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We appreciate Out et al for their interest in our article.1Lu Y. et al.Gastroenterology. 2012; 143: 1630-1640Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar We agree that cholestasis is a term encompassing diseases in which bile flow is reduced or arrested and substances normally excreted into bile are retained. However, increased serum BA concentration and liver enzymes are used as a universal indicator of cholestasis, which is also mentioned by Out et al and others.2Wagner M. et al.J Hepatol. 2009; 51: 565-580Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar Here, our results showed that these parameters were altered in mice with dexamethasone treatment and patients with Cushing syndrome or obesity. In addition, we found that BA levels were elevated in systemic lupus erythematosis (SLE) patients receiving glucocorticoid treatment (data not shown), which has been demonstrated previously by others.3Yamanishi Y. et al.Gastroenterol Jpn. 1985; 20: 246-251Crossref PubMed Scopus (9) Google Scholar Based on our present study, BA excretion was relatively reduced compared with its synthesis and resulted in its accumulation in the livers in the state of glucocorticoid excess. Therefore, cholestasis, in our opinion, may be more broadly defined. Numerous studies have implicated the farnesoid X receptor (FXR) as a central regulator of BA homeostasis. Notably, the BA synthesis and transport machinery are under the control of FXR. In mice with dexamethasone treatment, we observed reduced expression of FXR target genes (SHP and Abcb4), as well as increased expression of BA synthesis genes (Cyp7A1 and Cyp8B1). Since these genes are under the direct or indirect regulation of FXR, we propose that glucocorticoids attenuate FXR transcriptional activity through the interaction of FXR and glucocorticoid receptor (GR), which in turn adds an additional mechanism for the BA overproduction. This transrepression model resembles a recent mechanism driving estradiol-mediated intrahepatic cholestasis in pregnancy in which ligand-activated estrogen receptor α (ERα) interacts with FXR and represses its transcriptional activity.4Milona A. et al.Hepatology. 2010; 52: 1341-1349Crossref PubMed Scopus (75) Google Scholar Interestingly, the Asbt gene promoter, as mentioned by Out et al, was also negatively regulated by the FXR-SHP signaling.5Li H. et al.Am J Physiol Gastrointest Liver Physiol. 2005; 288: G60-G66Crossref PubMed Scopus (66) Google Scholar Therefore, the mechanism of the GR/FXR cascade we proposed might also be involved in the up-regulation of Asbt expression by glucocorticoids. Moreover, it has been reported that activation of FXR reduced fecal bile acid excretion in mice,6Jung D. et al.J Lipid Res. 2007; 48: 2693-2700Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar suggesting that dexamethasone treatment might increase fecal bile acid excretion. As suggested by Out et al, the measurement of fecal bile acids will further strengthen our understanding of the physiology observed by glucocorticoid treatment. Previous studies showed that glucocorticoids promote BA production in hepatocytes by up-regulation of Cyp7A1.7Crestani M. et al.J Lipid Res. 1995; 36: 2419-2432Abstract Full Text PDF PubMed Google Scholar We also found that hepatic BA formation was reduced in db/db mice with GR knockdown.1Lu Y. et al.Gastroenterology. 2012; 143: 1630-1640Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar However, a recent study showed that liver-specific knockdown of GR increased systemic BA levels during the fasted-to-fed transition in C57BL/6J mice.8Rose A.J. et al.Cell Metab. 2011; 14: 123-130Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar Although the reason for this inconsistency is unclear, the animal models and feeding conditions were different in these 2 studies. In addition, as mentioned by Out et al, recent studies suggested that intestine FXR could regulate the hepatic BA pool in mice by inducing FGF15 expression.9Modica S. et al.Gastroenterology. 2012; 142: 355-365Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar However, we observed that hepatic BA contents were reduced in db/db mice administrated with GR shRNA adenovirus, which was specifically targeted to the liver, but not other tissues. Thus, our data suggest that hepatic FXR plays an important role in glucocorticoid-induced cholestasis. While we employed global FXR knockout mice in our article, it will be very interesting to further distinguish the roles of intestine and liver FXR signaling using enterocyte-specific and hepatocyte-specific knockout animals in future studies. Bile Acids and CholestasisGastroenterologyVol. 144Issue 2PreviewIt was with great interest that we read the study on the molecular mechanism via which glucocorticoids interact with bile acid homeostasis by Lu et al.1 In this article several intriguing findings were noted, and we would like to share some comments. Full-Text PDF