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Activation of nucle...
Activation of nuclear receptor PXR induces atherogenic lipids and PCSK9 through SREBP2-mediated mechanism
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- Karpale, Mikko (author)
- Research Unit of Biomedicine, University of Oulu, Oulu, Finland; Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland; Biocenter Oulu, Oulu, Finland
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- Käräjämäki, Aki Juhani (author)
- Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland; Department of gastroenterology, Clinics of Internal Medicine, Vaasa Central Hospital, Vaasa, Finland; Abdominal Center, Department of Internal Medicine, Oulu University Hospital, Oulu, Finland
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- Kummu, Outi (author)
- Research Unit of Biomedicine, University of Oulu, Oulu, Finland; Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland; Biocenter Oulu, Oulu, Finland
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- Gylling, Helena (author)
- University of Helsinki and Helsinki University Central Hospital, Heart and Lung Center, Helsinki, Finland
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- Hyötyläinen, Tuulia, 1971- (author)
- Örebro universitet,Institutionen för naturvetenskap och teknik
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- Oresic, Matej, 1967- (author)
- Örebro universitet,Institutionen för medicinska vetenskaper,Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
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- Tolonen, Ari (author)
- Admescope Ltd, Oulu, Finland
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- Hautajärvi, Heidi (author)
- Admescope Ltd, Oulu, Finland
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- Savolainen, Markku J. (author)
- Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland; Biocenter Oulu, Oulu, Finland; Research Unit of Internal Medicine, University of Oulu, Oulu, Finland
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- Ala-Korpela, Mika (author)
- Biocenter Oulu, Oulu, Finland; Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland
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- Hukkanen, Janne (author)
- Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland; Biocenter Oulu, Oulu, Finland; Research Unit of Internal Medicine, University of Oulu, Oulu, Finland
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- Hakkola, Jukka (author)
- Research Unit of Biomedicine, University of Oulu, Oulu, Finland; Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland; Biocenter Oulu, Oulu, Finland
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(creator_code:org_t)
- 2021-05-14
- 2021
- English.
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In: British Journal of Pharmacology. - : Macmillan Publishers Ltd.. - 0007-1188 .- 1476-5381. ; 178:12, s. 2461-2481
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https://doi.org/10.1...
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Abstract
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- BACKGROUND AND PURPOSE: Many drugs and environmental contaminants induce hypercholesterolemia and promote the risk of atherosclerotic cardiovascular disease. The mechanisms involved are poorly defined precluding efficient prediction and prevention. 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. Furthermore, we used high-fat diet fed wildtype and PXR knockout mice to investigate the mechanisms and pathways 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 IDL, LDL and total cholesterol and lathosterol-cholesterol ratio, a marker of cholesterol synthesis, suggesting increased cholesterol synthesis. Mechanistic studies in mice indicated that PXR activation launches 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 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 SREBP2 in response to PXR activation.CONCLUSION AND IMPLICATIONS: PXR activation induces cholesterol synthesis and elevates 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Keyword
- LDL
- PCSK9
- PXR
- SREBP2
- cholesterol
- hypercholesterolemia
- lathosterol
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Karpale, Mikko
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Käräjämäki, Aki ...
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Kummu, Outi
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Gylling, Helena
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Hyötyläinen, Tuu ...
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Oresic, Matej, 1 ...
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Tolonen, Ari
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Hautajärvi, Heid ...
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Savolainen, Mark ...
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Ala-Korpela, Mik ...
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Hukkanen, Janne
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Hakkola, Jukka
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Pharmacology and ...
- Articles in the publication
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British Journal ...
- By the university
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Örebro University