Estrogen receptor ligands ameliorate fatty liver through a nonclassical estrogen receptor/Liver X receptor pathway in mice. Issue 5 (27th March 2014)

• Record Type: Journal Article
• Authors: Han, Song‐iee; Komatsu, Yoko; Murayama, Akiko; Steffensen, Knut R.; Nakagawa, Yoshimi; Nakajima, Yuka; Suzuki, Michiko; Oie, Shohei; Parini, Paolo; Vedin, Lise‐Lotte; Kishimoto, Hiroyuki; Shimano, Hitoshi; Gustafsson, Jan‐Åke; Yanagisawa, Junn
• Is Part Of: Hepatology. Volume 59:Issue 5(2014:May)
• Page Start: 1791
• Page End: 1802
• Publication Date: 2014-03-27
• Subjects: Heart -- Diseases -- Nursing -- Periodicals; Lungs -- Diseases -- Nursing -- Periodicals; Intensive care nursing -- Periodicals; Foie -- Maladies -- Périodiques; 616.362
• DOI: 10.1002/hep.26951
• Languages: English
• ISSNs: 0270-9139

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Liver X receptor (LXR) activation stimulates triglyceride (TG) accumulation in the liver. Several lines of evidence indicate that estradiol‐17β (E2) reduces TG levels in the liver; however, the molecular mechanism underlying the E2 effect remains unclear. Here, we show that administration of E2 attenuated <italic>sterol regulatory element‐binding protein</italic> (<italic>SREBP</italic>)<italic>‐1</italic> expression and TG accumulation induced by LXR activation in mouse liver. In <italic>estrogen receptor alpha</italic> (<italic>ERα</italic>) knockout (KO) and liver‐specific <italic>ERα</italic> KO mice, E2 did not affect <italic>SREBP‐1</italic> expression or TG levels. Molecular analysis revealed that ERα is recruited to the <italic>SREBP‐1c</italic> promoter through direct binding to LXR and inhibits coactivator recruitment to LXR in an E2‐dependent manner. Our findings demonstrate the existence of a novel liver‐dependent mechanism controlling TG accumulation through the nonclassical ER/LXR pathway. To confirm that a nonclassical ER/LXR pathway regulates ERα‐dependent inhibition of LXR activation, we screened ERα ligands that were able to repress LXR activation without enhancing ERα transcriptional activity, and, as a result, we identified the phytoestrogen, phloretin. In mice, phloretin showed no estrogenic activity; however, it did reduce <italic>SREBP‐1</italic> expression and TG levels in liver of mice fed a high‐fat diet to an extent similar to that of E2. <italic>Conclusion</italic>: We propose that ER ligands reduce TG levels in the liver by inhibiting LXR activation through a nonclassical pathway. Our results also indicate that the effects of ER on TG accumulation can be distinguished from its estrogenic effects by a specific ER ligand. (H<sc>epatology</sc> 2014;59:1791–1802)</p> </abstract>