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Activation of pregnane X receptor induces atherogenic lipids and PCSK9 by a SREBP2-mediated mechanism.
- Source :
-
British Journal of Pharmacology . Jun2021, Vol. 178 Issue 12, p2461-2481. 21p. 1 Diagram, 6 Graphs, 1 Map. - Publication Year :
- 2021
-
Abstract
- <bold>Background and Purpose: </bold>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.<bold>Experimental Approach: </bold>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.<bold>Key Results: </bold>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.<bold>Conclusion and Implications: </bold>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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *PREGNANE X receptor
*STEROL regulatory element-binding proteins
*LDL cholesterol
*POLLUTANTS
*LOW density lipoproteins
*LIPIDS
*NUCLEAR receptors (Biochemistry)
*PROTEINS
*RESEARCH
*ANIMAL experimentation
*RESEARCH methodology
*CELL receptors
*MEDICAL cooperation
*EVALUATION research
*COMPARATIVE studies
*DRUGS
*RESEARCH funding
*MICE
Subjects
Details
- Language :
- English
- ISSN :
- 00071188
- Volume :
- 178
- Issue :
- 12
- Database :
- Academic Search Index
- Journal :
- British Journal of Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 150473730
- Full Text :
- https://doi.org/10.1111/bph.15433