New insights on the xenobiotic-sensing nuclear receptors in liver diseases--CAR and PXR--.
The xenobiotic receptors CAR and PXR constitute two important members of the NR1I nuclear receptor family. They function as sensors of toxic byproducts derived from the endogenous metabolism and of exogenous chemicals, in order to enhance their elimination. They regulate numerous genes which are involved in drug and xenobiotic metabolism, including Phase I (cytochrome P450), Phase II (conjugation catalyzed by sulfotransferases, glucuronosyltransferases and glutathione S-transferases), and transporters (multidrug resistance proteins, multidrug resistance-associated proteins, and organic anion-transporting polypeptides). Although CAR and PXR were initially characterized as xenosensors, it is now evident that CAR and PXR also trigger pleiotropic effects on physiological or pathological functions. Recent studies have shown that the activation of CAR and PXR alters lipid metabolism, glucose homeostasis, and inflammation. Therefore, in addition to regulating drug elimination pathways, they also play important roles in regulating metabolic pathways. As a result, these receptors may be closely associated with the pathogenesis of many diseases. However, the pathophysiological roles of CAR and PXR are not fully understood. The purpose of this review is to discuss the physiological and pathological roles of CAR and PXR in liver diseases.
Kakizaki
Satoru
S
Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan. kakizaki@showa.gunma-u.ac.jp
Yamazaki
Yuichi
Y
Takizawa
Daichi
D
Negishi
Masahiko
M
D000818:Animals; D001663:Bilirubin / Q000378:metabolism; D015519:Bone Density; D000090702:Constitutive Androstane Receptor; D004347:Drug Interactions; D005234:Fatty Liver / Q000209:etiology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D008107:Liver Diseases / Q000209:etiology*; D008113:Liver Neoplasms / Q000209:etiology; D008115:Liver Regeneration; D004364:Pharmaceutical Preparations / Q000378:metabolism; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D011987:Receptors, Steroid / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D015262:Xenobiotics / Q000378:metabolism*
D000090702:Constitutive Androstane Receptor; D004364:Pharmaceutical Preparations; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D015262:Xenobiotics; D005947:Glucose; D001663:Bilirubin