The pregnane X receptor (PXR, NR1I2) is a xenobiotic-sensing nuclear receptor that modulates the metabolic response to drugs and toxic agents. Both PXR activation and deficiency promote hepatic triglyceride accumulation, a hallmark feature of alcoholic liver disease. However, the molecular mechanism of PXR-mediated activation of ethanol (EtOH)-induced steatosis is unclear. Here, using male wildtype (WT) and -null mice, we examined PXR-mediated regulation of chronic EtOH-induced hepatic lipid accumulation and hepatotoxicity. EtOH ingestion for 8 weeks significantly (1.8-fold) up-regulated mRNA levels in WT mice. The EtOH exposure also increased mRNAs encoding hepatic constitutive androstane receptor (3-fold) and its target, (220-fold), in a PXR-dependent manner. Furthermore, WT mice had higher serum EtOH levels and developed hepatic steatosis characterized by micro- and macrovesicular lipid accumulation. Consistent with the development of steatosis, lipogenic gene induction was significantly increased in WT mice, including sterol regulatory element-binding protein 1c target gene fatty-acid synthase (3.0-fold), early growth response-1 (3.2-fold), and TNFα (3.0-fold), whereas the expression of peroxisome proliferator-activated receptor α target genes was suppressed. Of note, PXR deficiency suppressed these changes and steatosis. Protein levels, but not mRNAs levels, of EtOH-metabolizing enzymes, including alcohol dehydrogenase 1, aldehyde dehydrogenase 1A1, and catalase, as well as the microsomal triglyceride transfer protein, involved in regulating lipid output were higher in-null than in WT mice. These findings establish that PXR signaling contributes to ALD development and suggest that PXR antagonists may provide a new approach for ALD therapy.

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The pregnane X receptor (PXR, NR1I2) is a xenobiotic-sensing nuclear receptor that defends against toxic agents. We have shown that PXR promotes chronic ethanol (EtOH)-induced steatosis. Therefore, we examined the role of PXR in binge EtOH-induced hepatotoxicity. Male wild type (WT) and Pxr-null mice were orally administered three binge doses of EtOH (4.5 g/kg, every 12 hours) and euthanized four hours after the final dose. Pxr-null mice displayed higher basal mRNA levels of hepatic lipogenic transcription factor sterol regulatory element binding protein 1c (Srebp-1c) and its target stearoyl-CoA desaturase 1 (Scd1) and the lipid peroxide detoxifying aldo-keto reductase 1b7 (Akr1b7) and higher protein levels of EtOH-metabolizing alcohol dehydrogenase 1 (ADH1). In both genotypes, binge EtOH-induced triglyceride accumulation was associated with inhibition of fatty acid β-oxidation and upregulation of Srebp-1c- regulated lipogenic genes and hepatic CYP2E1 protein. Unexpectedly, gene expression of Cyp2b10, a constitutive androstane receptor target gene, implicated in EtOH hepatotoxicity, was PXR-dependent upregulated by binge EtOH. Also, PXR-dependent was the binge EtOH-induced inhibition of hepatic Akr1b8 mRNA, and protein levels of aldehyde dehydrogenase (ALDH) 1A1 and anti-apoptotic Bcl-2, but increased pro-apoptotic Bax protein expression, leading to increases in residual EtOH concentration and the cellular oxidative stress marker, malondialdehyde. In contrast, Pxr-null mice displayed increased Akr1b7 gene and ADH1 protein expression and hypertriglyceridemia following binge EtOH exposure. Taken together, this study demonstrates that PXR ablation prevents EtOH induced upregulation of Cyp2b10 and that PXR potentiates binge EtOH-induced oxidative stress and inhibition of EtOH catabolism, but protects against alcoholic hyperlipidemia.

Tumor cell contamination (TCC) of peripheral blood stem cells (PBSCs) is a major risk in the autologous PBSC transplant setting. However, the effect of different mobilization regimens (cytokines only versus cytokines + chemotherapy) on TCC of PBSCs and its impact on treatment outcomes have not been systematically reviewed. In the present meta-analysis, we aimed to investigate this effect in breast cancer patients since multiple studies have been conducted in this setting. We systematically searched MEDLINE and Cochrane Library up to May 2012. Seventeen studies (1,819 patients) were assessed. There was no significant difference in the incidence of TCC of PBSCs between the two mobilization regimens. When the analysis was restricted to granulocyte colony-stimulating factor as a cytokine, this difference was again not significant. We also found that TCC of PBSCs was associated with a higher annual recurrence rate in these patients. This suggests that there may be a significant risk for reinfusion of tumor cell-positive PBSCs, and whether it can increase the risk of disease recurrence needs to be determined. This study also raises important questions regarding the causes of TCC of PBSCs. These issues should be investigated systematically in PBSC transplant patients.

Pregnane X receptor (PXR) is a drug receptor with novel functions in promoting non-alcoholic fatty liver disease (NAFLD). We hypothesize that PXR worsens NAFLD accompanied by gut dysbiosis. Wild-type and PXR-knockout mice were fed control or high fat diet (HFD) for 16-weeks. Serum parameters, liver histopathology, transcriptomic profiling, 16S-rDNA sequencing, and bile acid (BA) metabolomics were performed. PXR enhanced HFD-induced weight gain, hepatic steatosis and inflammation especially in males, accompanied by male-specific and PXR-dependent up-regulation in pro-inflammatory cytokines and microbial response-related genes in liver, an increase in intestinal Firmicutes/Bacteroides ratio (hallmark of obesity) and the pro-inflammatory Lactobacillus, and a decrease in the anti-obese Allobaculum and the anti-inflammatory Bifidobacterum. The gut dysbiosis was associated with a reduction of hepatic beneficial BAs in males. In conclusion, PXR exacerbates hepatic steatosis and inflammation accompanied by obesity- and inflammation-prone gut microbiome signature, suggesting that gut microbiome may contribute to PXR-mediated exacerbation of NAFLD.