Liver X receptor agonist downregulates growth hormone signaling in the liver

Fahad Zadjali, Amilcar Flores-Morales, Fahad Zadjali, Gunnar Norstedt, Fahad Zadjali, Ruyman Santana-Farre, Mercedes Mirecki-Garrido, Ewa Ellis, Fahad Zadjali

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 overexpres-sion 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.

Original languageEnglish
Pages (from-to)471-478
Number of pages8
JournalHormone Molecular Biology and Clinical Investigation
Volume8
Issue number2
DOIs
Publication statusPublished - 2011

Fingerprint

Growth Hormone
Down-Regulation
STAT5 Transcription Factor
Liver
Sterol Regulatory Element Binding Protein 1
STAT Transcription Factors
Response Elements
Cytokines
Hepatocytes
Liver X Receptors
Genes
Somatotropin Receptors
Hyperlipidemias
Luciferases
Proteolysis
Atherosclerosis
Pharmacology
Messenger RNA
DNA

Keywords

  • 9-cis retinoic acid
  • growth hormone
  • lipid
  • LXR
  • RXR
  • SOCS2
  • T0901317

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)
  • Molecular Biology
  • Endocrinology

Cite this

Zadjali, F., Flores-Morales, A., Zadjali, F., Norstedt, G., Zadjali, F., Santana-Farre, R., ... Zadjali, F. (2011). Liver X receptor agonist downregulates growth hormone signaling in the liver. Hormone Molecular Biology and Clinical Investigation, 8(2), 471-478. https://doi.org/10.1515/HMBCI.2011.125

Liver X receptor agonist downregulates growth hormone signaling in the liver. / Zadjali, Fahad; Flores-Morales, Amilcar; Zadjali, Fahad; Norstedt, Gunnar; Zadjali, Fahad; Santana-Farre, Ruyman; Mirecki-Garrido, Mercedes; Ellis, Ewa; Zadjali, Fahad.

In: Hormone Molecular Biology and Clinical Investigation, Vol. 8, No. 2, 2011, p. 471-478.

Research output: Contribution to journalArticle

Zadjali, F, Flores-Morales, A, Zadjali, F, Norstedt, G, Zadjali, F, Santana-Farre, R, Mirecki-Garrido, M, Ellis, E & Zadjali, F 2011, 'Liver X receptor agonist downregulates growth hormone signaling in the liver', Hormone Molecular Biology and Clinical Investigation, vol. 8, no. 2, pp. 471-478. https://doi.org/10.1515/HMBCI.2011.125
Zadjali, Fahad ; Flores-Morales, Amilcar ; Zadjali, Fahad ; Norstedt, Gunnar ; Zadjali, Fahad ; Santana-Farre, Ruyman ; Mirecki-Garrido, Mercedes ; Ellis, Ewa ; Zadjali, Fahad. / Liver X receptor agonist downregulates growth hormone signaling in the liver. In: Hormone Molecular Biology and Clinical Investigation. 2011 ; Vol. 8, No. 2. pp. 471-478.
@article{9487b0809f2d4ff795613978287fd296,
title = "Liver X receptor agonist downregulates growth hormone signaling in the liver",
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 overexpres-sion 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.",
keywords = "9-cis retinoic acid, growth hormone, lipid, LXR, RXR, SOCS2, T0901317",
author = "Fahad Zadjali and Amilcar Flores-Morales and Fahad Zadjali and Gunnar Norstedt and Fahad Zadjali and Ruyman Santana-Farre and Mercedes Mirecki-Garrido and Ewa Ellis and Fahad Zadjali",
year = "2011",
doi = "10.1515/HMBCI.2011.125",
language = "English",
volume = "8",
pages = "471--478",
journal = "Hormone Molecular Biology and Clinical Investigation",
issn = "1868-1883",
publisher = "Walter de Gruyter GmbH",
number = "2",

}

TY - JOUR

T1 - Liver X receptor agonist downregulates growth hormone signaling in the liver

AU - Zadjali, Fahad

AU - Flores-Morales, Amilcar

AU - Zadjali, Fahad

AU - Norstedt, Gunnar

AU - Zadjali, Fahad

AU - Santana-Farre, Ruyman

AU - Mirecki-Garrido, Mercedes

AU - Ellis, Ewa

AU - Zadjali, Fahad

PY - 2011

Y1 - 2011

N2 - 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 overexpres-sion 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.

AB - 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 overexpres-sion 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.

KW - 9-cis retinoic acid

KW - growth hormone

KW - lipid

KW - LXR

KW - RXR

KW - SOCS2

KW - T0901317

UR - http://www.scopus.com/inward/record.url?scp=84891731025&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84891731025&partnerID=8YFLogxK

U2 - 10.1515/HMBCI.2011.125

DO - 10.1515/HMBCI.2011.125

M3 - Article

AN - SCOPUS:84891731025

VL - 8

SP - 471

EP - 478

JO - Hormone Molecular Biology and Clinical Investigation

JF - Hormone Molecular Biology and Clinical Investigation

SN - 1868-1883

IS - 2

ER -