Curtailing FGF19’s mitogenicity by suppressing its receptor dimerization ability

Niu, Jianlou; Zhao, Jing; Wu, Jing; Qiao, Guanting; Gu, Junlian; Zhou, Chuanren; Li, Qi; Lei, Ying; Wang, Dezhong; Lin, Huan; Li, Xiaokun; Mohammadi, Moosa; Huang, Zhifeng

doi:10.1073/pnas.2010984117

Cited by 16 publications

(16 citation statements)

References 46 publications

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“…In parallel experiments, we administered mFGF4 and rFGF19 as positive controls; in both cases, these proteins are known to induce full proliferative activity 2 , 4 , 37 . Consistent with published literature 38 , 39 , rFGF19 treatment led to dramatic increase in the expression of hepatic proliferation markers (Supplementary Fig. 10j, k ).…”

Section: Resultssupporting

confidence: 91%

Paracrine FGFs target skeletal muscle to exert potent anti-hyperglycemic effects

et al. 2021

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Several members of the FGF family have been identified as potential regulators of glucose homeostasis. We previously reported that a low threshold of FGF-induced FGF receptor 1c (FGFR1c) dimerization and activity is sufficient to evoke a glucose lowering activity. We therefore reasoned that ligand identity may not matter, and that besides paracrine FGF1 and endocrine FGF21, other cognate paracrine FGFs of FGFR1c might possess such activity. Indeed, via a side-by-side testing of multiple cognate FGFs of FGFR1c in diabetic mice we identified the paracrine FGF4 as a potent anti-hyperglycemic FGF. Importantly, we found that like FGF1, the paracrine FGF4 is also more efficacious than endocrine FGF21 in lowering blood glucose. We show that paracrine FGF4 and FGF1 exert their superior glycemic control by targeting skeletal muscle, which expresses copious FGFR1c but lacks β-klotho (KLB), an obligatory FGF21 co-receptor. Mechanistically, both FGF4 and FGF1 upregulate GLUT4 cell surface abundance in skeletal muscle in an AMPKα-dependent but insulin-independent manner. Chronic treatment with rFGF4 improves insulin resistance and suppresses adipose macrophage infiltration and inflammation. Notably, unlike FGF1 (a pan-FGFR ligand), FGF4, which has more restricted FGFR1c binding specificity, has no apparent effect on food intake. The potent anti-hyperglycemic and anti-inflammatory properties of FGF4 testify to its promising potential for use in the treatment of T2D and related metabolic disorders.

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Section: Resultssupporting

confidence: 91%

Paracrine FGFs target skeletal muscle to exert potent anti-hyperglycemic effects

et al. 2021

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“…The 3D structure of the FGF23-FGFR1c complex determined by X-ray crystallography revealed it requires an obligatory interaction with KLα and heparan sulfate (HS) for a 1:1:1:1 assembly for signaling [ 144 ]. Based on these data and biochemical evidence of FGF19 signaling accumulated in the past [ 10 , 11 , 12 , 13 , 14 ], FGF15/19-FGFR4 also requires interaction with KLβ and HS for signaling with a 1:1:1:1 ratio [ 145 , 146 ]. Furthermore, FGF19 mutants with reduced dimerization potential elicit lower mitogenic activity accompanied with lower induced ERK1/2 phosphorylation, whereas hepatic Cyp7a1 expression reduced to similar levels as liver treated with WT [ 145 , 147 , 148 ].…”

Section: Regulation Production and Biological Function Of Fgf15/19mentioning

confidence: 99%

Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis

Katafuchi,

Makishima

2022

IJMS

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Bile acids (BAs) are a group of amphiphilic molecules consisting of a rigid steroid core attached to a hydroxyl group with a varying number, position, and orientation, and a hydrophilic side chain. While BAs act as detergents to solubilize lipophilic nutrients in the small intestine during digestion and absorption, they also act as hormones. Farnesoid X receptor (FXR) is a nuclear receptor that forms a heterodimer with retinoid X receptor α (RXRα), is activated by BAs in the enterohepatic circulation reabsorbed via transporters in the ileum and the colon, and plays a critical role in regulating gene expression involved in cholesterol, BA, and lipid metabolism in the liver. The FXR/RXRα heterodimer also exists in the distal ileum and regulates production of fibroblast growth factor (FGF) 15/FGF19, a hormone traveling via the enterohepatic circulation that activates hepatic FGF receptor 4 (FGFR4)-β-klotho receptor complex and regulates gene expression involved in cholesterol, BA, and lipid metabolism, as well as those regulating cell proliferation. Agonists for FXR and analogs for FGF15/19 are currently recognized as a promising therapeutic target for metabolic syndrome and cholestatic diseases.

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“…FGF family is divided into endocrine FGFs and paracrine FGFs, and endocrine type FGF19/21 has been widely studied in the field of metabolism. Mounting evidence showed that FGFs interact with FGFR in the 1:1 FGF-FGFR complex to facilitate FGF-FGFR dimerization, with increased intracellular receptor tyrosine kinase activity that triggers various downstream signaling pathways ( Huang et al, 2017 ; Zinkle and Mohammadi, 2018 ; Niu et al, 2020 ). So these endocrine/paracrine FGFs may also share the same mode of action and regulated the development of GDM.…”

Section: Discussionmentioning

confidence: 99%

FGF4, A New Potential Regulator in Gestational Diabetes Mellitus

et al. 2022

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Background: Gestational diabetes mellitus (GDM) is associated with adverse maternal and neonatal outcomes, however the underlying mechanisms remain elusive. The aim of this study was to find efficient regulator of FGFs in response to the pathogenesis of GDM and explore the role of the FGFs in GDM.Methods: We performed a systematic screening of placental FGFs in GDM patients and further in two different GDM mouse models to investigate their expression changes. Significant changed FGF4 was selected, engineered, purified, and used to treat GDM mice in order to examine whether it can regulate the adverse metabolic phenotypes of the diabetic mice and protect their fetus.Results: We found FGF4 expression was elevated in GDM patients and its level was positively correlated to blood glucose, indicating a physiological relevance of FGF4 with respect to the development of GDM. Recombinant FGF4 (rFGF4) treatment could effectively normalize the adverse metabolic phenotypes in high fat diet induced GDM mice but not in STZ induced GDM mice. However, rFGF4 was highly effective in reduce of neural tube defects (NTDs) of embryos in both the two GDM models. Mechanistically, rFGF4 treatment inhibits pro-inflammatory signaling cascades and neuroepithelial cell apoptosis of both GDM models, which was independent of glucose regulation.Conclusions/interpretation: Our study provides novel insight into the important roles of placental FGF4 and suggests that it may serve as a promising diagnostic factor and therapeutic target for GDM.

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Curtailing FGF19’s mitogenicity by suppressing its receptor dimerization ability

Cited by 16 publications

References 46 publications

Paracrine FGFs target skeletal muscle to exert potent anti-hyperglycemic effects

Paracrine FGFs target skeletal muscle to exert potent anti-hyperglycemic effects

Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis

FGF4, A New Potential Regulator in Gestational Diabetes Mellitus

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