University of Oulu

Karpale, M., Käräjämäki, A. J., Kummu, O., Gylling, H., Hyötyläinen, T., Orešič, M., Tolonen, A., Hautajärvi, H., Savolainen, M. J., Ala-Korpela, M., Hukkanen, J., & Hakkola, J. (2021). Activation of pregnane X receptor induces atherogenic lipids and PCSK9 by a SREBP2-mediated mechanism. Br J Pharmacol. 2021; 178: 2461– 2481.

Activation of pregnane X receptor induces atherogenic lipids and PCSK9 by a SREBP2-mediated mechanism

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Author: Karpale, Mikko1,2,3; Käräjämäki, Aki Juhani2,4,5; Kummu, Outi1,2,3;
Organizations: 1Research Unit of Biomedicine, University of Oulu, Oulu, Finland
2Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
3Biocenter Oulu, University of Oulu, Oulu, Finland
4Department of gastroenterology, Clinics of Internal Medicine, Vaasa Central Hospital, Vaasa, Finland
5Abdominal Center, Department of Internal Medicine, Oulu University Hospital, Oulu, Finland
6Heart and Lung Center, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
7School of Science and Technology, Örebro University, Örebro, Sweden
8School of Medical Sciences, Örebro University, Örebro, Sweden
9Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
10Admescope Ltd., Oulu, Finland
11Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland
12NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland
13Research Unit of Internal Medicine, University of Oulu, Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 9.1 MB)
Persistent link:
Language: English
Published: John Wiley & Sons, 2021
Publish Date: 2021-08-19


Background and purpose: Many drugs and environmental contaminants induce hypercholesterolemia and promote the risk of atherosclerotic cardiovascular disease. We tested the hypothesis that pregnane X receptor (PXR), a xenobiotic-sensing nuclear receptor, regulates the level of circulating atherogenic lipids in humans and utilized mouse experiments to identify the mechanisms involved.

Experimental approach: We performed serum NMR metabolomics in healthy volunteers administered rifampicin, a prototypical human PXR ligand or placebo in a crossover setting. We used high-fat diet fed wild-type and PXR knockout mice to investigate the mechanisms mediating the PXR-induced alterations in cholesterol homeostasis.

Key results: Activation of PXR induced cholesterogenesis both in pre-clinical and clinical settings. In human volunteers, rifampicin increased intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and total cholesterol and lathosterol–cholesterol ratio, a marker of cholesterol synthesis, suggesting increased cholesterol synthesis. Experiments in mice indicated that PXR activation causes widespread induction of the cholesterol synthesis genes including the rate-limiting Hmgcr and upregulates the intermediates in the Kandutsch–Russell cholesterol synthesis pathway in the liver. Additionally, PXR activation induced plasma proprotein convertase subtilisin/kexin type 9 (PCSK9), a negative regulator of hepatic LDL uptake, in both mice and humans. We propose that these effects were mediated through increased proteolytic activation of sterol regulatory element-binding protein 2 (SREBP2) in response to PXR activation.

Conclusions and implications: PXR activation induces cholesterol synthesis, elevating LDL and total cholesterol in humans. The PXR–SREBP2 pathway is a novel regulator of the cholesterol and PCSK9 synthesis and a molecular mechanism for drug- and chemical-induced hypercholesterolemia.

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Series: British journal of pharmacology
ISSN: 0007-1188
ISSN-E: 1476-5381
ISSN-L: 0007-1188
Volume: 178
Issue: 12
Pages: 2461 - 2481
DOI: 10.1111/bph.15433
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: The study was financially supported by the grants from the Academy of Finland (grants 286743 and 323706), the Novo Nordisk Foundation (grants NNF14OC0010653 and NNF15OC0015846), the Finnish Medical Foundation, the Finnish Foundation for Cardiovascular Research, the Northern Finland Health Care Support Foundation, the Diabetes Research Foundation and the Sigrid Juselius Foundation. This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 825762 (EDCMET).
EU Grant Number: (825762) EDCMET - Metabolic effects of Endocrine Disrupting Chemicals: novel testing METhods and adverse outcome pathways
Academy of Finland Grant Number: 286743
Detailed Information: 286743 (Academy of Finland Funding decision)
323706 (Academy of Finland Funding decision)
Copyright information: © 2021 The Authors. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.