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. 2021 Jun;178(12):2461-2481.
doi: 10.1111/bph.15433. Epub 2021 May 14.

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

Mikko Karpale  1   2   3 , Aki Juhani Käräjämäki  2   4   5 , Outi Kummu  1   2   3 , Helena Gylling  6 , Tuulia Hyötyläinen  7 , Matej Orešič  8   9 , Ari Tolonen  10 , Heidi Hautajärvi  10 , Markku J Savolainen  2   3   11 , Mika Ala-Korpela  3   12   13 , Janne Hukkanen  2   3   11 , Jukka Hakkola  1   2   3
Affiliations
Free article

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

Mikko Karpale et al. Br J Pharmacol. 2021 Jun.
Free article

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.

Keywords: LDL; PCSK9; PXR; SREBP2; cholesterol; hypercholesterolemia; lathosterol.

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References

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