Abstract：
The pregnane X receptor (PXR, NR1I2), a xenobiotic-sensing nuclear receptor signaling potentiates ethanol (EtOH)-induced hepatotoxicity in male mice, however, how PXR signaling modulates EtOH-induced hepatotoxicity in female mice is unknown. Wild type (WT) and Pxr-null mice received 5 % EtOH-containing diets or paired-fed control diets for 8 weeks followed by assessment of liver injury, EtOH elimination rates, histology, and changes in gene and protein expression; microarray and bioinformatic analyses were also employed to identify PXR targets in chronic EtOH-induced hepatotoxicity. In WT females, EtOH ingestion significantly increased serum ethanol and alanine aminotransferase (ALT) levels, hepatic Pxr mRNA, constitutive androstane receptor activation, Cyp2b10 mRNA and protein, oxidative stress, endoplasmic stress (phospho-elF2α) and pro-apoptotic (Bax) protein expression. Unexpectedly, EtOH-fed female Pxr-null mice displayed increased EtOH elimination and elevated levels of hepatic acetaldehyde detoxifying aldehyde dehydrogenase 1a1 (Aldh1a1) mRNA and protein, EtOH-metabolizing alcohol dehydrogenase 1 (ADH1), and lipid suppressing microsomal triglyceride transport protein (MTP) protein, aldo-keto reductase 1b7 (Akr1b7) and Cyp2a5 mRNA, but suppressed CYP2B10 protein levels, with evidence of protection against chronic EtOH-induced oxidative stress and hepatotoxicity. While liver injury was not different between the two WT sexes, female sex may suppress EtOH-induced macrovesicular steatosis in the liver. Several genes and pathways important in retinol and steroid hormone biosynthesis, chemical carcinogenesis, and arachidonic acid metabolism were upregulated by EtOH in a PXR-dependent manner in both sexes. Together, these data establish that female Pxr-null mice are resistant to chronic EtOH-induced hepatotoxicity and unravel the PXR-dependent and -independent mechanisms that contribute to EtOH-induced hepatotoxicity.
摘要：
孕烷X受体（PXR，NR1I2),外源性生物敏感核受体信号增强乙醇（EtOH）诱导的雄性小鼠肝毒性，然而,PXR信号如何调节EtOH诱导的雌性小鼠肝毒性尚不清楚.野生型（WT）和Pxr-null小鼠接受含有5％EtOH的饮食或配对喂养的对照饮食8周，然后评估肝损伤，EtOH消除率,组织学,以及基因和蛋白质表达的变化；微阵列和生物信息学分析也用于鉴定慢性EtOH诱导的肝毒性中的PXR靶标。在WT女性中，摄入EtOH显着增加血清乙醇和丙氨酸氨基转移酶（ALT）水平，肝PxrmRNA，组成型雄甾烷受体（CAR）激活，Cyp2b10mRNA和蛋白，氧化应激，和内质应激（磷酸-elF2α）和促凋亡（Bax）蛋白表达。出乎意料的是,用EtOH喂养的雌性Pxr-null小鼠显示出增加的EtOH消除和升高的肝乙醛解毒醛脱氢酶1a1（Aldh1a1）mRNA和蛋白质水平，乙醇代谢醇脱氢酶1（ADH1），和脂质抑制微粒体甘油三酯转运蛋白（MTP）蛋白，aldo-keto还原酶1b7（Akr1b7）和Cyp2a5mRNA，但抑制了CYP2B10蛋白水平，有证据表明可以抵抗慢性EtOH诱导的氧化应激和肝毒性。虽然两个WT性别之间的肝损伤没有差异，女性可以抑制EtOH诱导的肝脏大泡性脂肪变性。视黄醇和类固醇激素生物合成中重要的几个基因和途径，化学致癌作用，在两种性别中，EtOH和花生四烯酸的代谢均以PXR依赖性方式上调。一起,这些数据证实了雌性Pxr-null小鼠对慢性EtOH诱导的肝毒性具有抗性,并揭示了导致EtOH诱导的肝毒性的PXR依赖性和非依赖性机制.
