Fibroblast growth factor 19 meets mammalian target of rapamycin: A mitogenic Tête‐à‐Tête under consideration
Authors: Elisabeth Krones, Martin Wagner
Journal: Hepatology (2016)

Potential conflict of interest: Nothing to report. See Article on Page 1289 Fibroblast growth factor 19 (FGF19) was initially identified as an enteric signaling molecule that was transcriptionally regulated by the bile acid receptor farnesoid X receptor and robustly suppressed cytochrome P450 7a1 (Cyp7a1), the rate‐limiting enzyme of bile acid synthesis in the liver. Subsequent studies revealed that FGF19 is more than just a brake on bile acid production.1 FGF19 acts as a circulating postprandial hormone that is released from the small intestine in response to luminal bile acids after a meal and peaks approximately 3 hours after food ingestion. Like insulin, which peaks earlier, FGF19 induces protein and glycogen synthesis and represses gluconeogenesis, thereby supporting the anabolic effects of insulin in a coordinated and temporal manner.2 The molecular pathways used by insulin and FGF19, however, differ. FGF19 acts through the Ras/extracellular signal‐regulated kinase (ERK) pathway (i.e., for protein and glycogen synthesis) and cyclic adenosine monophosphate response element‐binding protein/peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (i.e., for repression of gluconeogenesis), while insulin acts predominantly through phosphoinositide 3/Akt signaling pathways.1 The effects of FGF19 and insulin on lipid metabolism vary. Insulin promotes de novo lipogenesis through stimulation of the transcription factor sterol regulatory element binding protein 1c, which is a master regulator of lipogenesis. In contrast, FGF19 represses sterol regulatory element binding protein 1c and therefore reduces lipogenesis and triglyceride biosynthesis.1 The main target tissue of FGF19 action is the liver. FGF19 preferably binds to the FGF receptor 4 (FGFR4)/β‐klotho complex, which is highly expressed in the liver and determines its tissue selectivity and metabolic activity. Binding to FGFR4/β‐klotho activates ERK and other downstream kinases,1 which is particularly important for the repressive effects on bile acid synthesis as the effects are lost when FGFR4 or β‐klotho is eliminated or ERK is inhibited.1 However, effects on glucose homeostasis are maintained. This suggests that receptors other than FGFR4 (i.e., FGFR1c) and/or other tissues (i.e., white and brown adipose tissue and/or the hypothalamus) may also contribute to the beneficial metabolic effects of FGF19.4 The effects of FGF19 on bile acid and glucose metabolism along with its favorable lipogenic profile highlight this hormone as a potential pharmaceutical treatment option in cholestatic and metabolic liver diseases. Pharmacological administration or overexpression of FGF19 improves cholestasis in various cholestatic mouse models and is promising in human primary biliary cholangitis.1 In mouse models of the metabolic syndrome FGF19 reduces glucose, hepatic triglyceride and cholesterol levels, and insulin resistance, while it increases metabolic rate and energy expenditure.1 Many of these metabolic features also resemble the effects of FGF21, another endocrine member of the FGF family that signals through FGFR1c/β‐klotho but lacks the effects on bile acid metabolism.1 The favorable metabolic effects of FGF19, however, come at the price of a promitogenic and tumorigenic feature,1 which is shared by insulin but not by FGF21. As a postprandial signaling response, FGF19 promotes cell proliferation.6 The proliferative capacity of FGF19 is not fully elucidated but is linked to FGFR4 and involves ERK6 and signal transducer and activator of transcription 37 signaling. The overall importance of FGFR4 signaling for the tumorigenic FGF19 effects is supported by observations that FGFR4 deletion or the use of FGFR4 inhibiting antibodies has robust antitumoral effects in the liver.1 This promitogenic downside effect of FGF19 has led to the search for FGF19 mimetics, which maintain their beneficial metabolic effects but lack proliferative capacity. A particular feature of these FGF19 mimetics is the presence of amino acid changes in the N‐terminal region of FGF19 that specifically lead to FGFR4 interaction.6 These FGF19 mimetics lack FGFR4 activity along with low or abolished proliferative potency but exhibit FGFR1c/β‐klotho‐mediated effects on glucose and lipid metabolism.8 Notably, suppressive effects on bile acid metabolism are impaired in line with lost FGFR4 activation. Another promising engineered variant of FGF19, called FGF19‐M70 or NGM282, however, maintains its activity on FGFR4 and ERK signaling and therefore fully retains bile acid regulatory activity but does not promote tumor formation.7 The antitumorigenic effects of the M70 variant are attributed to a lack of signal transducer and activator of transcription 3 signaling. FGF19‐M70 is regarded as a selective modulator or "biased ligand" to activate the metabolic, but not the tumorigenic, signaling of FGFR47 and has therefore entered clinical trials for cholestatic disorders and type 2 diabetes.1 In this issue of hepatology, Wan and colleagues for the first time link endogenous FGF19 to mammalian target of rapamycin (mTOR) signaling,10 which is the central signaling hub to integrate nutritional inputs with anabolic responses and cell‐cycle progression. The authors nicely show that FGF19 robustly activates mTOR signaling in the presence of amino acids and that this mTOR activation is independent of FGF19‐ERK signaling but instead depends on Ral proteins. Although most effects were studied in human hepatoma cells, the authors also showed that FGF19 activates mTOR in normal mouse liver and adipocyte cell lines, the latter presumably expressing FGFR1c/β‐klotho. Importantly, the investigators reported that not only the proliferative effects of FGF19 but also some of the metabolic effects are mediated by mTOR. FGF19‐mediated changes in expression of genes involved in fatty acid oxidation (i.e., Cpt1α and Mcad), glucose metabolism (i.e., Hif1α and G6pase), and bile acid metabolism (i.e., Cyp7b1 Cyp8b1, but importantly not Cyp7a1) were prevented by inhibition of mTOR with rapamycin. Consequently, FGF19‐induced fatty acid oxidation was also reduced by rapamycin. This interesting study by Wan and colleagues demonstrates that mTOR is a novel and indispensable mediator of mitogenic and importantly metabolic FGF19 effects, which needs to be considered when FGF19 is induced or pharmacologically applied.10 What could FGF19‐mediated mTOR activation imply for FGF19 as a potential pharmacological compound? Due to the promitogenic effects of endogenous FGF19, only the FGF19‐M70/NGM282 variant is currently under clinical investigation in several phase 2 clinical trials for primary biliary cholangitis, primary sclerosing cholangitis, functional constipation, type 2 diabetes, and nonalcoholic liver disease (https://clinicaltrials.gov). None of the FGF19 mimetics has specifically been tested for effects on mTOR activation, but all compounds show less8 or absent9 hepatocyte proliferation in bromodeoxyuridine proliferation assays and lack of hepatic tumor formation after application of long‐term supraphysiological doses.7 Moreover, FGF19‐M70/NGM282 results in less P‐S6, which is the common end result of (both the ERK and) the mTOR pathway. This implies that FGF19‐M70/NGM282 may also have less activity on the mTOR pathway than its endogenous mother compound. In addition, for full activation of mTOR by FGF19, a steady amino acid supply, as it occurs postprandially but not constantly, has to be present.10 It would be interesting to learn whether FGF19 mimetics retain some mTOR activity and if the selective modulation of FGFR4 signaling by FGF19‐M70/NGM282 also refers to the reported mTOR‐dependent effects on lipid metabolism. Another intriguing question is whether FGF19‐mediated mTOR activation depends on a specific FGFR and β‐klotho as two of the engineered FGF19 mimetics do not stimulate FGFR4 and hepatocyte proliferation but retain effects on glucose metabolism through activity on FGFR1c/β‐klotho.8 Also, the mTOR contribution to bile acid metabolism in terms of bile acid pool size and composition remains to be determined. While the engineered variants of FGF19 lack mitogenic effects and maintain some of the metabolic FGF19 features, it remains open whether endogenous FGF19 induction by farnesoid X receptor ligands, which are also investigated as therapeutics in cholestasis and nonalcoholic fatty liver disease, shows long‐term proliferative effects. In mice, activation of farnesoid X receptor and subsequent FGF19 induction show promising effects on hepatocellular carcinoma due to normalization of bile acid metabolism,1 but trials assessing safety issues from chronic FGF19 stimulation in humans are avidly awaited.