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Licensed Unlicensed Requires Authentication Published by De Gruyter November 1, 2011

Liver X receptor agonist downregulates growth hormone signaling in the liver

  • Fahad Zadjali EMAIL logo , Ruyman Santana-Farre , Mercedes Mirecki-Garrido , Ewa Ellis , Gunnar Norstedt , Leandro Fernandez-Perez and Amilcar Flores-Morales

Abstract

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. Growth hormone (GH) is known to regulate hepatic metabolism and the absence of hepatic GH receptors (GHR) leads to hepatic steatosis. In this study, we analyzed whether the actions of LXR agonists could involve interference with GH signaling. We showed that LXR agonists impair GH signaling in hepatocytes. LXR agonist treatment attenuated GH induction of suppressor of cytokine signaling 2 (SOCS2), SOCS3, and CIS mRNA levels in BRL-4 cells. Likewise, the activity of a luciferase reporter vector driven by the GH response element (GHRE) of the SOCS2 gene was inhibited by simultaneous treatment with an LXR agonist. The inhibitory effect of LXR agonists on GH signals can be mimicked by overexpression of the LXR regulated factors, sterol regulatory element binding protein 1 (SREBP1) and SREBP2, in hepatic cells. In both cases total and phosphorylated signal transducers and activators of transcription 5b (STAT5b) protein levels were significantly reduced. DNA binding assays demonstrated that SREBP1 binds to an E-box within a previously defined GHRE in the SOCS2 gene promoter, but does not compete with STAT5b binding to a nearby site in the same promoter construct. 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 degradation. The findings provide a new insight into the understanding of the molecular actions of LXR agonists, which may be of relevance to their pharmacological actions.


Corresponding author: Fahad Zadjali, Department of Molecular Medicine and Surgery, Karolinska Institutet, CMM L8:01, 17176 Stockholm, Sweden Phone: +46 (0) 851773203

Received: 2011-8-29
Accepted: 2011-11-9
Published Online: 2011-11-01
Published in Print: 2011-11-01

©2011 by Walter de Gruyter Berlin Boston

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