Separating mitogenic and metabolic activities of fibroblast growth factor 19 (FGF19)

Abstract

FGF19 and FGF21 are distinctive members of the FGF family that function as endocrine hormones. Their potent effects on normalizing glucose, lipid, and energy homeostasis in disease models have made them an interesting focus of research for combating the growing epidemics of diabetes and obesity. Despite overlapping functions, FGF19 and FGF21 have many discrete effects, the most important being that FGF19 has both metabolic and proliferative effects, whereas FGF21 has only metabolic effects. Here we identify the structural determinants dictating differential receptor interactions that explain and distinguish these two physiological functions. We also have generated FGF19 variants that have lost the ability to induce hepatocyte proliferation but that still are effective in lowering plasma glucose levels and improving insulin sensitivity in mice. Our results add valuable insight into the structure-function relationship of FGF19/FGF21 and identify the structural basis underpinning the distinct proliferative feature of FGF19 compared with FGF21. In addition, these studies provide a road map for engineering FGF19 as a potential therapeutic candidate for treating diabetes and obesity.he FGF19 subfamily members, consisting of FGF19, FGF21, and FGF23, are distinctive members of the FGFs. Most of the FGF family members function in paracrine fashion to regulate processes of development, transformation, and angiogenesis. In contrast, the weak affinity toward heparan sulfate of the pericellular space as well as the presence of intramolecular disulfide bonds allows the FGF19 subfamily members to escape from the extracellular compartment into circulation and to function as endocrine hormones (1-3).The subfamily members FGF19 and FGF21 share the ability to regulate glucose, lipid, and energy homeostasis (4-7). Both FGF19-and FGF21-transgenic mice are resistant to diet-induced obesity and have decreased body fat mass and improved insulin sensitivity, glucose disposal, and plasma lipid parameters (7,8). Injection of recombinant FGF19 or FGF21 protein into diabetic mice resulted in the reduction of serum glucose and insulin levels, improved glucose tolerance, and reduced hepatosteatosis and body weight (4-6, 9-11). These effects regarding correction of metabolic imbalances were potent, beneficial, and suggested that FGF19 and FGF21 might be exciting candidates for combating the growing epidemics of diabetes and obesity. Potential unwanted mitogenic activity, however, has been observed in FGF19-transgenic mice, which developed hepatocellular carcinoma within 12 mo and showed increased hepatocyte proliferation as early as 2-4 mo of age (12). The increased hepatocyte proliferation also has been observed in normal mice injected with recombinant FGF19 for 6 d (12); however, such a proliferative effect has not been observed in FGF21-treated animals (13). Therefore, the key distinction between FGF19 and FGF21 is that FGF19 has both metabolic and proliferative effects, whereas FGF21 has only metabolic effects.The interactions between para...

Signaling Pathways in Liver Cancer

“…BrdU-labeling index of hepatocytes was eight fold higher in the transgenic mice than age-matched wild type mice at 2 to 4 months of age (Nicholes et al, 2002). Furthermore, recombinant FGF19 protein also induced a significant higher BrdU-labeling index after being injected into normal mice (Nicholes et al, 2002;Wu et al, 2010a;Wu et al, 2010b). These results strongly support the notion that FGF19 can induce hepatocellular proliferation which eventually leads to development of HCC.…”

“…Strong FGFR4 mRNA was detected in hepatocytes adjacent to central vein by in situ hybridization, and the hepatic dysplasia foci and BrdU labeling from FGF19 transgenic livers are also located around central vein. In addition, activation of FGFR4 alone was sufficient to induce hepatocyte proliferation (Wu et al, 2010a;Wu et al, 2010b) and FGF19 induced hepatocytes proliferation was not observed in FGFR4 knockout mice, confirming the role played by FGFR4 in hepatocarcinogenesis (Wu et al, 2011).…”

Dual actions of fibroblast growth factor 19 on lipid metabolism

“…Recombinant FGF19, FGF21, and FGF19dCTD proteins used in this study were expressed and purifi ed from Escherichia coli as previously described ( 13,15 ). our previous report demonstrating that activation of FGFR4 alone does not improve glucose parameters ( 15 ).…”

Plasticity in Interactions of Fibroblast Growth Factor 1 (FGF1) N Terminus with FGF Receptors Underlies Promiscuity of FGF1

“…2B) (30). Furthermore, a recent study, in which N-terminal sequences between FGF19 and FGF21 were swapped to map residues in FGF19 that permit binding of FGF19 to FGFR4, led to the identification of residues 38 -42 at the N terminus of FGF19 as the key determinants of FGF19-FGFR4 specificity (70). This FGF19 N-terminal region corresponds to the FGF1 region that mediates degenerate binding of FGF1 to both alternative splice isoforms of FGFR2 (Fig.…”