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Sökning: onr:"swepub:oai:DiVA.org:oru-90333" > Activation of nucle...

LIBRIS Formathandbok  (Information om MARC21)
FältnamnIndikatorerMetadata
00006508naa a2200541 4500
001oai:DiVA.org:oru-90333
003SwePub
008210310s2021 | |||||||||||000 ||eng|
0247 a https://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-903332 URI
0247 a https://doi.org/10.1111/bph.154332 DOI
040 a (SwePub)oru
041 a engb eng
042 9 SwePub
072 7a ref2 swepub-contenttype
072 7a art2 swepub-publicationtype
1001 a Karpale, Mikkou Research Unit of Biomedicine, University of Oulu, Oulu, Finland; Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland; Biocenter Oulu, Oulu, Finland4 aut
2451 0a Activation of nuclear receptor PXR induces atherogenic lipids and PCSK9 through SREBP2-mediated mechanism
264 c 2021-05-14
264 1b Macmillan Publishers Ltd.c 2021
338 a print2 rdacarrier
500 a 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
520 a 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.
650 7a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Farmakologi och toxikologi0 (SwePub)301022 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Pharmacology and Toxicology0 (SwePub)301022 hsv//eng
653 a LDL
653 a PCSK9
653 a PXR
653 a SREBP2
653 a cholesterol
653 a hypercholesterolemia
653 a lathosterol
7001 a Käräjämäki, Aki Juhaniu 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, Finland4 aut
7001 a Kummu, Outiu Research Unit of Biomedicine, University of Oulu, Oulu, Finland; Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland; Biocenter Oulu, Oulu, Finland4 aut
7001 a Gylling, Helenau University of Helsinki and Helsinki University Central Hospital, Heart and Lung Center, Helsinki, Finland4 aut
7001 a Hyötyläinen, Tuulia,d 1971-u Örebro universitet,Institutionen för naturvetenskap och teknik4 aut0 (Swepub:oru)tihn
7001 a Oresic, Matej,d 1967-u Örebro universitet,Institutionen för medicinska vetenskaper,Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland4 aut0 (Swepub:oru)moc
7001 a Tolonen, Ariu Admescope Ltd, Oulu, Finland4 aut
7001 a Hautajärvi, Heidiu Admescope Ltd, Oulu, Finland4 aut
7001 a Savolainen, Markku J.u 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, Finland4 aut
7001 a Ala-Korpela, Mikau 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, Finland4 aut
7001 a Hukkanen, Janneu 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, Finland4 aut
7001 a Hakkola, Jukkau Research Unit of Biomedicine, University of Oulu, Oulu, Finland; Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland; Biocenter Oulu, Oulu, Finland4 aut
7102 a Research Unit of Biomedicine, University of Oulu, Oulu, Finland; Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland; Biocenter Oulu, Oulu, Finlandb 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, Finland4 org
7730 t British Journal of Pharmacologyd : Macmillan Publishers Ltd.g 178:12, s. 2461-2481q 178:12<2461-2481x 0007-1188x 1476-5381
8564 u https://doi.org/10.1111/bph.15433y Fulltext
8564 u https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/bph.15433
8564 8u https://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-90333
8564 8u https://doi.org/10.1111/bph.15433

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