Estrogen receptor ligands ameliorate fatty liver through a nonclassical estrogen receptor/Liver X receptor pathway in mice

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. Conclusion: 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. (Hepatology 2014;59:1791–1802)