PPARα-dependent induction of the energy homeostasis-regulating nuclear receptor NR1i3 (CAR) in rat hepatocytes: Potential role in starvation adaptation

Universität Potsdam, Institut für Ernährungswissenschaft, Biochemie der Ernährung, Arthur-Scheunert-Allee 114-116, D-14558, Nuthetal, Germany.
FEBS Letters (Impact Factor: 3.17). 01/2008; 581(29):5617-26. DOI: 10.1016/j.febslet.2007.11.011
Source: PubMed


A tight hormonal control of energy homeostasis is of pivotal relevance for animals. Recent evidence suggests an involvement of the nuclear receptor NR1i3 (CAR). Fasting induces CAR by largely unknown mechanisms and CAR-deficient mice are defective in fasting adaptation. In rat hepatocytes CAR was induced by WY14643, a PPARalpha-agonist. A DR1 motif in the CAR promoter was necessary and sufficient for this control. The PPARalpha-dependent increase in CAR potentiated the phenobarbital-induced transcription of the prototypical CAR-dependent gene CYP2B1. Since free fatty acids are natural ligands for PPARalpha, a fasting-induced increase in free fatty acids might induce CAR. In accordance with this hypothesis, CAR induction by fasting was abrogated in PPARalpha-deficient mice.

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    • "In addition to its xenobiotic function, CAR has recently been suggested to play an endobiotic role in energy metabolism, ranging from thyroid hormone metabolism and calorie restriction response [37] [38] to lipogenesis [39] [40] [41]. CAR might also regulate energy metabolism by interacting with the peroxisome proliferators activated receptor α (PPARα) and PPARγ coactivator-1α (PGC-1α), both of which are key regulators of adaptive responses to starvation [42] [43]. "
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    ABSTRACT: The regulation of lipid metabolism is central to energy homeostasis in higher multicellular organisms. Lipid homeostasis depends on factors that are able to transduce metabolic parameters into regulatory events representing the fundamental components of the general control system. Nuclear receptors form a superfamily of ligand-activated transcription factors implicated in various physiological functions including energy metabolism. The constitutive androstane receptor (CAR, NR1I3), initially identified as a xenobiotic-sensing receptor, may also have roles in lipid homeostasis. The nuclear receptors liver X receptors (LXRs, NR1H2/3) and peroxisome proliferator-activated receptors (PPARs, NR1C) have been known for their roles in lipid metabolism. LXR is a sterol sensor that promotes lipogenesis, whereas PPARα controls a variety of genes in several pathways of lipid metabolism. This chapter focuses primarily on the role of CAR in lipid metabolism directly or through its cross talk with LXRs and PPARα.
    Vitamins & Hormones 02/2013; 91:243-58. DOI:10.1016/B978-0-12-407766-9.00010-9 · 2.04 Impact Factor
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    • "Fasting is also accompanied by an increase in the concentration of free fatty acids, which are endogenous ligands for PPARα. We have recently shown that CAR was induced by fasting in mice in a PPARα-dependent manner (Wieneke et al., 2007). Thus, the synergistic induction of thyroid hormone inactivating enzymes by CAR activators and PPARα agonists described here might be the basis for an efficient induction of thyroid hormone-metabolizing enzymes during fasting. "
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    ABSTRACT: Energy balance is maintained by controlling both energy intake and energy expenditure. Thyroid hormones play a crucial role in regulating energy expenditure. Their levels are adjusted by a tight feedback-controlled regulation of thyroid hormone production/incretion and by their hepatic metabolism. Thyroid hormone degradation has previously been shown to be enhanced by treatment with phenobarbital or other antiepileptic drugs due to a CAR-dependent induction of phase II enzymes of xenobiotic metabolism. We have recently shown, that PPAR alpha agonists synergize with phenobarbital to induce another prototypical CAR target gene, CYP2B1. Therefore, it was tested whether a PPAR alpha agonist could enhance the phenobarbital-dependent acceleration of thyroid hormone elimination. In primary cultures of rat hepatocytes the apparent half-life of T3 was reduced after induction with a combination of phenobarbital and the PPAR alpha agonist WY14643 to a larger extent than after induction with either compound alone. The synergistic reduction of the half-life could be attributed to a synergistic induction of CAR and the CAR target genes that code for enzymes and transporters involved in the hepatic elimination of T3, such as OATP1A1, OATP1A3, UGT1A3 and UGT1A10. The PPAR alpha-dependent CAR induction and the subsequent induction of T3-eliminating enzymes might be of physiological significance for the fasting-induced reduction in energy expenditure by fatty acids as natural PPAR alpha ligands. The synergism of the PPAR alpha agonist WY14643 and phenobarbital in inducing thyroid hormone breakdown might serve as a paradigm for the synergistic disruption of endocrine control by other combinations of xenobiotics.
    Toxicology and Applied Pharmacology 08/2009; 240(1):99-107. DOI:10.1016/j.taap.2009.07.014 · 3.71 Impact Factor
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    • "It has been postulated for some time that CAR function is regulated by both endogenous and exogenous inducing agents including metabolic control through AMPK (AMP-activated protein kinase) [52], interaction with the forkhead transcription factor FoxO1 (forkhead box O1) [53] and activation during fasting [54]. It has also been postulated that CAR function can be modulated by the fatty-acid-sensitive transcription factor PPARα [33,34]. However, this mechanism of CAR activation would not appear to explain the hepatic phenotype, as no changes in CAR expression were found and also linoleic acid activated CAR directly. "
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    ABSTRACT: The liver is responsible for key metabolic functions, including control of normal homoeostasis in response to diet and xenobiotic metabolism/detoxification. We have shown previously that inactivation of the hepatic cytochrome P450 system through conditional deletion of POR (P450 oxidoreductase) induces hepatic steatosis, liver growth and P450 expression. We have exploited a new conditional model of POR deletion to investigate the mechanism underlying these changes. We demonstrate that P450 induction, liver growth and hepatic triacylglycerol (triglyceride) homoeostasis are intimately linked and provide evidence that the observed phenotypes result from hepatic accumulation of unsaturated fatty acids, which mediate these phenotypes by activation of the nuclear receptor CAR (constitutive androstane receptor) and, to a lesser degree, PXR (pregnane X receptor). To our knowledge this is the first direct evidence that P450s play a major role in controlling unsaturated fatty acid homoeostasis via CAR. The regulation of P450s involved in xenobiotic metabolism by this mechanism has potentially significant implications for individual responses to drugs and environmental chemicals.
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