Evodia alkaloids suppress gluconeogenesis and lipogenesis by activating the constitutive androstane receptor

Yu, Lushan; Wang, Zhangting; Huang, Minmin; Li, Yingying; Zeng, Kui; Lei, Jinxiu; Chen, Baian; Lü, Jing; Xie, Wen; Zeng, Su

doi:10.1016/j.bbagrm.2015.10.001

Cited by 28 publications

(19 citation statements)

References 45 publications

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“…These gluconeogenic genes are mainly controlled by hepatocyte nuclear factor-4α (HNF4α), cAMP-response element-binding protein (CREB) and forkhead box O1 (FoxO1) transcription factors, PGC1α coactivator, and by GR; PPARα, LXRs, or SREBP-1c are dominant in regulation of lipid metabolism genes ( Miao et al, 2006 ; Oh et al, 2013 ; Gao et al, 2015 ). hCAR activation has previously been reported to suppress the expression of gluconeogenic enzymes G6Pase and PEPCK1 in primary human hepatocytes pre-treated with FSK ( Gao et al, 2015 ) and in mice under nutritional stress (high-fat diet, in leptin-deficient obese mice, under fasting conditions) ( Miao et al, 2006 ; Dong et al, 2009 ; Gao et al, 2009 ; Yarushkin et al, 2013 ; Yu et al, 2016 ). The regulation of the fatty acids and steroids synthetic enzymes HMGCS2 and FASN after treatment with the mCAR agonist TCPOBOP in mice after high- fat or 1% cholesterol diet has been confirmed several times ( Gao et al, 2009 ; Rezen et al, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

Teriflunomide Is an Indirect Human Constitutive Androstane Receptor (CAR) Activator Interacting With Epidermal Growth Factor (EGF) Signaling

et al. 2018

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The constitutive androstane receptor (CAR) is a nuclear receptor involved mainly in xenobiotic and endobiotic metabolism regulation. CAR is activated directly by its ligands via the ligand binding domain (LBD) or indirectly by inhibition of the epidermal growth factor (EGF) signaling. We found that leflunomide (LEF) and its main metabolite teriflunomide (TER), both used for autoimmune diseases treatment, induce the prototype CAR target gene CYP2B6 in primary human hepatocytes. As TER was discovered to be an EGF receptor antagonist, we sought to determine if TER is an indirect activator of CAR. In primary human hepatocytes and in differentiated HepaRG cells, we found that LEF and TER up-regulate CAR target genes CYP2B6 and CYP3A4 mRNAs and enzymatic activities. TER stimulated CAR+A mutant translocation into the nucleus but neither LEF nor TER activated the CAR LBD, CAR3 variant or pregnane X receptor (PXR) in gene reporter assays. Interestingly, TER significantly up-regulated CAR mRNA expression, a result which could be a consequence of both EGF receptor and ELK-1 transcription factor inhibition by TER or by TER-mediated activation of glucocorticoid receptor (GR), an upstream hormonal regulator of CAR. We can conclude that TER is a novel indirect CAR activator which through EGF inhibition and GR activation controls both detoxification and some intermediary metabolism genes.

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Section: Discussionmentioning

confidence: 99%

Teriflunomide Is an Indirect Human Constitutive Androstane Receptor (CAR) Activator Interacting With Epidermal Growth Factor (EGF) Signaling

et al. 2018

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“…Mechanistically, CAR-mediated energy homeostasis appears to be involved in a combined repression of an array of genes associated with gluconeogenesis, fatty acid synthesis, and energy expenditure such as phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase), fatty acid synthase, and stearoyl-CoA desaturase-1 (Yu et al, 2016). This downregulation is involved in the prevention of the FOXO1 transcription factor from interacting with insulin response element binding sites located upstream of genes such as PEPCK1, G6Pase, and insulin-like growth factor-binding protein 1 (Kodama et al, 2004).…”

Section: Constitutive Androstane Receptormentioning

confidence: 99%

“…Activation of CAR in mice has been shown to mitigate hepatic steatosis, increase glucose tolerance and insulin sensitivity, and alleviate or prevent obesity in diabetic mouse models (Dong et al, 2009;Gao et al, 2009). CAR-mediated antilipogenic effects were also observed in hyperlipidemic HepG2 cell cultures treated with evodia alkaloids (Yu et al, 2016). Furthermore, the hormone irisin was recently identified as a direct target of CAR and protects HFD-induced obese mice through the CAR-irisin axis (Mo et al, 2016).…”

Section: Constitutive Androstane Receptormentioning

confidence: 99%

The Roles of Xenobiotic Receptors: Beyond Chemical Disposition

et al. 2018

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Over the past 20 years, the ability of the xenobiotic receptors to coordinate an array of drug-metabolizing enzymes and transporters in response to endogenous and exogenous stimuli has been extensively characterized and well documented. The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are the xenobiotic receptors that have received the most attention since they regulate the expression of numerous proteins important to drug metabolism and clearance and formulate a central defensive mechanism to protect the body against xenobiotic challenges. However, accumulating evidence has shown that these xenobiotic sensors also control many cellular processes outside of their traditional realms of xenobiotic metabolism and disposition, including physiologic and/or pathophysiologic responses in energy homeostasis, cell proliferation, inflammation, tissue injury and repair, immune response, and cancer development. This review will highlight recent advances in studying the noncanonical functions of xenobiotic receptors with a particular focus placed on the roles of CAR and PXR in energy homeostasis and cancer development.

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“…This interaction was demonstrated to result in a CAR-induced attenuation of FOXO target gene expression, such as of genes coding for gluconeogenesis enzymes, phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase), or the cyclin-dependent kinase inhibitor, p21, and also FOXO1 itself [27] . CAR-mediated suppression of FOXO1 (along with hepatocyte nuclear factor 4α, HNF4α) was suggested to be responsible for the anti-gluconeogenesis effects of certain alkaloids [28] . Similarly, PXR activation was shown to affect gluconeogenesis not only through FOXO1 inhibition but also through competition for PPARγ coactivator (PGC) 1α, a known coregulator of FOXOs as well as other transcriptional regulators, such as HNF4α (for review, see [29] ).…”

Section: Interactions Between Foxos and Xenosensorsmentioning

confidence: 99%

Cellular adaptation to xenobiotics: Interplay between xenosensors, reactive oxygen species and FOXO transcription factors

2017

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Cells adapt to an exposure to xenobiotics by upregulating the biosynthesis of proteins involved in xenobiotic metabolism. This is achieved largely via activation of cellular xenosensors that modulate gene expression. Biotransformation of xenobiotics frequently comes with the generation of reactive oxygen species (ROS). ROS, in turn, are known modulators of signal transduction processes. FOXO (forkhead box, class O) transcription factors are among the proteins deeply involved in the cellular response to stress, including oxidative stress elicited by the formation of ROS. On the one hand, FOXO activity is modulated by ROS, while on the other, FOXO target genes include many that encode antioxidant proteins – thereby establishing a regulatory circuit. Here, the role of ROS and of FOXOs in the regulation of xenosensor transcriptional activities will be discussed. Constitutive androstane receptor (CAR), pregnane X receptor (PXR), peroxisome proliferator-activated receptors (PPARs), arylhydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (Nrf2) all interact with FOXOs and/or ROS. The two latter not only fine-tune the activities of xenosensors but also mediate interactions between them. As a consequence, the emerging picture of an interplay between xenosensors, ROS and FOXO transcription factors suggests a modulatory role of ROS and FOXOs in the cellular adaptive response to xenobiotics.

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Evodia alkaloids suppress gluconeogenesis and lipogenesis by activating the constitutive androstane receptor

Cited by 28 publications

References 45 publications

Teriflunomide Is an Indirect Human Constitutive Androstane Receptor (CAR) Activator Interacting With Epidermal Growth Factor (EGF) Signaling

Teriflunomide Is an Indirect Human Constitutive Androstane Receptor (CAR) Activator Interacting With Epidermal Growth Factor (EGF) Signaling

The Roles of Xenobiotic Receptors: Beyond Chemical Disposition

Cellular adaptation to xenobiotics: Interplay between xenosensors, reactive oxygen species and FOXO transcription factors

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