In addition, the gene-expression analysis demonstrates a significant modulation of several nuclear receptor target genes (e.g., BTK inhibitor liver X receptor, farnesoid X receptor, and PPARγ). However, changes were not found in the expression of these nuclear receptors by qRT-PCR or microarray analysis, suggesting that nuclear receptors are not direct transcriptional targets

of HIF. Interestingly, in mice with the conditional Vhl deletion, adipose differentiation-related protein (ADFP) was significantly induced and thought to be critical in the liver steatotic phenotype.14 However, in the VhlF/F;AlbERcre mice after tamoxifen treatment, no increase in ADFP was observed at any time point assessed (data not shown), suggesting that the increase in ADFP is a late secondary response or because of developmental defects after conditional Vhl disruption. These data highlight the importance of temporal gene disruption of Vhl to identify direct mediators of response. One important mediator of lipid homeostasis, ANGPTL3, an endogenous lipoprotein lipase (LPL) inhibitor,30-32 was identified as an HIF-responsive gene. ANGPTL3 is important in regulating serum triglycerides levels.20 In tamoxifen-treated VhlF/F;AlbERcre mice, the increase of ANGPTL3 correlated to an increase in serum triglycerides, and ANGPTL3 directly increased

lipid accumulation in Hepa-1 cells, as assessed by oil red O staining. Currently, it is not known whether the increase in lipid accumulation is through the LPL http://www.selleckchem.com/products/jq1.html inhibitor function of ANGPTL3, but is a clear point of emphasis for future studies. Angptl3 gene expression and promoter activity were rapidly induced by HIF-2α. However, no HREs were identified in the promoter,

suggesting that its activation is HIF-2α-mediated through an indirect mechanism. The HIF-responsive region was localized to a 100-bp region directly proximal to the transcription initiation site, and HIF-2α regulation of this sequence 上海皓元 is being further assessed. During the preparation of this article, others published similar findings in a temporally deleted, liver-specific VHL mouse model, in which disruption of Vhl was induced by tail vein injection of adenovirus encoding cre recombinase (ad-Cre).33 Five days after an injection of ad-Cre, mice demonstrated dramatic steatosis and a decrease in PPARα signaling, thus establishing, as does the present study, that HIF signaling has a primary role in liver lipid homeostasis. Furthermore, the present study demonstrates that these are immediate, rapid responses of HIF-2α signaling. Interestingly, after ad-Cre injection, mice demonstrated rapid death in an HIF-dependent manner, where the median survival was 6 days.