FGF15/FGFR4 Integrates Growth Factor Signaling with Hepatic Bile Acid Metabolism and Insulin Action

Abstract

The current studies show FGF15 signaling decreases hepatic forkhead transcription factor 1 (FoxO1) activity through phosphatidylinositol (PI) 3-kinase-dependent phosphorylation. The bile acid receptor FXR (farnesoid X receptor) activates expression of fibroblast growth factor (FGF) 15 in the intestine, which acts through hepatic FGFR4 to suppress cholesterol-7␣ hydroxylase (CYP7A1) and limit bile acid production. Because FoxO1 activity and CYP7A1 gene expression are both increased by fasting, we hypothesized CYP7A1 might be a FoxO1 target gene. Consistent with recently reported results, we show CYP7A1 is a direct target of FoxO1. Additionally, we show that the PI 3-kinase pathway is key for both the induction of CYP7A1 by fasting and the suppression by FGF15. FGFR4 is the major hepatic FGF receptor isoform and is responsible for the hepatic effects of FGF15. We also show that expression of FGFR4 in liver was decreased by fasting, increased by insulin, and reduced by streptozotocin-induced diabetes, implicating FGFR4 as a primary target of insulin regulation. Because insulin and FGF both target the PI 3-kinase pathway, these observations suggest FoxO1 is a key node in the convergence of FGF and insulin signaling pathways and functions as a key integrator for the regulation of glucose and bile acid metabolism.Hepatic cholesterol is converted to bile acids, secreted into the gallbladder, and during a meal is released into the small intestine to enhance digestion and absorption of dietary lipids and fat-soluble vitamins. The majority of the bile acid pool (95%) is recycled back to the liver, whereas the remaining 5% is eliminated through fecal excretion (1, 2). This is an important route for the elimination of excess cholesterol and underscores the importance that bile acids play in regulating mammalian cholesterol metabolism. The initial and rate-controlling step in the classic pathway for cholesterol conversion into bile acids is catalyzed by cholesterol 7␣-hydroxylase (CYP7A1).2 CYP7A1 regulation is primarily transcriptional, and expression of its gene is dynamically regulated by hormones and metabolites (2-6). Importantly, bile acids themselves regulate CYP7A1 gene expression through a multicomponent negative feedback pathway. One of the molecular pathways for bile acid regulation is initiated by the activation of the farnesoid X receptor (FXR) responding directly to bile acid agonists (7). Ligand-activated FXR directly binds to a site in the promoter for the small heterodimer partner (SHP) gene and induces expression of SHP mRNA (8, 9). The translated SHP protein lacks the signature nuclear receptor zinc finger DNA binding domain but uses its conserved dimerization motif to form protein-protein contacts with DNA bound activators, usually other nuclear receptors, to inhibit or interfere with their activation potential (10, 11).The first identified target for SHP repression was the CYP7A1 promoter, and SHP was proposed to interfere with activation by the DNA-bound monomeric liver receptor homologue 1 (LRH-1) nucl...

FoxO transcription factors are required for hepatic HDL cholesterol clearance

“…The second mechanism involves the conversion of cholesterol into bile acids through a series of enzymatic reactions, in which Cyp7a1 encodes the rate-limiting enzyme (53,54). All 3 genes -Abcg5, Abcg8, and Cyp7a1 -are reportedly regulated by hepatic FoxO1 (55)(56)(57)(58). Moreover, we have previously reported that an additional enzyme involved in bile acid synthesis, Cyp8b1, is a FoxO1 target (10).…”

Insulin-dependent suppression of cholesterol 7α-hydroxlase is a possible link between glucose and cholesterol metabolisms

“…Feeding (physiological increase of insulin) decreased CYP7A1 mRNA by 90% compared to the fasting state in mice. The fasting induction of CYP7A1 was blunted in liver-specific FOXO1 knock-out mice (Shin and Osborne, 2009). In contrast, insulin at physiological concentrations showed dual effects on human CYP7A1 gene expression; a rapid stimulation of human CYP7A1 through FOXO1 inactivation and a late repression of CYP7A1 mediated by prolonged insulin exposure-induced SREBP-1c (Li et al, 2006).…”

Administration of Ampicillin Elevates Hepatic Primary Bile Acid Synthesis through Suppression of Ileal Fibroblast Growth Factor 15 Expression

“…FGF19 signaling is also involved in the regulation of glucose, lipid metabolism, and bile acid metabolism (Bhatnagar et al, 2009;Shin and Osborne, 2009). Administration of human FGF19 or transgenic expression of human FGF19 in mice enhanced energy expenditure and fatty acid oxidation and reduced hepatic, serum triglyceride, and glucose levels (Tomlinson et al, 2002;Fu et al, 2004).…”