Activation of pregnane X receptor induces atherogenic lipids and PCSK9 by a SREBP2-mediated mechanism.
LDL
PCSK9
PXR
SREBP2
cholesterol
hypercholesterolemia
lathosterol
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
revised:
09
02
2021
received:
08
10
2020
accepted:
28
02
2021
pubmed:
10
3
2021
medline:
6
7
2021
entrez:
9
3
2021
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Substances chimiques
Pharmaceutical Preparations
0
Pregnane X Receptor
0
Receptors, LDL
0
Sterol Regulatory Element Binding Protein 2
0
PCSK9 protein, human
EC 3.4.21.-
Pcsk9 protein, mouse
EC 3.4.21.-
Proprotein Convertase 9
EC 3.4.21.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2461-2481Subventions
Organisme : Academy of Finland
ID : 286743
Organisme : Academy of Finland
ID : 323706
Organisme : H2020 Societal Challenges
ID : 825762
Organisme : Novo Nordisk Foundation
ID : NNF14OC0010653
Organisme : Novo Nordisk Foundation
ID : NNF15OC0015846
Organisme : Sigrid Juselius Foundation
Organisme : Diabetes Research Foundation
Organisme : Northern Finland Health Care Support Foundation
Organisme : Finnish Foundation for Cardiovascular Research
Organisme : Finnish Medical Foundation
Informations de copyright
© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
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