Gastroenterology
Volume 137, Issue 5 , Pages 1577-1579, November 2009

A Novel Role for the Fibroblast Growth Factor 21 in Acute Pancreatitis

  • Hana Algül

      Affiliations

    • Corresponding Author InformationReprint requests Address requests for reprints to: Hana Algül, MD, MPH, II. Medizinische Klinik, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Strasse 22, D-81675 München, Germany

Medizinische Klinik, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany

published online 01 October 2009.

Article Outline

 

See “Fibroblast growth factor 21 reduces the severity of cerulein-induced pancreatitis in mice,” by Johnson CL, Weston JY, Chadi SA, et al, on page 1795.

Fibroblast growth factors (FGFs) have various biological activities in diverse developmental and metabolic processes.1 Currently, 22 FGF family orthologs are conserved between human and mouse genomes. Based on their structural similarities and modes of actions, these members of the family are divided into seven subfamilies. Most FGFs mediate their biological responses as extracellular acting proteins by binding to and activating cell surface tyrosine kinase FGF receptors (FGFRs). One critical feature of FGF signaling is that it requires βKlotho, a single-pass transmembrane, as an obligate coreceptor to bind and activate FGFRs. These receptors signal by activating various intracellular pathways implicated in cell survival, cell fate determination, cell polarity, and cell growth and differentiation.2 Genetic disruption of individual FGF genes in mice reveals further their diversity. Phenotypes range from early embryonic lethality to subtle changes in adult physiology (reviewed in Itoh and Ornitz1).

Interestingly, members of the Fgf19 subfamily, which includes FGF19, FGF15, and FGF21, are characterized by 2 essential features that discriminate them from other FGF members. These growth factors act in a fashion similar to hormones by exerting systemic effects. Although expressed in the intestine, FGF19, for example, modulates bile acid synthesis in the liver. FGF21, largely expressed in the liver, functions as a potent activator of glucose uptake in adipocytes. Even more, studies in various animal models have revealed that FGF21 affects numerous beneficial metabolic alterations without apparent adverse effects. Its overexpression in mice, for example, protects animals from diet-induced obesity and its administration to diabetic rodents and monkeys lowers blood glucose and triglyceride levels (reviewed in Itoh and Ornitz1).

FGFs are known to be involved in several diseases such as cardiovascular disorders, but also in acute pancreatitis (AP). Obesity and elevated blood glucose and triglyceride levels are known to be severity predictors or inducers of AP in humans.3 AP is a reversible inflammatory process of the pancreas. Mild AP has a very low mortality rate (<1%), whereas the death rate for severe AP can be 10%–30%. Based on the concept that necrotic damage in the pancreas finally results in fibrotic remodelling of the organ (necrosis–fibrosis sequence), recurrent episodes of AP can finally lead to chronic pancreatitis with endocrine and exocrine insufficiency.4

Owing to Hans Chiari's concept of autodigestion and the recent identification of mutations of genes encoding digestive enzymes or their inhibitor in patients with hereditary pancreatitis, recent efforts have emphasized disrupting intra-acinar activation of digestive enzymes.5 Clinical trials with protease inhibitors in therapeutic and prophylactic settings have been. Therefore, there remains a need for the identification of novel targets.3, 6, 7, 8

In this issue of Gastroenterology Johnson et al9 break new ground and identify a novel and hitherto unknown role of FGF21 in AP. Using the classical in vivo models of pancreatitis the authors demonstrate rapid FGF21 expression (within minutes), thereby suggesting an important function in the onset of inflammation. Taking advantage of FGF21 knockout (Fgf21−/−) and transgenic (FGF21Tg) mouse models the study demonstrates convincingly a protective role for FGF21 against cellular damage during inflammation. Their findings suggest that, in addition to the protective elements on acinar cells, FGF21 inhibits the early activation of pancreatic stellate cells (PSC), thereby attenuating fibrotic remodelling (Figure 1). Mice lacking the Fgf21 gene in the whole organism revealed increased tissue damage and lethality in 2 models of AP. Correspondingly, high FGF21 serum levels in transgenic mice expressing human FGF21 from the apolipoprotein E promoter in the liver leads to less susceptibility to AP as compared with wild-type and Fgf21−/− mice.

  • View full-size image.
  • Figure 1. 

    Schematic illustration of the effects of FGF21 during AP. Acinar cell damage results in FGF21 expression. Then, PDGF and subsequent activation of PSCs are inhibited. Furthermore, FGF21 can act as inhibitor of the Egr-1 pathway by acting in a paracrine/autocrine fashion via the βKlotho receptor.

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Which mechanisms regulate FGF21 expression? 

This study supports the premise that injured pancreatic acinar cells express the βKlotho receptor and this represents a paracrine or autocrine basis for the regulation of FGF21. Unlike the increased expression of growth factors FGF1, -2, -7, and -10 during pancreatic regeneration transient Fgf21 induction seems to be restricted to the early phase of inflammation.10 Damage to the pancreas can occur owing to several reasons. Cerulein acts as a Ca2+ mobilizing secretagogue in various cells. Similarly, thapsigargin inhibits endoplasmic Ca2+-adenosine 5′-triphosphatase Ca2+-ATPase, thereby raising calcium levels within the acinar cell. Even isolation of acinar cells or incubation overnight is sufficient to expose these cells to stress. Interestingly, in all scenarios, acinar cells express FGF21. This, however, is different from the recently identified FGF21-inducing signaling cascade that involves the peroxisome proliferator-activated receptor gamma (PPAR-γ). The PPAR-γ troglitazone failed to induce FGF21 expression in isolated acinar cells, although PPAR-γ agonists attenuate acute inflammation in both pancreatic cell lines and mouse models of AP.11, 12 Therefore, this study in Gastroenterology still leaves us with unanswered questions as to how FGF21 is expressed.

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How does FGF21 execute its beneficial effects? 

The effects of FGF21 are pleiotropic. Activation of rapid signaling pathways and nuclear translocation of transcription factors have been identified as critical regulators and modulators of local and systemic damage during AP.13 Johnson et al9 found that FGF21 is able to interfere with the phosphorylation of extracellular signal–regulated kinase (ERK1)/2, c-JUN, and the expression of the proinflammatory and profibrotic transcription factor Early growth response-1 (Egr-1). Although it induces the mitogen-activated protein kinase (MAPK)/ERK cascade, FGF21 inhibits the induction of Egr-1. Attenuation of Egr-1 by FGF21 has been surmised to be a key mechanism. This finding, however, requires clarification. How is it possible to activate the proinflammatory MAPK cascade and inhibit the proinflammatory transcription factor Egr-1 at the same time with the net effect of anti-inflammation during the onset of AP? Activation of the MAPK cascade has been shown to contribute to the severity of pancreatitis.13, 14 The complexity of this intracellular signaling network remains unresolved in Johnson et al's study9 and requires further elucidation.

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How does FGF21 influence lipid metabolism in acinar cells during AP? 

Another conundrum emerges when metabolism in Fgf21−/− and FGF21Tg mice is considered. It is well established that FGF21 reduces body weight, plasma glucose, and lipid levels by regulating energy homeostasis, hepatic glucose and lipid metabolism, and insulin sensitivity. The actions of FGF21 on different organs are possibly mediated through induction of signaling transduction and alteration in gene expression. Recently, inhibition of the transcription factor SREBP-1 by FGF21 has been considered as a critical mechanism in attenuating lipogenesis during hepatic steatosis.15 Clinically, disturbances in triglycerides levels are known to be associated with AP. Johnson et al9 observed an inverse correlation between serum triglycerides and FGF21 expression levels. Mice lacking FGF 21 displayed lipid accumulation in the pancreas. This phenomenon is in line with the clinical experience in patients with acquired or inherited metabolic/lipid disorders. These patients are more susceptible to AP and more likely to develop severe complications.4 However, in the study by Johnson et al,9 it is unresolved whether the metabolic and morphologic changes in the pancreas are due to indirect effects of FGF21 on the liver or adipocytes, respectively, or a result of FGF21 actions on acinar cells.

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Does FGF21 influence the intracellular trypsin activation in the onset of AP? 

The discovery of mutations in the genes encoding cationic trypsinogen (PRSS1), the trypsin degrading enzyme chymotrypsinogen C (CTRC), and the pancreatic secretory trypsin inhibitor (SPINK1), which are associated with chronic pancreatitis, have supported the concept that intrapancreatic activation of digestive enzymes is a key mechanism in AP.5 Conversion of trypsinogen to trypsin occurs very early, but its interdependence with transcription factors has been controversial.7, 8 Whether FGF21 expression participates in the activation of trypsin is unclear.

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How does FGF21 communicate between acinar cells and PSCs? 

Interestingly, the study by Johnson et al provides a remarkable link between acute acinar cell injury and activation of PSC.16 PSCs are the main source of extracellular matrix constituents that induce fibrosis during pancreatitis.17 The platelet-derived growth factor (PDGF) is a well-characterized mitogen for PSCs. Johnson et al identify a link between the level of FGF21 and the expression of PDGF, thereby suggesting that FGF 21 regulates the concomitant stimulation of PSCs in the acute phase (Figure 1). Following the so-called necrosis–fibrosis sequence hypothesis, it is tempting to assume that the FGF21 axis marks an early event in the determination of fibrotic remodelling after AP. This could be of use in a clinical setting, where the progression of fibrosis in patients with recurrent AP can be delayed or even stopped.

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Where does the field of FGFs and AP go in the future? 

In summary, the study by Johnson et al9 adds novel and provocative insights to the role of FGF21 in acinar cell physiology and pancreatic inflammation. Fgf21 is an immediate response gene that is transcribed rapidly during the onset of AP. Interestingly, FGF21 function not only is associated with acute injury, but is also needed to reduce tissue inflammation and fibrosis. However, how FGF21 achieves these functions remains to be elucidated. It seems that certain growth factors are synthesized and secreted during pancreatic injury, thereby exerting not only protective functions, but also fostering regeneration. Therefore, further studies on the roles of growth factors in pancreatitis will hopefully shed new insights on underlying pathophysiology and lead to improvements in therapy and/or prophylaxis of this disease.

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References 

  1. Itoh N, Ornitz DM. Functional evolutionary history of the mouse Fgf gene family. Dev Dyn. 2008;237:18–27
  2. Katoh M. FGF signaling network in the gastrointestinal tract (review). Int J Oncol. 2006;29:163–168
  3. Pandol SJ, Saluja AK, Imrie CW–. Acute pancreatitis: bench to the bedside. Gastroenterology. 2007;132:1127–1151
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  9. Johnson CL, Weston JY, Chadi SA, et al. Fibroblast Growth Factor 21 reduces the severity of caerulein-induced pancreatitis in mice. Gastroenterology. 2009;137:1795–1804
  10. Ishiwata T, Naito Z, Lu YP, et al. Differential distribution of fibroblast growth factor (FGF)-7 and FGF-10 in L-arginine-induced acute pancreatitis. Exp Mol Pathol. 2002;73:181–190
  11. Konturek PC, Dembinski A, Warzecha Z, et al. Pioglitazone, a specific ligand of peroxisome proliferator-activated receptor-gamma, protects pancreas against acute cerulein-induced pancreatitis. World J Gastroenterol. 2005;11:6322–6329
  12. Shimizu K, Kobayashi M, Tahara J, et al. Cytokines and peroxisome proliferator-activated receptor gamma ligand regulate phagocytosis by pancreatic stellate cells. Gastroenterology. 2005;128:2105–2118
  13. Namkung W, Yoon JS, Kim KH, et al. PAR2 exerts local protection against acute pancreatitis via modulation of MAP kinase and MAP kinase phosphatase signaling. Am J Physiol Gastrointest Liver Physiol. 2008;295:G886–G894
  14. Kim JY, Kim KH, Lee JA, et al. Transporter-mediated bile acid uptake causes Ca2+-dependent cell death in rat pancreatic acinar cells. Gastroenterology. 2002;122:1941–1953
  15. Xu J, Lloyd DJ, Hale C, et al. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes. 2009;58:250–259
  16. Algul H, Treiber M, Lesina M, et al. Mechanisms of disease: chronic inflammation and cancer in the pancreas—a potential role for pancreatic stellate cells?. Nat Clin Pract Gastroenterol Hepatol. 2007;4:454–462
  17. Bachem MG, Schneider E, Gross H. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. – Gastroenterology. 1998;115:421–432

 Conflicts of interest The author discloses no conflicts.

PII: S0016-5085(09)01665-5

doi:10.1053/j.gastro.2009.09.024

Refers to article:

  • Additional Online Content AvailableEditorial Accompanies Article Fibroblast Growth Factor 21 Reduces the Severity of Cerulein-Induced Pancreatitis in Mice , 07 August 2009

    Charis L. Johnson, Jacqueline Y. Weston, Sami A. Chadi, Elena N. Fazio, Murray W. Huff, Alexei Kharitonenkov, Anja Köester, Christopher L. Pin
    Gastroenterology November 2009 (Vol. 137, Issue 5, Pages 1795-1804)

Gastroenterology
Volume 137, Issue 5 , Pages 1577-1579, November 2009

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