Endocrine Abstracts

The Liver X Receptor (LXR) agonists have been shown to influence the development of hyperlipidemia and atherosclerosis in mouse models. It has also been demonstrated that some LXR agonists can cause hepatic steatosis in experimental animals. GH is also known to regulate hepatic metabolism and absence of the hepatic GH receptors leads to hepatic steatosis. In this study we analyzed whether actions of LXR agonists could involve interference with GH signaling. We showed that LXR agonist impairs GH signaling in hepatocytes. LXR agonist treatment attenuated GH induction of SOCS2, SOCS3, and CIS mRNA levels in BRL-4 cells. Likewise, the activity of the GH sensitive reporter vector was inhibited by a simultaneous treatment with LXR agonist. The inhibitory effect of LXR agonist on GH signals can be mimicked by overexpression of the LXR regulated factors SREBP1a and SREBP2 in hepatic cells. In both cases, total and phosphorylated STAT5b protein levels were significantly reduced. DNA binding assays demonstrated that SREBP1 binds to an E-box within a previously defined GH responsive element in the SOCS2 gene promoter but does not compete with STAT5b binding to a nearby site in the same response element. Taken together, our findings indicate that the inhibitory effects of LXR agonists on GH signaling are mediated by SREBP1, through the downregulation of STAT5b gene transcription and stimulation of STAT5b protein turnover. The described findings provide new insight in understanding the molecular actions of LXR agonists, which may be of relevance for their pharmacological actions.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported however, funding details unavailable.