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

Karpale, Mikko; Käräjämäki, Aki Juhani; Kummu, Outi; Gylling, Helena; Hyötyläinen, Tuulia; Orešič, Matej; Tolonen, Ari; Hautajärvi, Heidi; Savolainen, Markku J.; Ala‐Korpela, Mika; Hukkanen, Janne; Hakkola, Jukka

doi:10.1111/bph.15433

Cited by 29 publications

(62 citation statements)

References 83 publications

(117 reference statements)

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“…Serum concentration of ApoB48, the intestinal form of ApoB, was decreased 14% by rifampicin dosing. During glucose challenge (2 h oral glucose tolerance test), PXR activation by rifampicin resulted in elevated concentrations of very small VLDL particles, remnant cholesterol, and total ApoB [30]. As in a previous study [24], rifampicin elevated serum lathosterol-to-cholesterol ratio [30], and, on the other hand, decreased serum concentrations of cholesterol synthesis precursors citrate and acetate, both suggesting increased cholesterol synthesis.…”

Section: Evidence For Induction Of Hypercholesterolemia By Pxr Activa...supporting

confidence: 56%

“…Changes in serum 4β-hydroxycholesterol, a marker of CYP3A4 activity [31] known to be elevated by PXR activation [11], correlated with these changes. The elevations of HDL-C (4%) and total ApoB (5%) by rifampicin were non-significant after correction for multiple testing, while the largest very low-density lipoprotein (VLDL) fractions tended to decrease [30]. Serum concentration of ApoB48, the intestinal form of ApoB, was decreased 14% by rifampicin dosing.…”

Section: Evidence For Induction Of Hypercholesterolemia By Pxr Activa...mentioning

confidence: 94%

“…Our recently published results indicate that rifampicin treatment increases human plasma cholesterol by activating PXR and hepatic cholesterol synthesis [30]. The same cholesterol synthesis-inducing effect could be repeated also in high-fat diet-fed mice, which were treated with selective murine PXR agonist, pregnenolone-16α-carbonitrile (PCN).…”

Section: Pxr In Cholesterol Synthesismentioning

confidence: 96%

“…We recently published combined results from two placebo-controlled cross-over trials [28,29] investigating the effect of 600 mg rifampicin for a week on plasma metabolomics, including all lipoprotein fractions and their lipid contents [30]. The study was the largest to date evaluating the effects of PXR activation on plasma metabolomics, with 34 healthy volunteers participating.…”

Section: Evidence For Induction Of Hypercholesterolemia By Pxr Activa...mentioning

confidence: 99%

“…This enabled us to study the molecular mechanisms in more detail. In the liver, PXR activation led to nuclear accumulation of active SREBP2 protein, widespread induction of its target genes, and increases in cholesterol and markers of cholesterol synthesis [30].…”

Section: Pxr In Cholesterol Synthesismentioning

confidence: 99%

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Nuclear Receptor PXR in Drug-Induced Hypercholesterolemia

Karpale

Hukkanen

Hakkola

2022

Cells

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Atherosclerosis is a major global health concern. The central modifiable risk factors and causative agents of the disease are high total and low-density lipoprotein (LDL) cholesterol. To reduce morbidity and mortality, a thorough understanding of the factors that influence an individual’s cholesterol status during the decades when the arteria-narrowing arteriosclerotic plaques are forming is critical. Several drugs are known to increase cholesterol levels; however, the mechanisms are poorly understood. Activation of pregnane X receptor (PXR), the major regulator of drug metabolism and molecular mediator of clinically significant drug–drug interactions, has been shown to induce hypercholesterolemia. As a major sensor of the chemical environment, PXR may in part mediate hypercholesterolemic effects of drug treatment. This review compiles the current knowledge of PXR in cholesterol homeostasis and discusses the role of PXR in drug-induced hypercholesterolemia.

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Section: Evidence For Induction Of Hypercholesterolemia By Pxr Activa...supporting

confidence: 56%

Section: Evidence For Induction Of Hypercholesterolemia By Pxr Activa...mentioning

confidence: 94%

Section: Pxr In Cholesterol Synthesismentioning

confidence: 96%

Section: Evidence For Induction Of Hypercholesterolemia By Pxr Activa...mentioning

confidence: 99%

Section: Pxr In Cholesterol Synthesismentioning

confidence: 99%

See 3 more Smart Citations

Nuclear Receptor PXR in Drug-Induced Hypercholesterolemia

Karpale

Hukkanen

Hakkola

2022

Cells

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Induction of hepatic CYP3A4 expression by cholesterol and cholic acid: Alterations of gene expression, microsomal activity, and pharmacokinetics

Minegishi,

Kobayashi,

Fujikura

et al. 2024

Pharmacology Res & Perspec

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Human cytochrome P450 3A4 (CYP3A4) is a drug‐metabolizing enzyme that is abundantly expressed in the liver and intestine. It is an important issue whether compounds of interest affect the expression of CYP3A4 because more than 30% of commercially available drugs are metabolized by CYP3A4. In this study, we examined the effects of cholesterol and cholic acid on the expression level and activity of CYP3A4 in hCYP3A mice that have a human CYP3A gene cluster and show human‐like regulation of the coding genes. A normal diet (ND, CE‐2), CE‐2 with 1% cholesterol and 0.5% cholic acid (HCD) or CE‐2 with 0.5% cholic acid was given to the mice. The plasma concentrations of cholesterol, cholic acid and its metabolites in HCD mice were higher than those in ND mice. In this condition, the expression levels of hepatic CYP3A4 and the hydroxylation activities of triazolam, a typical CYP3A4 substrate, in liver microsomes of HCD mice were higher than those in liver microsomes of ND mice. Furthermore, plasma concentrations of triazolam in HCD mice were lower than those in ND mice. In conclusion, our study suggested that hepatic CYP3A4 expression and activity are influenced by the combination of cholesterol and cholic acid in vivo.

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Adverse outcome pathway for pregnane X receptor-induced hypercholesterolemia

Itkonen,

Hakkola,

Rysä

2023

Arch Toxicol

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Pharmaceuticals and environmental contaminants contribute to hypercholesterolemia. Several chemicals known to cause hypercholesterolemia, activate pregnane X receptor (PXR). PXR is a nuclear receptor, classically identified as a sensor of chemical environment and regulator of detoxification processes. Later, PXR activation has been shown to disrupt metabolic functions such as lipid metabolism and recent findings have shown PXR activation to promote hypercholesterolemia through multiple mechanisms. Hypercholesterolemia is a major causative risk factor for atherosclerosis and greatly promotes global health burden. Metabolic disruption by PXR activating chemicals leading to hypercholesterolemia represents a novel toxicity pathway of concern and requires further attention. Therefore, we constructed an adverse outcome pathway (AOP) by collecting the available knowledge considering the molecular mechanisms for PXR-mediated hypercholesterolemia. AOPs are tools of modern toxicology for systematizing mechanistic knowledge to assist health risk assessment of chemicals. AOPs are formalized and structured linear concepts describing a link between molecular initiating event (MIE) and adverse outcome (AO). MIE and AO are connected via key events (KE) through key event relationships (KER). We present a plausible route of how PXR activation (MIE) leads to hypercholesterolemia (AO) through direct regulation of cholesterol synthesis and via activation of sterol regulatory element binding protein 2-pathway.

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

Cited by 29 publications

References 83 publications

Nuclear Receptor PXR in Drug-Induced Hypercholesterolemia

Nuclear Receptor PXR in Drug-Induced Hypercholesterolemia

Induction of hepatic CYP3A4 expression by cholesterol and cholic acid: Alterations of gene expression, microsomal activity, and pharmacokinetics

Adverse outcome pathway for pregnane X receptor-induced hypercholesterolemia

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