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Activation of nucle...
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Karpale, MikkoResearch Unit of Biomedicine, University of Oulu, Oulu, Finland; Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland; Biocenter Oulu, Oulu, Finland
(författare)
Activation of nuclear receptor PXR induces atherogenic lipids and PCSK9 through SREBP2-mediated mechanism
- Artikel/kapitelEngelska2021
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2021-05-14
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Macmillan Publishers Ltd.2021
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printrdacarrier
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LIBRIS-ID:oai:DiVA.org:oru-90333
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https://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-90333URI
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https://doi.org/10.1111/bph.15433DOI
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Språk:engelska
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Sammanfattning på:engelska
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Ämneskategori:ref swepub-contenttype
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Ämneskategori:art swepub-publicationtype
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Funding Agencies:Sigrid Juselius Foundation Diabetes Research Foundation Northern Finland Health Care Support Foundation Finnish Foundation for Cardiovascular Research Finnish Medical Foundation H2020 Societal Challenges 825762
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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.
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Käräjämäki, Aki JuhaniMedical 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
(författare)
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Kummu, OutiResearch Unit of Biomedicine, University of Oulu, Oulu, Finland; Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland; Biocenter Oulu, Oulu, Finland
(författare)
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Gylling, HelenaUniversity of Helsinki and Helsinki University Central Hospital, Heart and Lung Center, Helsinki, Finland
(författare)
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Hyötyläinen, Tuulia,1971-Örebro universitet,Institutionen för naturvetenskap och teknik(Swepub:oru)tihn
(författare)
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Oresic, Matej,1967-Örebro universitet,Institutionen för medicinska vetenskaper,Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland(Swepub:oru)moc
(författare)
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Tolonen, AriAdmescope Ltd, Oulu, Finland
(författare)
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Hautajärvi, HeidiAdmescope Ltd, Oulu, Finland
(författare)
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Savolainen, Markku J.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
(författare)
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Ala-Korpela, MikaBiocenter 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
(författare)
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Hukkanen, JanneMedical 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
(författare)
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Hakkola, JukkaResearch Unit of Biomedicine, University of Oulu, Oulu, Finland; Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland; Biocenter Oulu, Oulu, Finland
(författare)
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Research Unit of Biomedicine, University of Oulu, Oulu, Finland; Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland; Biocenter Oulu, Oulu, FinlandMedical 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
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:British Journal of Pharmacology: Macmillan Publishers Ltd.178:12, s. 2461-24810007-11881476-5381
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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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