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Abstract

  1. Top of page
  2. Abstract
  3. FGF15/19
  4. FGF21
  5. Acknowledgements
  6. References

Fibroblast growth factors (FGFs) 15/19 and 21 belong to the FGF endocrine subfamily. They present the intriguing characteristic to be transcribed and secreted in certain tissues and to act as hormones. The insulin-mimetic properties of FGF21 and the regulatory role of FGF15/19 in bile acid and glucose homeostasis endorse these hormones as druggable targets in metabolic disorders. Here, we present details on discoveries, identification, transcriptional regulation, and mechanism of actions of FGF15/19 and FGF21 with a critical perspective view on their putative role as metabolic integrators in the liver. (HEPATOLOGY 2012;56:2404–2411)

The fibroblast growth factors (FGFs) family comprises 22 members classified, by gene-locus analyses and mechanisms of action, into seven subfamilies and recognized as crucial modulators of cell proliferation, differentiation, embryonic development, and organogenesis1, 2 (Fig. 1). Eighteen members are secreted proteins, whereas four FGFs are intracellular signaling proteins. Most of the 18 secreted FGFs bind and activate cell-surface tyrosine kinase FGF receptors (FGFRs) by a high-affinity interaction with heparan sulfate glycosaminoglycans (HSGAGs). Unlike the canonic FGFs that act as autocrine and paracrine factors, three members, namely, FGF15, FGF19, and FGF23 (also known as the FGF19 subfamily), display extremely low affinity to HSGAGs, thus functioning as endocrine hormones and exerting metabolic actions distant from the tissues from which they are secreted. FGF19 subfamily members require single-pass transmembrane glycoproteins, named klotho proteins (α-klotho and β-klotho), to bind FGFRs and activate FGF-signaling pathways. Recently, the FGF19 subfamily has received great attention because its members coordinately govern bile acid (BA) and glucose metabolism and modulate vitamin D and phosphate homeostasis.3, 4 In this review, we focus on the metabolic activities of FGF15/19 and 21, placing emphasis on the liver as a major target tissue.

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Figure 1. Members of the FGF gene family and their evolutionary relationship. The 22 members could be divided into seven subfamilies. Four FGFs act as intracellular signaling proteins. Fifteen FGFs are secreted proteins acting through autocrine/paracrine mechanisms. Three FGFs form an endocrine subfamily that regulates different metabolic pathways through a hormone-like mode of action.

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FGF15/19

  1. Top of page
  2. Abstract
  3. FGF15/19
  4. FGF21
  5. Acknowledgements
  6. References

Identification.

Initially described as a direct target of the chimeric oncoprotein, E2A-PBX1, in the brain,5 FGF15 has been the first FGF19 subfamily member to be identified. Although the FGF15 gene shares only 51% amino-acid identity with its human ortholog, FGF19,6, 7 FGF15 and FGF19 messenger RNA (mRNA) expression patterns are similar (mostly small intestine, fetal cartilage, skin, retina, and gallbladder)8, 9 and, as ileum-derived postprandial hormones, govern similarly both BA and glucose metabolism.10

Expression Regulation and Mechanism of Action.

Earlier studies in primary human hepatocytes underscored the pivotal role of the nuclear receptor, farnesoid X receptor (FXR; NR1H4), and its endogenous ligands (BAs) in the transcriptional regulation of FGF19. Holt et al. showed, in human cells treated with FXR agonist or chenodeoxycholic acid, that the FGF19 gene contains a functional FXRE within the second intron.11 Subsequently, through the use of electrophoretic mobility shift assay and cell-based reporter assays, it has been shown that FXR binds to an IR1 motif in the mouse ortholog, Fgf15, as a retinoid X receptor (NR2B1) heterodimer and directly regulates the FGF15 promoter12 (Fig. 2). In addition to BA and FXR, the regulation of FGF15/19 gene expression is also under the control of pregnane X receptor (NR1I2), but only in colon cancer cells.13 Once transcribed, FGF15/19 protein is secreted into the portal circulation and reaches the liver, where it acts on the FGFR4/β-klotho receptor complex.14-16 Studies employing chimera of FGF19 protein have revealed that the C-terminus region is responsible for the binding to β-klotho, whereas the N-terminus seems important for FGFR activation.17 The endocrine hormone, FGF15/19, controls hepatic metabolism in response to nutritional status by inhibition of BA and glucose synthesis and stimulation of protein and glycogen synthesis.10 Recent studies have revealed the FGF15/19 mechanism of action in the liver by identifying the extracellular signal-related kinase (ERK)1/2/mitogen-activated protein kinase (MAPK) pathway as a mediator of FGF15/19 inhibitory effect on BA synthesis,18 the RAS/ERK/p90 ribosomal S6 kinase pathway as crucial for the FGF15/19 ability to increase protein and glycogen synthesis,19 and the dephosphorylation and inactivation of cyclic adenosine monophosphate cyclic adenosine monophosphate regulatory element binding protein (CREB) as the driving force to down-regulate gluconeogenesis.20

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Figure 2. Transcriptional regulation of FGF15/19 and FGF21 genes. In enterocytes, FGF15/19 expression is induced by the BA-dependent activation of FXR. Hepatic FGF21 mRNA levels are induced by KD, fasting, nonesterified FA (NEFA), fenofibrate, and RORα activation while being down-regulated by PGC-1α via Rev-Erbα. In adipocytes, SIRT1 inhibition, PPARγ agonists, and feeding induce FGF21 gene expression.

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In Vivo Metabolic Effects.

A tissue must express both β-klotho and FGFR4 to be a target of FGF19, and klotho dependency determines the tissue specificity of endocrine FGFs. The highest levels of β-klotho and FGFR4 are measured in the liver, which represents the main target organ of FGF15/19 action.9

Gain- and loss-of-function studies underscored the physiological relevance of FGF15/19 in BA metabolism. BAs are anionic detergents that are synthesized in the liver from cholesterol, stored in the gallbladder, and released in the small intestine upon feeding. They allow the digestion and absorption of fatty acids (FAs), cholesterol, and lipophilic vitamins. Most BAs (95%) are reabsorbed in the ileum and return to the liver through the portal vein. FGF19 regulates BA homeostasis by repression of cholesterol-7α-hydroxylase (CYP7A1),11 the rate-limiting enzyme in the classical pathway of BA synthesis. A gain-of-function study conducted in mice showed that BA or FXR-agonist administration induces FGF15 transcription and activates the FGF15/FGFR4 pathway, thus inhibiting CYP7A1. Of note, the FGF15/FGFR4-signaling pathway synergizes with the small heterodimer partner (NR0B2) in vivo to repress CYP7A1 expression through the involvement of the Jun N-terminal kinase–dependent pathway.12 Animal models harboring deletions on the FGF15-signaling axis provided further evidence for the pivotal role of FGF15/19 in preserving BA homeostasis. FGF15−/−, FGFR4−/−, and β-klotho−/− mice showed increased CYP7A1 expression and enlarged BA pool size.12, 21, 22 Moreover, FGF15/19 is involved in BA homeostasis by its action on gallbladder emptying and refilling.23 FGFR4−/− and FGF15−/− mice have reduced gallbladder volume that can be restored by FGF19 administration. A well-known inducer of gallbladder emptying is cholecystokinin (CCK), and FGF15/19 administration is able to oppose CCK action directly by relaxing gallbladder smooth muscle and inducing gallbladder refilling.23 This finding suggests that when luminal BAs, which increase postprandially, reach the ileum, they induce FGF15/19 to initiate gallbladder relaxation and refilling.

Studies in transgenic (Tg) mice expressing FGF19 in muscle24 and in FGF19-treated mice25 uncovered FGF15/19′s role in governing lipid and glucose metabolism under fed and fasted states. In mice, FGF19 activation resulted in decreased liver fat content, triglycerides (TGs), total cholesterol, and plasma glucose levels and, by increased energy expenditure, FA oxidation, brown tissue mass, and insulin sensitivity. In addition, FGF19 Tg mice were protected from high-fat-diet–induced obesity. In the liver (Fig. 3), FGF19 down-regulates acetyl coenzyme A (CoA) carboxylase 2, a repressor of FA oxidation, and stearoyl CoA desaturase 1, a lipogenic enzyme.25 Interestingly, FGF-19 is also able to suppress insulin-induced stimulation of FA synthesis through repression of sterol regulatory element-binding protein-1c (SREBP-1c), a key transcriptional activator of lipogenic genes, along with an increased activity of signal transducer and activator of transcription 3 and a decreased expression of peroxisome proliferator-activated receptor-γ (PPARγ) coactivator-1β (PGC-1β), an activator of SREBP-1c activity.26

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Figure 3. Metabolic effects of FGF15/19 and FGF21 in the liver. FGF15/19, by binding to the FGFR4/β-klotho complex, reduces BA and glucose synthesis and lowers TG levels while inducing FA oxidation and glycogen and protein synthesis. FGF21, by binding to the FGFR1c/β-klotho complex, stimulates gluconeogenesis, FA oxidation, and ketogenesis and increases GH resistance.

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After a meal, FGF19 works in a coordinated temporal fashion with another postprandial hormone, namely insulin, to promote glycogen synthesis and inhibit gluconeogenesis, although by distinct signaling pathways and upon different timing of their postprandial release. Serum FGF19 levels peak approximately 3 hours after a meal27 and increase glycogen synthesis by activation of the Ras/ERK pathway; in contrast, serum insulin levels peak within 1 hour after a meal and stimulate glycogen synthesis by the phosphoinositide 3-kinase/protein kinase B (Akt) pathway.28 To date, gluconeogenesis inhibition is also differently mediated by FGF19 and insulin by dephosphorylation and inactivation of CREB and Akt-dependent phosphorylation and FoxO1 degradation, respectively29 (Fig. 4).

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Figure 4. FGFs and insulin and glucagon-driven signaling pathways control hepatic gluconeogenesis. In a fed state, FGF15/19 cooperates with insulin in inhibiting gluconeogenesis, whereas upon prolonged fasting/starvation, FGF21 partners with glucagon in promoting glucose synthesis. Signaling pathways underlying gluconeogenesis modulation are depicted, along with hormone timing of release after a meal or a fast and half-lives.

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Relevance to Human Disease and Therapeutic Potential.

The physiological relevance of the enterohepatic BA/FXR/FGF19 axis has been recently highlighted in humans, thus implicating the pharmacological modulation of this axis in the context of BA- and glucose-related metabolic disorders.

In healthy individuals, serum FGF19 levels peak after the postprandial rise in serum BA levels and are followed by a declining phase of BA synthesis,27 thus underlying the reciprocal interaction between FGF19 and BA levels; accordingly, abnormalities in BA metabolism are expected to be associated with changes in FGF19 expression and function. Patients with extrahepatic cholestasis show elevated FGF19 plasma level and mRNA expression that can be lowered in response to a restoration of healthy bile flux by biliary stent.30 A reduction in liver response to elevated plasma FGF19 levels was observed in patients with insulin resistance and nonalcoholic fatty liver disease (NAFLD).31 A reduced FGF19 production, along with increased BA synthesis and diarrhea, were reported in patients with primary BA malabsorption,32 where FGF19 or FXR-agonist administration could prove to be beneficial.33 Finally, reduced FGF19 and elevated serum BA levels were also reported in inflammatory bowel disease patients with resection of the distal ileum.34 Collectively, these findings suggest that modulating FGF19 levels could offer benefits in a plethora of BA-related metabolic disorders. To this end, a recent study showed that induction of FGF15 expression by intestinal FXR overexpression protected against cholestasis, along with reduction of BA pool size (secondary to CYP7A1 repression).35

FGF19′s ability to lower liver fat content, triglycerides (TGs), total cholesterol, and plasma glucose levels and to improve insulin sensitivity while avoiding the prolipogenic properties of insulin makes this postprandial hormone a promising therapeutic agent for the treatment of metabolic syndrome and type 1 and 2 diabetes. However, the observation that FGF19 Tg mice developed hepatocellular carcinomas (HCCs) within 12 months of age and displayed nuclear accumulation of β-catenin has cast doubt on the safety and effectiveness of a chronic administration of this hormone.36 Moreover, in HCC patients, FGF19 expression is up-regulated and correlates with poor prognosis, thus indicating that FGF19 inhibition could offer protection against tumor progression.37 Accordingly, a recent study highlighted a cross-talk between FGF19/FGFR4 and β-catenin, thus suggesting that inactivation of FGF19 and/or FGFR4 could rescue cells from a deregulated β-catenin signaling.38 Strategies aimed at limiting FGF19-mediated hepatocyte proliferation while preserving its potent effects on normalizing glucose, lipid, and energy homeostasis are urgently needed. In this respect, the removal of the N-terminal segment, responsible for FGFR4 binding, appears to maintain only the beneficial pharmacological activity of FGF19.39, 40 Finally, Ge et al. recently reported the generation of a FGF19 variant (FGF19-7) that is equally effective as wild-type FGF19 in regulating glucose and lipid metabolism, but does not induce hepatocyte proliferation; the absence of tumor-promoting effects has been ascribed to the bias toward β-klotho/FGFR1c receptor complex and to the inability to activate FGFR4.41

FGF21

  1. Top of page
  2. Abstract
  3. FGF15/19
  4. FGF21
  5. Acknowledgements
  6. References

Identification.

First identified in mouse embryos by homology-based polymerase chain reaction, FGF21 is a secreted protein of 210 amino acids with a hydrophobic N-terminus signal sequence.42 The amino-acid sequence of mouse FGF21 is highly identical to the human FGF21. Initially, FGF21 mRNA was reported to be expressed in the liver and at lower levels in the thymus.42 Recently, FGF21 was also found to be highly expressed in pancreas, testis, and at lower levels in duodenum and adipose tissue.9

Expression Regulation and Mechanism of Action.

An intricate network encompassing nuclear receptors, nutritional stimuli, and hormones participates in the tissue-specific transcriptional regulation of the FGF21 gene, thus influencing its crucial role in the adaptive response to starvation and preservation of whole-body energy homeostasis. Earlier studies from Badman and Inagaki highlighted the pivotal role of nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα; NR1C1), thus identifying FGF21 as a mediator of PPARα pleiotropic actions in the liver43, 44 (Fig. 2). Studies in both primary hepatocytes treated with PPARα agonists and in mice fasted or fed with ketogenic diet (KD) provided clear evidence that PPARα induces FGF21 transcription by binding to PPARα recognition sites on the FGF21 gene promoter; accordingly, PPARα knockout (KO) animals fail to induce FGF21 gene transcription. More recent gain- and loss-of-function studies in primary hepatocytes have revealed that hepatic FGF21 transcription is also regulated by PGC-1α (by Rev-Erbα [NR1D1]) and by the retinoid acid receptor-related orphan receptor alpha (RORα; NR1F1).45, 46 Moreover, the hepatic FGF21 gene is also induced by high-carbohydrate diets by activation of carbohydrate response element-binding protein.47 White adipose tissue (WAT) is an important FGF21 target organ, and studies in vitro and in vivo underscored the role of nuclear receptor PPARγ (NR1C3), transcription factor sirtuin 1 (SIRT1), and fast/refeeding regimens in the transcriptional regulation of the FGF21 gene in WAT.48-51 Of note, FGF21 transcription is induced by insulin in skeletal muscle and by cold exposure in brown adipose tissue.10 Although FGF21 shares with FGF15/19 the need of β-klotho and FGFR (mostly FGFR1c isoform) to exert its metabolic actions,52 FGF21 differs from FGF15/19 in the ability to act in an endocrine fashion in the liver, whereas it functions in an autocrine manner in the WAT.10 Finally, studies in mice treated with thiazolidinedione (TDZ) or fasted revealed that, in the liver, FGF21 binds FGFR1c and stimulates FGF receptor substrate (FRS)2α and 2β phosphorylation and ERK1/2, whereas in WAT, FRS1 phosphorylation is followed by a transient activation of MAPK.3, 16

In Vivo Metabolic Effects.

The first evidence of the metabolic activities of FGF21 was provided by a high-throughput screening of molecules able to stimulate glucose uptake in cultured adipocytes; FGF21 protein was found to stimulate glucose uptake in an insulin-independent manner and by induction of glucose transporter 1 mRNA and protein levels.3 The physiological relevance of this finding was confirmed by studies employing the administration of recombinant FGF21 protein in mice and nonhuman primates.3, 53 FGF21 gain of function resulted in reduced plasma glucose, TG, and insulin levels, improved insulin sensitivity, and resistance to diet-induced obesity and dyslipidemia. Later studies have revealed that FGF21 and PPARγ cooperate in promoting adipocyte glucose transport and differentiation, thus suggesting the existence of a functional relationship between FGF21 and PPARγ activation.54 A recent contribution from the Mangelsdorf/Kliewer laboratory identified FGF21 as a key mediator of the physiologic and pharmacological actions of PPARγ in adipocytes; of note, FGF21, induced by feeding and TDZ administration, functions to potentiate TDZ effects on adipocyte differentiation and gene expression.51 Conversely, FGF21 loss of function is associated with impaired PPARγ signaling, decreased fat mass, and resistance to TDZ insulin-sensitizing properties. It is interesting to note that FGF21 gene transcription is induced by feeding in WAT, whereas it is induced by fasting in the liver. This differential regulation is relevant from a physiological point of view and can be a target of pharmacological manipulation in the context of type 2 diabetes, obesity, and metabolic syndrome. The liver is the primary source of circulating FGF21 levels, and the integrated regulation of its metabolism by FGF21 has been recently documented in response to fasting and KD consumption.55 FGF21 induces gluconeogenesis by increase in glucose-6-phosphate and phosphoenol-pyruvate carbokinase, ketogenesis, and FA oxidation.56 The physiological relevance of the critical role of FGF21 for energy balance both at basal condition and upon KD feeding has been underscored in FGF21 KO animals.57-59 FGF21-deficient mice tolerate short fasting and are refractory to starvation while displaying marked impaired ketogenesis, hepatosteatosis, disrupted glucose control, and weight gain when placed on KD. Moreover, FGF21-deficient mice exhibited increased maturation of the lipogenic transcription factor, SREBP1c, without changes in SREBP1 mRNA and protein levels.60 Of note, FGF21 metabolic actions include growth hormone (GH) resistance61 and induction of torpor, as elegantly reviewed by Potthoff et al.10 It is worth noting that FGF21, although exerting insulin-like properties in WAT, functions similarly to glucagon in the liver. However, unlike glucagon, FGF21 does not promote glycogenolysis56 (Fig. 4).

Overall, FGF21 acts as an endocrine hormone in the liver to govern and coordinate the adaptive response during starvation, though functioning as an autocrine fed-state factor in the WAT, to regulate adipocyte function and gene expression.

Relevance to Human Disease and Therapeutic Potential.

FGF21 ability to govern glucose and lipid metabolism in partnership with the major controllers of energy homeostasis (insulin and glucagon) and to elicit beneficial effects in response to nutritional stress (including starvation) in a tissue-specific manner makes this atypical FGF an attractive therapeutic target. Moreover, unlike FGF15/19, FGF21 does not exert mitogenic effects.3 In humans, circulating FGF21 levels rise at midnight, reach a peak in the early morning, and then decline to basal concentrations early in the afternoon.62 This circadian rhythm is suggested to be controlled, in part, by circulating free FAs, whose peak precedes, by 3-4 hours, the one of FGF21.63 Circulating FGF21 levels were found increased upon prolonged fasting in healthy subjects and upon PPARα agonist treatment in both type 2 diabetes and obese patients.64-66 Moreover, serum FGF21 levels were found to be increased in NAFLD patients.67 It is worth mentioning that, unlike in rodents, neither short-term fasting nor KD feeding stimulate FGF21 in humans, and FGF21 transcription is not always detected in human WAT.65, 67 Although the broad-based metabolic benefits in rodent models make FGF21 a promising antidiabetic agent, increasing evidence stemming from in vivo studies calls into question the safety and feasibility of chronic FGF21 administration. First, the pharmacology and physiology of FGF21 are somewhat discordant, with a clear dichotomy between the effects of the endogenous peptide and the recombinant proteins. Second, high doses of FGF21 protein cause hypoglycemia. Third, FGF21 overexpression has been recently associated with bone loss, thus raising concerns for FGF21 use in diabetic patients who already exhibit increased skeletal fragility.68 In addition, FGF21 has a very short half-life, which may forestall its introduction in the clinic, although FGF21 analogs, recently developed by using PEGylation procedures to prolong the duration of action, were shown to provide beneficial effects as the native protein.69 Given the high variability in the interindividual FGF21 levels in humans and not-yet conclusive evidence for a beneficial role of FGF21 manipulation in the context of human diseases, further human studies are urgently needed.

In conclusion, FGF15/19 and FGF21 are hormones that, after being secreted by certain tissues, are able to direct their metabolic actions in various districts of our body. The liver is definitively a major target tissue for both hormones. FGF15/19 and FGF21 actions are mainly prometabolic and antiobesity. They both regulate antilipogenic pathways with positive inputs, in terms of energy expenditure and control of glucose homeostasis. Indeed, the insulin-mimetic properties of FGF21 and the regulatory role of FGF15/19 in BA and glucose homeostasis endorse these hormones as druggable targets in metabolic disorders.

Acknowledgements

  1. Top of page
  2. Abstract
  3. FGF15/19
  4. FGF21
  5. Acknowledgements
  6. References

The authors are grateful to R. Le Donne for art work. The authors apologize to our distinguished colleagues whose work was not cited owing to format limitations.

References

  1. Top of page
  2. Abstract
  3. FGF15/19
  4. FGF21
  5. Acknowledgements
  6. References
  • 1
    Itoh N, Ornitz DM. Evolution of the Fgf and Fgfr gene families. Trends Genet 2004; 20: 563-569.
  • 2
    Beenken A, Mohammadi M. The FGF family: biology, pathophysiology, and therapy. Nat Rev Drug Discov 2009; 8: 235-253.
  • 3
    Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, et al. FGF-21 as a novel metabolic regulator. J Clin Invest 2005; 115: 1627-1635.
  • 4
    Wöhrle S, Bonny O, Beluch N, Gaulis S, Stamm C, Scheibler M, et al. FGF receptors control vitamin D and phosphate homeostasis by mediating renal FGF23 signaling and regulating FGF23 expression in bone. J Bone Miner Res 2011; 26: 2486-2497.
  • 5
    McWhirter JR, Goulding M, Weiner JA, Chun J, Murre C. A novel fibroblast growth factor gene expressed in the developing nervous system is a downstream target of the chimeric homeodomain oncoprotein E2A-Pbx1. Development 1997; 124: 3221-3232.
  • 6
    Nishimura T, Utsunomiya Y, Hoshikawa M, Ohuchi H, Itoh N. Structure and expression of a novel human FGF, FGF-19, expressed in the fetal brain. Biochim Biophys Acta 1999; 1444: 148-151.
  • 7
    Wright TJ, Ladher R, McWhirter J, Murre C, Schoenwolf GC, Mansour SL. Mouse FGF15 is the ortholog of human and chick FGF19, but is not uniquely required for otic induction. Dev Biol 2004; 269: 264-275.
  • 8
    Xie MH, Holcomb I, Deuel B, Dowd P, Huang A, Vagts A, et al. FGF-19, a novel fibroblast growth factor with unique specificity for FGFR4. Cytokine 1999; 11: 729-735.
  • 9
    Fon Tacer K, Bookout AL, Ding X, Kurosu H, John GB, Wang L, et al. Research resource: comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol Endocrinol 2010; 24: 2050-2064.
  • 10
    Potthoff MJ, Kliewer SA, Mangelsdorf DJ. Endocrine fibroblast growth factors 15/19 and 21: from feast to famine. Genes Dev 2012; 26: 312-324.
  • 11
    Holt JA, Luo G, Billin AN, Bisi J, McNeill YY, Kozarsky KF, et al. Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev 2003; 17: 1581-1591.
  • 12
    Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG, et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2005; 2: 217-225.
  • 13
    Wang H, Venkatesh M, Li H, Goetz R, Mukherjee S, Biswas A, et al. Pregnane X receptor activation induces FGF19-dependent tumor aggressiveness in humans and mice. J Clin Invest 2011; 121: 3220-3232.
  • 14
    Lin BC, Wang M, Blackmore C, Desnoyers LR. Liver-specific activities of FGF19 require Klotho beta. J Biol Chem 2007; 282: 27277-27284.
  • 15
    Wu X, Ge H, Gupte J, Weiszmann J, Shimamoto G, Stevens J, et al. Co-receptor requirements for fibroblast growth factor-19 signaling. J Biol Chem 2007; 282: 29069-29072.
  • 16
    Kurosu H, Choi M, Ogawa Y, Dickson AS, Goetz R, Eliseenkova AV, et al. Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J Biol Chem 2007; 282: 26687-26695.
  • 17
    Wu X, Lemon B, Li X, Gupte J, Weiszmann J, Stevens J, et al. C-terminal tail of FGF19 determines its specificity toward Klotho co-receptors. J Biol Chem 2008; 283: 33304-33309.
  • 18
    Song KH, Li T, Owsley E, Strom S, Chiang JY. Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7alpha-hydroxylase gene expression. HEPATOLOGY 2009; 49: 297-305.
  • 19
    Kir S, Beddow SA, Samuel VT, Miller P, Previs SF, Suino-Powell K, et al. FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis. Science 2011; 331: 1621-1624.
  • 20
    Potthoff MJ, Boney-Montoya J, Choi M, He T, Sunny NE, Satapati S, et al. FGF15/19 regulates hepatic glucose metabolism by inhibiting the CREB-PGC-1alpha pathway. Cell Metab 2011; 13: 729-738.
  • 21
    Yu C, Wang F, Kan M, Jin C, Jones RB, Weinstein M, et al. Elevated cholesterol metabolism and bile acid synthesis in mice lacking membrane tyrosine kinase receptor FGFR4. J Biol Chem 2000; 275: 15482-15489.
  • 22
    Ito S, Fujimori T, Furuya A, Satoh J, Nabeshima Y, Nabeshima Y. Impaired negative feedback suppression of bile acid synthesis in mice lacking betaKlotho. J Clin Invest 2005; 115: 2202-2208.
  • 23
    Choi M, Moschetta A, Bookout AL, Peng L, Umetani M, Holmstrom SR, et al. Identification of a hormonal basis for gallbladder filling. Nat Med 2006; 12: 1253-1255.
  • 24
    Tomlinson E, Fu L, John L, Hultgren B, Huang X, Renz M, et al. Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology 2002; 143: 1741-1747.
  • 25
    Fu L, John LM, Adams SH, Yu XX, Tomlinson E, Renz M, et al. Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. Endocrinology 2004; 145: 2594-2603.
  • 26
    Bhatnagar S, Damron HA, Hillgartner FB. Fibroblast growth factor-19, a novel factor that inhibits hepatic fatty acid synthesis. J Biol Chem 2009; 284: 10023-10033.
  • 27
    Lundasen T, Galman C, Angelin B, Rudling M. Circulating intestinal fibroblast growth factor 19 has a pronounced diurnal variation and modulates hepatic bile acid synthesis in man. J Intern Med 2006; 260: 530-536.
  • 28
    Kir S, Kliewer SA, Mangelsdorf DJ. Roles of FGF19 in liver metabolism. Cold Spring Harb Symp Quant Biol 2011; 76: 130-144.
  • 29
    Shin DJ, Osborne TF. FGF15/FGFR4 integrates growth factor signaling with hepatic bile acid metabolism and insulin action. J Biol Chem 2009; 284: 11110-11120.
  • 30
    Schaap FG, van der Gaag NA, Gouma DJ, Jansen PL. High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis. HEPATOLOGY 2009; 49: 1228-1235.
  • 31
    Schreuder TC, Marsman HA, Lenicek M, van Werven JR, Nederveen AJ, Jansen PL, et al. The hepatic response to FGF19 is impaired in patients with nonalcoholic fatty liver disease and insulin resistance. Am J Physiol Gastrointest Liver Physiol 2010; 298: G440-G445.
  • 32
    Walters JR, Tasleem AM, Omer OS, Brydon WG, Dew T, le Roux CW. A new mechanism for bile acid diarrhea: defective feedback inhibition of bile acid biosynthesis. Clin Gastroenterol Hepatol 2009; 7: 1189-1194.
  • 33
    Jung D, Inagaki T, Gerard RD, Dawson PA, Kliewer SA, Mangelsdorf DJ, et al. FXR agonists and FGF15 reduce fecal bile acid excretion in a mouse model of bile acid malabsorption. J Lipid Res 2007; 48: 2693-2700.
  • 34
    Lenicek M, Duricova D, Komarek V, Gabrysova B, Lukas M, Smerhovsky Z, et al. Bile acid malabsorption in inflammatory bowel disease: assessment by serum markers. Inflamm Bowel Dis 2011; 17: 1322-1327.
  • 35
    Modica S, Petruzzelli M, Bellafante E, Murzilli S, Salvatore L, Celli N, et al. Selective activation of nuclear bile acid receptor FXR in the intestine protects mice against cholestasis. Gastroenterology 2011; 142: 355-365.e1-e4.
  • 36
    Nicholes K, Guillet S, Tomlinson E, Hillan K, Wright B, Frantz GD, et al. A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. Am J Pathol 2002; 160: 2295-2307.
  • 37
    Miura S, Mitsuhashi N, Shimizu H, Kimura F, Yoshidome H, Otsuka M, et al. Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma. BMC Cancer 2012; 12: 56.
  • 38
    Pai R, Dunlap D, Qing J, Mohtashemi I, Hotzel K, French DM. Inhibition of fibroblast growth factor 19 reduces tumor growth by modulating beta-catenin signaling. Cancer Res 2008; 68: 5086-5095.
  • 39
    Wu AL, Coulter S, Liddle C, Wong A, Eastham-Anderson J, French DM, et al. FGF19 regulates cell proliferation, glucose and bile acid metabolism via FGFR4-dependent and independent pathways. PLoS One 2011; 6: e17868.
  • 40
    Wu X, Ge H, Lemon B, Vonderfecht S, Baribault H, Weiszmann J, et al. Separating mitogenic and metabolic activities of fibroblast growth factor 19 (FGF19). Proc Natl Acad Sci U S A 2010; 107: 14158-14163.
  • 41
    Ge H, Baribault H, Vonderfecht S, Lemon B, Weiszmann J, Gardner J, et al. Characterization of a FGF19 variant with altered receptor specificity revealed a central role for FGFR1c in the regulation of glucose metabolism. PLoS One 2012; 7: e33603.
  • 42
    Nishimura T, Nakatake Y, Konishi M, Itoh N. Identification of a novel FGF, FGF-21, preferentially expressed in the liver. Biochim Biophys Acta 2000; 1492: 203-206.
  • 43
    Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, et al. Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. Cell Metab 2007; 5: 415-425.
  • 44
    Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab 2007; 5: 426-437.
  • 45
    Estall JL, Ruas JL, Choi CS, Laznik D, Badman M, Maratos-Flier E, et al. PGC-1alpha negatively regulates hepatic FGF21 expression by modulating the heme/Rev-Erb(alpha) axis. Proc Natl Acad Sci U S A 2009; 106: 22510-22515.
  • 46
    Wang Y, Solt LA, Burris TP. Regulation of FGF21 expression and secretion by retinoic acid receptor-related orphan receptor alpha. J Biol Chem 2010; 285: 15668-15673.
  • 47
    Iizuka K, Takeda J, Horikawa Y. Glucose induces FGF21 mRNA expression through ChREBP activation in rat hepatocytes. FEBS Lett 2009; 583: 2882-2886.
  • 48
    Muise ES, Azzolina B, Kuo DW, El-Sherbeini M, Tan Y, Yuan X, et al. Adipose fibroblast growth factor 21 is up-regulated by peroxisome proliferator-activated receptor gamma and altered metabolic states. Mol Pharmacol 2008; 74: 403-412.
  • 49
    Wang H, Qiang L, Farmer SR. Identification of a domain within peroxisome proliferator-activated receptor gamma regulating expression of a group of genes containing fibroblast growth factor 21 that are selectively repressed by SIRT1 in adipocytes. Mol Cell Biol 2008; 28: 188-200.
  • 50
    Oishi K, Konishi M, Murata Y, Itoh N. Time-imposed daily restricted feeding induces rhythmic expression of Fgf21 in white adipose tissue of mice. Biochem Biophys Res Commun 2011; 412: 396-400.
  • 51
    Dutchak PA, Katafuchi T, Bookout AL, Choi JH, Yu RT, Mangelsdorf DJ, et al. Fibroblast growth factor-21 regulates PPARgamma activity and the antidiabetic actions of thiazolidinediones. Cell 2012; 148: 556-567.
  • 52
    Suzuki M, Uehara Y, Motomura-Matsuzaka K, Oki J, Koyama Y, Kimura M, et al. betaKlotho is required for fibroblast growth factor (FGF) 21 signaling through FGF receptor (FGFR) 1c and FGFR3c. Mol Endocrinol 2008; 22: 1006-1014.
  • 53
    Kharitonenkov A, Wroblewski VJ, Koester A, Chen YF, Clutinger CK, Tigno XT, et al. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology 2007; 148: 774-781.
  • 54
    Moyers JS, Shiyanova TL, Mehrbod F, Dunbar JD, Noblitt TW, Otto KA, et al. Molecular determinants of FGF-21 activity-synergy and cross-talk with PPARgamma signaling. J Cell Physiol 2007; 210: 1-6.
  • 55
    Fisher FM, Estall JL, Adams AC, Antonellis PJ, Bina HA, Flier JS, et al. Integrated regulation of hepatic metabolism by fibroblast growth factor 21 (FGF21) in vivo. Endocrinology 2011; 152: 2996-3004.
  • 56
    Potthoff MJ, Inagaki T, Satapati S, Ding X, He T, Goetz R, et al. FGF21 induces PGC-1alpha and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proc Natl Acad Sci U S A 2009; 106: 10853-10858.
  • 57
    Hotta Y, Nakamura H, Konishi M, Murata Y, Takagi H, Matsumura S, et al. Fibroblast growth factor 21 regulates lipolysis in white adipose tissue but is not required for ketogenesis and triglyceride clearance in liver. Endocrinology 2009; 150: 4625-4633.
  • 58
    Badman MK, Koester A, Flier JS, Kharitonenkov A, Maratos-Flier E. Fibroblast growth factor 21-deficient mice demonstrate impaired adaptation to ketosis. Endocrinology 2009; 150: 4931-4940.
  • 59
    Coskun T, Bina HA, Schneider MA, Dunbar JD, Hu CC, Chen Y, et al. Fibroblast growth factor 21 corrects obesity in mice. Endocrinology 2008; 149: 6018-6027.
  • 60
    Zhang Y, Lei T, Huang JF, Wang SB, Zhou LL, Yang ZQ, et al. The link between fibroblast growth factor 21 and sterol regulatory element binding protein 1c during lipogenesis in hepatocytes. Mol Cell Endocrinol 2011; 342: 41-47.
  • 61
    Inagaki T, Lin VY, Goetz R, Mohammadi M, Mangelsdorf DJ, Kliewer SA. Inhibition of growth hormone signaling by the fasting-induced hormone FGF21. Cell Metab 2008; 8: 77-83.
  • 62
    Andersen B, Beck-Nielsen H, Hojlund K. Plasma FGF21 displays a circadian rhythm during a 72 hour fast in healthy female volunteers. Clin Endocrinol (Oxf) 2011; 75: 514-519.
  • 63
    Yu H, Xia F, Lam KS, Wang Y, Bao Y, Zhang J, et al. Circadian rhythm of circulating fibroblast growth factor 21 is related to diurnal changes in fatty acids in humans. Clin Chem 2011; 57: 691-700.
  • 64
    Christodoulides C, Dyson P, Sprecher D, Tsintzas K, Karpe F. Circulating fibroblast growth factor 21 is induced by peroxisome proliferator-activated receptor agonists but not ketosis in man. J Clin Endocrinol Metab 2009; 94: 3594-3601.
  • 65
    Galman C, Lundasen T, Kharitonenkov A, Bina HA, Eriksson M, Hafstrom I, et al. The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARalpha activation in man. Cell Metab 2008; 8: 169-174.
  • 66
    Mraz M, Bartlova M, Lacinova Z, Michalsky D, Kasalicky M, Haluzikova D, et al. Serum concentrations and tissue expression of a novel endocrine regulator fibroblast growth factor-21 in patients with type 2 diabetes and obesity. Clin Endocrinol (Oxf) 2009; 71: 369-375.
  • 67
    Dushay J, Chui PC, Gopalakrishnan GS, Varela-Rey M, Crawley M, Fisher FM, et al. Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease. Gastroenterology 2010; 139: 456-463.
  • 68
    Wei W, Dutchak PA, Wang X, Ding X, Wang X, Bookout AL, et al. Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor gamma. Proc Natl Acad Sci U S A 2012; 109: 3143-3148.
  • 69
    Mu J, Pinkstaff J, Li Z, Skidmore L, Li N, Myler H, et al. FGF21 analogs of sustained action enabled by orthogonal biosynthesis demonstrate enhanced antidiabetic pharmacology in rodents. Diabetes 2012; 61: 505-512.