Article

PPARalpha-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: 3.34). 01/2008; 581(29):5617-26. DOI: 10.1016/j.febslet.2007.11.011
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
96 Views
  • Source
    [Show abstract] [Hide abstract]
    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 01/2013; 91:243-58. · 1.78 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Dietary restriction (DR) is the gold standard intervention used to delay aging, and much recent research has focused on the identification of possible DR mimetics. Energy sensing pathways, including insulin/IGF1 signaling, sirtuins, and mammalian Target of Rapamycin (mTOR), have been proposed as pathways involved in the antiaging actions of DR, and compounds that affect these pathways have been suggested to act as DR mimetics, including metformin (insulin/IGF1 signaling), resveratrol (sirtuins), and rapamycin (mTOR). Rapamycin is a promising DR mimetic because it significantly increases both health span and life span in mice. Unfortunately, rapamycin also leads to some negative effects, foremost among which is the induction of insulin resistance, potentially limiting its translation into humans. To begin clarifying the mechanism(s) involved in insulin resistance induced by rapamycin, we compared several aspects of liver metabolism in mice treated with DR or rapamycin for 6 months. Our data suggest that although both DR and rapamycin inhibit lipogenesis, activate lipolysis, and increased serum levels of nonesterified fatty acids, only DR further activates β-oxidation of the fatty acids leading to the production of ketone bodies.
    The Journals of Gerontology Series A Biological Sciences and Medical Sciences 04/2014; · 4.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Reduced expression of the INDY (I'm not dead yet) tricarboxylate carrier increased life span in different species by mechanisms akin to caloric restriction. The mammalian INDY homolog (mIndy) gene expression seems to be regulated by hormonal and/or nutritional factors. The underlying mechanisms are still unknown. The current study revealed that mIndy expression and [(14)C]-citrate uptake was induced by physiological concentrations of glucagon via a cAMP- and cAMP-responsive-element-binding protein (CREB)-dependent mechanism in primary rat hepatocytes. The promoter sequence of mIndy located upstream of the most frequent transcription start site was determined by 5'-race. In silico analysis identified a CREB-binding site within this promoter fragment of mIndy. Functional relevance for the CREB-binding site was demonstrated with reporter gene constructs, which were induced by CREB activation when under the control of a fragment of wild type promoter whereas promoter activity was lost after site directed mutagenesis of the CREB-binding site. Moreover, CREB binding to this promoter element was confirmed by chromatin immunoprecipiation in rat liver. In vivo studies revealed that mIndy was induced in livers of fasted as well as HFD-streptozotocin-diabetic rats, in which CREB is constitutively activated. mIndy induction was completely prevented when CREB was depleted in these rats by antisense oligonucleotides. Together, these data suggest that mIndy is a CREB-dependent glucagon target gene, which is induced in fasting and in type 2 diabetes. Increased mINDY expression might contribute to the metabolic consequences of diabetes in the liver.
    Diabetes 11/2013; · 7.90 Impact Factor

Full-text (2 Sources)

Download
50 Downloads
Available from
May 28, 2014