu, Oulu, Finland
4Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
5Center for Life-Course Health Research, University of Oulu, Oulu, Finland
6Department of Chemistry, Örebro University, Örebro, Sweden
7Admescope Ltd., Oulu, Finland
8School of Medical Sciences, Örebro University, Örebro, Sweden
9Faculty of Health Sciences, School of Pharmacy, University of Eastern Finland, Kuopio, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2 MB)
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Language: English
Published: Frontiers Media, 2020
Publish Date: 2020-06-22


Activation of pregnane X receptor (PXR) elevates circulating 4β-hydroxycholesterol (4βHC), an agonist of liver X receptor (LXR). PXR may also regulate 25-hydroxycholesterol and 27-hydroxycholesterol. Our aim was to elucidate the roles of PXR and oxysterols in the regulation of cholesterol transporters. We measured oxysterols in serum of volunteers dosed with PXR agonist rifampicin 600 mg/day versus placebo for a week and analyzed the expression of cholesterol transporters in mononuclear cells. The effect of 4βHC on the transport of cholesterol and the expression of cholesterol transporters was studied in human primary monocyte-derived macrophages and foam cells in vitro. The expression of cholesterol transporters was measured also in rat tissues after dosing with a PXR agonist. The levels of 4βHC were elevated, while 25-hydroxycholesterol and 27-hydroxycholesterol remained unchanged in volunteers dosed with rifampicin. The expression of ATP binding cassette transporter A1 (ABCA1) was induced in human mononuclear cells in vivo. The influx of cholesterol was repressed by 4βHC, as was the expression of influx transporter lectin-like oxidized LDL receptor-1 in vitro. The cholesterol efflux and the expression of efflux transporters ABCA1 and ABCG1 were induced. The expression of inducible degrader of the LDL receptor was induced. In rats, PXR agonist increased circulating 4βHC and expression of LXR targets in peripheral tissues, especially ABCA1 and ABCG1 in heart. In conclusion, PXR activation-elevated 4βHC is a signaling molecule that represses cholesterol influx and induces efflux. The PXR-4βHC-LXR pathway could link the hepatic xenobiotic exposure and the regulation of cholesterol transport in peripheral tissues.

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Series: Frontiers in pharmacology
ISSN: 1663-9812
ISSN-E: 1663-9812
ISSN-L: 1663-9812
Volume: 11
Article number: 361
DOI: 10.3389/fphar.2020.00361
Type of Publication: A1 Journal article – refereed
Field of Science: 118 Biological sciences
1182 Biochemistry, cell and molecular biology
Funding: The study was financially supported by the grants from the Academy of Finland [Grants 286743, 276747]; the Novo Nordisk Foundation [Grants NNF14OC0010653, NNF15OC0015846]; the Duodecim Society of Oulu; the Finnish Medical Foundation; the Finnish Foundation for Cardiovascular Research; the Northern Finland Health Care Support Foundation; and the Diabetes Research Foundation.
Academy of Finland Grant Number: 286743
Detailed Information: 286743 (Academy of Finland Funding decision)
Dataset Reference: The Supplementary Material for this article can be found online at:
Copyright information: © 2020 Salonurmi, Nabil, Ronkainen, Hyötyläinen, Hautajärvi, Savolainen, Tolonen, Orešič, Känsäkoski, Rysä, Hakkola and Hukkanen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.