Abstract
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 Pxr-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 Pxr mRNA levels in WT mice. The EtOH exposure also increased mRNAs encoding hepatic constitutive androstane receptor (3-fold) and its target, Cyp2b10 (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 Pxr-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.
Highlights
The pregnane X receptor (PXR, NR1I2) is a xenobiotic-sensing nuclear receptor that modulates the metabolic response to drugs and toxic agents
During the 8-week feeding period, whereas food intake was similar in all groups, a significant decrease in body weight was observed in both EtOH-fed WT and Pregnane X receptor (Pxr)-null mice, compared with their respective controls (Table 1) and consistent with what was observed by others [46]
This study investigated the effect of chronic EtOH administration on steatosis, hepatotoxicity, hepatic lipid profiles, lipid and alcohol metabolism pathways, PXR target genes, and inflammatory and cellular stress gene and protein expression in Pxr-null mice
Summary
Recent reports indicate that activation of PXR inhibits nuclear factor B, inflammation, and fibrosis [25,26,27,28] In addition to these beneficial effects, PXR activation has been implicated in gut dysbiosis and metabolic abnormalities, tumor promotion, chemoresistance, and response of cancer cells to chemotherapeutic agents (29 –31). A recent report indicates that human PXR gene variants are associated with liver injury in non-alcoholic fatty liver disease (NAFLD), in which PXR polymorphisms increase the risk of susceptibility to a more severe form of NAFLD [34]. None of the two lines of Pxr-null mice has been evaluated for EtOH–induced hepatotoxicity, recent reports indicate that PXR deficiency protects mice against high-fat diet (HFD)-induced obesity [37,38,39]. Male WT and Pxr-null mice were fed control (pair-fed) or the standard Lieber-Decarli liquid diet containing 5% EtOH for 8 weeks and were evaluated for changes in hepatic gene expression, histology, and hepatotoxicity
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