Off-target lipid metabolism disruption by the mouse constitutive androstane receptor ligand TCPOBOP in humanized mice

Skoda, Josef; Dohnalová, Klára; Chalupský, Karel; Stahl, Aaron; Templin, Markus F.; Maixnerová, Jana; Mičuda, Stanislav; Grøntved, Lars; Braeuning, Albert; Pávek, Petr

doi:10.1016/j.bcp.2021.114905

Cited by 9 publications

(5 citation statements)

References 59 publications

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“…A heatmap of the positively enriched genes in the gene set Chemical Carcinogenesis is shown in Figure 6 E, showing stronger regulation by PFOA in the PPARα −/− mice than in the wildtype mice. Many of these genes are significantly upregulated by the rodent-specific Pregnane X Receptor (PXR) agonist pregnenolone 16α-carbonitrile (PCN) (GSE136667) [ 58 ], as well as by the Constitutive Androstane Receptor (CAR) agonist TCPOBOP (GSE186654) [ 59 ], suggesting that they are PXR and CAR target genes.…”

Section: Resultsmentioning

confidence: 99%

Exposure to low-dose perfluorooctanoic acid promotes hepatic steatosis and disrupts the hepatic transcriptome in mice

Attema¹,

Janssen²,

Rijkers³

et al. 2022

Molecular Metabolism

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Section: Resultsmentioning

confidence: 99%

Exposure to low-dose perfluorooctanoic acid promotes hepatic steatosis and disrupts the hepatic transcriptome in mice

Attema¹,

Janssen²,

Rijkers³

et al. 2022

Molecular Metabolism

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“…Pavek and colleagues confirmed the lipidreductive effect in wild-type mice upon TCPOBOP-dependent CAR activation. However, in their humanized CAR mouse model, TCPOBOP treatment led to increased serum and liver lipid levels [115]. Although TCPOBOP in the humanized mice did not seem to enhance CAR activation itself, the basal constitutive activity remained high [115].…”

Section: Role Of Car In Lipid Metabolismmentioning

confidence: 97%

“…However, in their humanized CAR mouse model, TCPOBOP treatment led to increased serum and liver lipid levels [115]. Although TCPOBOP in the humanized mice did not seem to enhance CAR activation itself, the basal constitutive activity remained high [115]. In contrast to the hepatoprotective role of CAR, in a NASH mouse model, Car-/-mice did not show altered lipid levels but a decreased level of serum ALT and decreased lipid peroxidation in the liver, suggesting a rather detrimental role of CAR in lipid metabolism [116].…”

Section: Role Of Car In Lipid Metabolismmentioning

confidence: 99%

AhR, PXR and CAR: From Xenobiotic Receptors to Metabolic Sensors

Rakateli,

Huchzermeier,

van der Vorst

2023

Cells

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Traditionally, xenobiotic receptors are known for their role in chemical sensing and detoxification, as receptor activation regulates the expression of various key enzymes and receptors. However, recent studies have highlighted that xenobiotic receptors also play a key role in the regulation of lipid metabolism and therefore function also as metabolic sensors. Since dyslipidemia is a major risk factor for various cardiometabolic diseases, like atherosclerosis and non-alcoholic fatty liver disease, it is of major importance to understand the molecular mechanisms that are regulated by xenobiotic receptors. In this review, three major xenobiotic receptors will be discussed, being the aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR) and the constitutive androstane receptor (CAR). Specifically, this review will focus on recent insights into the metabolic functions of these receptors, especially in the field of lipid metabolism and the associated dyslipidemia.

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“…However, TCPOBOP regulated lipid homeostasis by increasing serum and liver triglyceride levels and promoting hepatocyte hypertrophy in humanized CAR mice without human CAR activation. This suggests that the roles of TCPOBOP on lipid metabolism are independent of human CAR activation (Skoda et al, 2022). Liver X receptors (LXR, NR1H2/3) function as cholesterol sensors, thus protecting mammals from cholesterol overload.…”

Section: Car In Lipid Metabolismmentioning

confidence: 99%

“…Treatment of mice with phenobarbital, another CAR activator, suppresses the interaction between PPARα and PGC1α in the liver, thus attenuating PPARα-dependent lipid metabolism (Shizu et al, 2020). However, phenobarbital significantly elevated plasma triglyceride levels in contrast to the action of TCPOBOP (Skoda et al, 2022). Interestingly, Alice et al…”

Section: Car In Lipid Metabolismmentioning

confidence: 99%

The Function of Xenobiotic Receptors in Metabolic Diseases

Zhang

Jia

et al. 2022

Drug Metab Dispos

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Metabolic diseases are a series of metabolic disorders that include obesity, diabetes, insulin resistance, hypertension, and hyperlipidemia. The increased prevalence of metabolic diseases has resulted in higher mortality and mobility rates over the past decades, and this has led to extensive research focusing on the underlying mechanisms. Xenobiotic receptors (XRs) are a series of xenobioticsensing nuclear receptors that regulate their downstream target genes expression, thus defending the body from xenobiotic and endotoxin attacks. XR activation is associated with the development of a number of metabolic diseases such as obesity, nonalcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D), and cardiovascular diseases, thus suggesting an important role for XRs in modulating metabolic diseases.However, the regulatory mechanism of XRs in the context of metabolic disorders under different nutrient conditions is complex and remains controversial. This review summarizes the effects of XRs on different metabolic components (cholesterol, lipids, glucose, and bile acids) in different tissues during metabolic diseases. As chronic inflammation plays a critical role in the initiation and progression of metabolic diseases, we also discuss the impact of XRs on inflammation to comprehensively recognize the role of XRs in metabolic diseases. This will provide new ideas for treating metabolic diseases by targeting XRs.

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Off-target lipid metabolism disruption by the mouse constitutive androstane receptor ligand TCPOBOP in humanized mice

Cited by 9 publications

References 59 publications

Exposure to low-dose perfluorooctanoic acid promotes hepatic steatosis and disrupts the hepatic transcriptome in mice

Exposure to low-dose perfluorooctanoic acid promotes hepatic steatosis and disrupts the hepatic transcriptome in mice

AhR, PXR and CAR: From Xenobiotic Receptors to Metabolic Sensors

The Function of Xenobiotic Receptors in Metabolic Diseases

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