Estrogen-Wnt Signaling Cascade Regulates Expression of Hepatic Fibroblast Growth Factor 21

We have generated the transgenic mouse line in which dominant negative TCF7L2 (TCF7L2DN) is specifically expressed in the liver during adulthood. Male but not female mice showed elevated hepatic and plasma triglyceride (TG) levels, indicating the existence of estrogen-β-cat/TCF signaling cascade that regulates hepatic lipid homeostasis. We show here that hepatic fibroblast growth factor 21 (FGF21) expression was reduced in male but not in female mice. The reduction was not associated with altered hepatic expression of peroxisome proliferator-activated receptor α (PPARα). In mouse primary hepatocytes (MPH), Wnt-3a treatment increased FGF21 expression in the presence of PPARα inhibitor. Results from our luciferase-reporter assay and chromatin immunoprecipitation suggest that evolutionarily conserved TCF binding motifs (TCFBs) on promoter mediate Wnt-3a-induced transactivation. Female mice showed reduced hepatic FGF21 production and circulating FGF21 level following ovariectomy (OVX), associated with reduced hepatic TCF expression and β-catenin S675 phosphorylation. Finally, in MPH, estradiol (E2) treatment enhanced FGF21 expression, as well as binding of TCF7L2 and ribonucleic acid (RNA) polymerase II to the promoter; and the enhancement can be attenuated by the G-protein-coupled estrogen receptor 1 (GPER) antagonist G15. Our observations hence indicate that hepatic FGF21 is among the effectors of the newly recognized E2-β-cat/TCF signaling cascade. FGF21 is mainly produced in the liver. Therapeutic effect of FGF21 analogues has been demonstrated in clinical trials on reducing hyperlipidemia. We show here that transcription is positively regulated by Wnt pathway effector β-cat/TCF. Importantly, hepatic β-cat/TCF activity can be regulated by the female hormone estradiol, involving GPER. The investigation enriched our understanding on hepatic FGF21 hormone production, and expanded our view on metabolic functions of the Wnt pathway in the liver.