Metabolomic Approaches Reveal the Role of CAR in Energy Metabolism.

The constitutive androstane receptor (CAR; NR1I3) contributes important regulatory roles in biotransformation, xenobiotic transport function, energy metabolism and lipid homeostasis. In this investigation, global serum and liver tissue metabolomes were assessed analytically in wild type and CAR-null transgenic mice using NMR, GC-MS and UPLC-MS/MS-based metabolomics. Significantly, CAR activation increased serum levels of fatty acids, lactate, ketone bodies and tricarboxylic acid cycle products, whereas levels of phosphatidylcholine, sphingomyelin, amino acids and liver glucose were decreased following short-term activation of CAR.

In vivo genome-wide binding interactions of mouse and human constitutive androstane receptors reveal novel gene targets.

The constitutive androstane receptor (CAR; NR1I3) is a nuclear receptor orchestrating complex roles in cell and systems biology. Species differences in CAR's effector pathways remain poorly understood, including its role in regulating liver tumor promotion. We developed transgenic mouse models to assess genome-wide binding of mouse and human CAR, following receptor activation in liver with direct ligands and with phenobarbital, an indirect CAR activator.

Activation of the Constitutive Androstane Receptor by Monophthalates.

Humans in industrialized areas are continuously exposed to phthalate plasticizers, prompting concerns of their potential toxicities. Previous studies from our laboratory and others have shown that various phthalates activate several mammalian nuclear receptors, in particular the constitutive androstane receptor (CAR), the pregnane X receptor (PXR), and the peroxisomal proliferator-activated receptors (PPARs), although often at concentration levels of questionable relevance to human exposure. We discovered that di(2-ethylhexyl) phthalate (DEHP) and di-isononyl phthalate (DiNP), two of the highest volume production agents, were potent activators of human CAR2 (hCAR2), a unique human CAR splice variant and, to a lesser degree, human PXR (hPXR).

Hepatic Aryl Hydrocarbon Receptor Attenuates Fibroblast Growth Factor 21 Expression.

The Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor involved in many physiological processes. Several studies indicate that AHR is also involved in energy homeostasis. Fibroblast growth factor 21 (FGF21) is an important regulator of the fasting and feeding responses.

Bioinformatic analysis of microRNA networks following the activation of the constitutive androstane receptor (CAR) in mouse liver.

The constitutive androstane receptor (CAR; NR1I3) is a member of the nuclear receptor superfamily that functions as a xenosensor, serving to regulate xenobiotic detoxification, lipid homeostasis and energy metabolism. CAR activation is also a key contributor to the development of chemical hepatocarcinogenesis in mice. The underlying pathways affected by CAR in these processes are complex and not fully elucidated.