title: Estrogen receptor ligands ameliorate fatty liver through a nonclassical estrogen receptor/Liver X receptor pathway in mice.
abstract: 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 sterol regulatory element-binding protein (SREBP)-1 expression and TG accumulation induced by LXR activation in mouse liver. In estrogen receptor alpha (ERα) knockout (KO) and liver-specific ERα KO mice, E2 did not affect SREBP-1 expression or TG levels. Molecular analysis revealed that ERα is recruited to the SREBP-1c 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 SREBP-1 expression and TG levels in liver of mice fed a high-fat diet to an extent similar to that of E2.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Song-iee
authors.initials: SI
authors.lastname: Han
authors.forename: Yoko
authors.initials: Y
authors.lastname: Komatsu
authors.forename: Akiko
authors.initials: A
authors.lastname: Murayama
authors.forename: Knut R
authors.initials: KR
authors.lastname: Steffensen
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Yuka
authors.initials: Y
authors.lastname: Nakajima
authors.forename: Michiko
authors.initials: M
authors.lastname: Suzuki
authors.forename: Shohei
authors.initials: S
authors.lastname: Oie
authors.forename: Paolo
authors.initials: P
authors.lastname: Parini
authors.forename: Lise-Lotte
authors.initials: LL
authors.lastname: Vedin
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kishimoto
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Shimano
authors.forename: Jan-Åke
authors.initials: JÅ
authors.lastname: Gustafsson
authors.forename: Junn
authors.initials: J
authors.lastname: Yanagisawa
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D004958:Estradiol / Q000494:pharmacology; D005234:Fatty Liver / Q000517:prevention & control*; D005260:Female; D008024:Ligands; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000037:antagonists & inhibitors / Q000502:physiology*; D010693:Phloretin / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011960:Receptors, Estrogen / Q000502:physiology*; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics; D015533:Transcriptional Activation; D014280:Triglycerides / Q000378:metabolism
chemical_list: D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011960:Receptors, Estrogen; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D004958:Estradiol; D010693:Phloretin