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

Wieneke, N.; Hirsch‐Ernst, Karen Ildico; Kuna, M; Kersten, Sander; Püschel, Gerhard

doi:10.1016/j.febslet.2007.11.011

Cited by 37 publications

(26 citation statements)

References 28 publications

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“…It has recently been shown that PPARa agonists lead to increased CAR expression via a PPRE (direct repeat 1, or DR1) in the CAR promoter (6). These same studies show that fasting-induced increases in free fatty acids (many of which are natural ligands for PPARa) induce CAR expression via PPARa activation.…”

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confidence: 59%

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The nuclear receptor CAR (NR1I3) regulates serum triglyceride levels under conditions of metabolic stress

Maglich

Lobe

Moore

2009

Journal of Lipid Research

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The nuclear receptor constitutive androstane receptor (CAR) (NR1I3) regulates hepatic genes involved in xenobiotic detoxification as well as genes involved in energy homeostasis. We provide data that extend the role of CAR to regulation of serum triglyceride levels under conditions of metabolic/nutritional stress. The typically high serum triglyceride levels of ob/ob mice were completely normalized when crossed onto a Car 2/2 (mice deficient for the Car gene) genetic background. Moreover, increases in serum triglycerides observed after a high-fat diet (HFD) regime were not observed in Car 2/2 animals. Conversely, pharmacologi-

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confidence: 59%

“…PPARa and CAR are induced in liver in response to fasting (6,7). It has recently been shown that PPARa agonists lead to increased CAR expression via a PPRE (direct repeat 1, or DR1) in the CAR promoter (6).…”

mentioning

confidence: 99%

The nuclear receptor CAR (NR1I3) regulates serum triglyceride levels under conditions of metabolic stress

Maglich

Lobe

Moore

2009

Journal of Lipid Research

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“…Fastingdependent induction of CAR is mediated primarily by hepatocyte nuclear factor 4α (HNF4α) and PPARα [44,45] . Whereas fasted WT mice exhibit a higher CAR mRNA level compared with fed mice, this fasting response is almost completely attenuated in either HNF4α or PPARα knockout mice.…”

Section: Transcriptional Regulation Of Carmentioning

confidence: 99%

Deciphering the roles of the constitutive androstane receptor in energy metabolism

et al. 2014

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The constitutive androstane receptor (CAR) is initially defined as a xenobiotic nuclear receptor that protects the liver from injury. Detoxification of damaging chemicals is achieved by CAR-mediated induction of drug-metabolizing enzymes and transporters. More recent research has implicated CAR in energy metabolism, suggesting a therapeutic potential for CAR in metabolic diseases, such as type 2 diabetes and obesity. A better understanding of the mechanisms by which CAR regulates energy metabolism will allow us to take advantage of its effectiveness while avoiding its side effects. This review summarizes the current progress on the regulation of CAR nuclear translocation, upstream modulators of CAR activity, and the crosstalk between CAR and other transcriptional factors, with the aim of elucidating how CAR regulates glucose and lipid metabolism.

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“…A species-dependent interaction was also observed among treatments with respect to gene regulation by the nuclear receptors CAR and PPAR. These changes may reflect species-dependent regulation of CAR responses after PPAR activation as discussed elsewhere (Guo et al, 2006;Wieneke et al, 2007;Saito et al, 2010;Rondini et al, 2016). In mouse hepatocytes, PPAR activation by the prototypical agonist Cipro decreased expression of the CAR target gene Fig.…”

Section: Regulation Of Hepatocellular Gene Expression By Isoprenoidsmentioning

confidence: 72%

Differential Regulation of Gene Expression by Cholesterol Biosynthesis Inhibitors That Reduce (Pravastatin) or Enhance (Squalestatin 1) Nonsterol Isoprenoid Levels in Primary Cultured Mouse and Rat Hepatocytes

Rondini

Duniec-Dmuchowski

Cukovic

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Squalene synthase inhibitors (SSIs), such as squalestatin 1 (SQ1), reduce cholesterol biosynthesis but cause the accumulation of isoprenoids derived from farnesyl pyrophosphate (FPP), which can modulate the activity of nuclear receptors, including the constitutive androstane receptor (CAR), farnesoid X receptor, and peroxisome proliferator-activated receptors (PPARs). In comparison, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (e.g., pravastatin) inhibit production of both cholesterol and nonsterol isoprenoids. To characterize the effects of isoprenoids on hepatocellular physiology, microarrays were used to compare orthologous gene expression from primary cultured mouse and rat hepatocytes that were treated with either SQ1 or pravastatin. Compared with controls, 47 orthologs were affected by both inhibitors, 90 were affected only by SQ1, and 51 were unique to pravastatin treatment (P , 0.05, $1.5-fold change). When the effects of SQ1 and pravastatin were compared directly, 162 orthologs were found to be differentially coregulated between the two treatments. Genes involved in cholesterol and unsaturated fatty acid biosynthesis were up-regulated by both inhibitors, consistent with cholesterol depletion; however, the extent of induction was greater in rat than in mouse hepatocytes. SQ1 induced several orthologs associated with microsomal, peroxisomal, and mitochondrial fatty acid oxidation and repressed orthologs involved in cell cycle regulation. By comparison, pravastatin repressed the expression of orthologs involved in retinol and xenobiotic metabolism. Several of the metabolic genes altered by isoprenoids were inducible by a PPARa agonist, whereas cytochrome P450 isoform 2B was inducible by activators of CAR. Our findings indicate that SSIs uniquely influence cellular lipid metabolism and cell cycle regulation, probably due to FPP catabolism through the farnesol pathway.

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

Abstract: A tight hormonal control of energy homeostasis is of pivotal relevance for animals. Recent evidence suggests an involvement of the nuclear receptor NR1i3

Cited by 37 publications

References 28 publications

The nuclear receptor CAR (NR1I3) regulates serum triglyceride levels under conditions of metabolic stress

The nuclear receptor CAR (NR1I3) regulates serum triglyceride levels under conditions of metabolic stress

Deciphering the roles of the constitutive androstane receptor in energy metabolism

Differential Regulation of Gene Expression by Cholesterol Biosynthesis Inhibitors That Reduce (Pravastatin) or Enhance (Squalestatin 1) Nonsterol Isoprenoid Levels in Primary Cultured Mouse and Rat Hepatocytes

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