Fibroblast growth factor 21 (FGF21) is a hepatic hormone that mediates adaptive changes in cellular metabolism caused by nutritional stress and myocardial ischemia. FGF21 has also drawn attention as a promising new approach to treat metabolic syndrome, as pharmacological administration of FGF21 reverses or attenuates obesity, type 2 diabetes, hyperlipidemia, and atherosclerosis. A key factor that has limited the development of exogenous FGF21 as a drug to treat metabolic syndrome is its short half-life in the circulation. An alternative approach to treat metabolic syndrome is to develop drugs that induce a sustained increase in endogenous FGF21 production. This led us to screen for blood-borne factors that control FGF21 expression in the liver. We discovered that bile acids stimulated a robust increase in FGF21 gene transcription and FGF21 secretion and that this effect was mediated not only by the ligand activation of the nuclear bile acid receptor FXR, but also by an undefined mechanism independent of ligand activation of FXR. In addition, we discovered that both glucagon and insulin stimulated an increase in FGF21 secretion. Glucagon acted at a translational and/or posttranslational step to increase FGF21 secretion, whereas insulin acted at a pretranslational step to stimulate FGF21 secretion. Interestingly, glucagon interacted with insulin in a synergistic manner to stimulate a greater elevation in FGF21 mRNA abundance and FGF21 secretion relative to that observed for glucagon or insulin alone. The stimulatory effect of bile acids, insulin, and glucagon on FGF21 expression and secretion was supported by studies with intact mice lacking one or more components of the bile acid (i.e. FXR), insulin (i.e. IRS-1 and IRS-2), and glucagon (i.e. glucagon receptor) signaling pathway, respectively. The goal of this proposal is to elucidate the mechanisms by which novel transcriptional pathways (i.e. bile acids, insulin, and insulin plus glucagon) and posttranscriptional pathways (i.e. glucagon) increase hepatic FGF21 production. In Aim 1, we will characterize the transcriptional mechanism(s) mediating the stimulatory effect of bile acids, insulin, and insulin plus glucagon on FGF21 secretion. In Aim 2, we will characterize the posttranscriptional mechanism(s) mediating the stimulatory effect of glucagon on hepatic FGF21 secretion. Results from these studies will uncover new approaches to enhance endogenous FGF21 production and reverse metabolic syndrome.
|Effective start/end date||01/01/2017 → 12/31/2018|