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

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Karpale , M , Karajamaki , AJ , Kummu , O , Gylling , H , Hyotylainen , T , Oresic , M , Tolonen , A , Hautajarvi , H , Savolainen , MJ , Ala-Korpela , M , Hukkanen , J & Hakkola , J 2021 , ' Activation of pregnane X receptor induces atherogenic lipids and PCSK9 by a SREBP2-mediated mechanism ' , British Journal of Pharmacology , vol. 178 , no. 12 , pp. 2461-2481 . https://doi.org/10.1111/bph.15433

Title: Activation of pregnane X receptor induces atherogenic lipids and PCSK9 by a SREBP2-mediated mechanism
Author: Karpale, M; Karajamaki, AJ; Kummu, O; Gylling, H; Hyotylainen, T; Oresic, M; Tolonen, A; Hautajarvi, H; Savolainen, MJ; Ala-Korpela, M; Hukkanen, J; Hakkola, J
Contributor organization: HUS Heart and Lung Center
Clinicum
Date: 2021-06
Language: eng
Number of pages: 21
Belongs to series: British Journal of Pharmacology
ISSN: 0007-1188
DOI: https://doi.org/10.1111/bph.15433
URI: http://hdl.handle.net/10138/337341
Abstract: 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. Conclusion 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.
Subject: cholesterol
hypercholesterolemia
lathosterol
LDL
PCSK9
PXR
SREBP2
HMG-COA REDUCTASE
MAGNETIC-RESONANCE METABOLOMICS
BILE-ACID SYNTHESIS
GLUCOSE-HOMEOSTASIS
INSULIN-RESISTANCE
CHOLESTEROL LEVELS
ENZYME-INDUCTION
CONCISE GUIDE
SERUM-LEVELS
METABOLISM
3111 Biomedicine
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: acceptedVersion


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