Relevant use of Klotho in FGF19 subfamily signaling system in vivo

Tomiyama, Katsunori; Maeda, Ryota; Urakawa, Itaru; Yamazaki, Y.; Tanaka, Tomohiro; Ito, Shinji; Nabeshima, Yoko; Tomita, Tsutomu; Odori, Shinji; Hosoda, Kiminori; Nakao, Kazuwa; Imura, Akihiro; Nabeshima, Yo‐ichi

doi:10.1073/pnas.0913986107

Cited by 137 publications

(147 citation statements)

References 34 publications

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“…In line with these findings, our present study demonstrated an indispensible role of ␤-klotho in FGF21-induced ERK1/2 activation, GLUT1 gene transactivation, and glucose uptake in adipocytes. In contrast, a recent study on ␤-klotho knock-out mice suggests that it is not required for FGF21 signaling pathways leading to the expression of hormone sensitive lipase and AtgI (23). However, whether or not ␤-klotho is essential for FGF21-induced GLUT1 expression and glucose uptake has not been addressed in this study.…”

Section: Discussioncontrasting

confidence: 43%

“…By contrast, a recent study on ␤-klotho knock-out mice suggests that ␤-klotho may not be essential for FGF21 signaling in adipose tissue (23). However, the latter report did not measure the impact of ␤-klotho deficiency on FGF21-induced glucose uptake in adipocytes.…”

Section: ␤-Klotho Is Required For Fgf21-induced Glut1 Expression and contrasting

confidence: 42%

“…Several in vitro studies demonstrated the essential role of ␤-klotho in conferring FGF21-induced ERK1/2 activation and glucose uptake in adipocytes (19,21,22). However, in contrary to in vitro data, a recent report on ␤-klotho knock-out mice suggests that it is not essential for FGF21 signaling in adipose tissues in vivo (23).…”

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confidence: 43%

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Fibroblast Growth Factor 21 Induces Glucose Transporter-1 Expression through Activation of the Serum Response Factor/Ets-Like Protein-1 in Adipocytes

Chen

Hui

et al. 2011

Journal of Biological Chemistry

143

107

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Background: FGF21 increases glucose uptake in adipocytes by enhancing the expression of glucose transporter-1 (GLUT1). Results: FGF21 induces the phosphorylation of the transcription factors serum response factor (SRF) and Ets-like protein-1 (Elk-1), which in turn bind to a highly conserved cis-element within the GLUT1 gene promoter for transcriptional activation. Such a stimulatory effect of FGF21 is impaired in adipose tissue of diet-induced obese mice. Conclusion: SRF and Elk-1 act synergistically to mediate FGF21-induced GLUT1 gene expression in adipocytes. Significance: The findings provide new molecular insights into the metabolic actions of FGF21 in its major target tissue.

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Section: Discussioncontrasting

confidence: 43%

Section: ␤-Klotho Is Required For Fgf21-induced Glut1 Expression and contrasting

confidence: 42%

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Fibroblast Growth Factor 21 Induces Glucose Transporter-1 Expression through Activation of the Serum Response Factor/Ets-Like Protein-1 in Adipocytes

Chen

Hui

et al. 2011

Journal of Biological Chemistry

143

107

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“…In humans, FGF23 signaling via several FGF receptor (FGFR) subtypes is thought to specifically require KLA, whereas hFGF19 and FGF21 reportedly require KLB (12)(13)(14). But other studies have shown that KLA can also act as a co-receptor for hFGF19 (15).…”

mentioning

confidence: 99%

“…Endocrine FGFs act via receptor tyrosine kinases but also require the presence of a co-receptor, alphaKlotho (KLA) 4 or betaKlotho (KLB) (12). In humans, FGF23 signaling via several FGF receptor (FGFR) subtypes is thought to specifically require KLA, whereas hFGF19 and FGF21 reportedly require KLB (12)(13)(14).…”

mentioning

confidence: 99%

Sulfated Glycosaminoglycans Are Required for Specific and Sensitive Fibroblast Growth Factor (FGF) 19 Signaling via FGF Receptor 4 and betaKlotho

Nakamura

Uehara

Asada

et al. 2011

Journal of Biological Chemistry

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Secreted from intestine, human fibroblast growth factor 19 (hFGF19) is an endocrine metabolic regulator that controls bile acid synthesis in the liver. Earlier studies have suggested that hFGF19 at 10 -100 nM levels signals through FGF receptor 4 (FGFR4) in the presence of a co-receptor, betaKlotho, but its activity and receptor specificity at physiological concentrations (picomolar levels) remain unclear. Here we report that hFGF19 at picomolar levels require sulfated glycosaminoglycans (sGAGs), such as heparan sulfate, heparin, and chondroitin sulfates, for its signaling via human FGFR4 in the presence of human betaKlotho. Importantly, sGAGs isolated from liver are highly active in enhancing the picomolar hFGF19 signaling. At nanomolar levels, in contrast, hFGF19 activates all types of human FGFRs, i.e. FGFR1c, FGFR2c, FGFR3c, and FGFR4 in the co-presence of betaKlotho and heparin and activates FGFR4 even in the absence of betaKlotho. These results show that sGAGs play crucial roles in specific and sensitive hFGF19 signaling via FGF receptors and suggest that hepatic sGAGs are involved in the highly potent and specific signaling of picomolar hFGF19 through FGFR4 and betaKlotho. The results further suggest that hFGF19 at pathological concentrations may evoke aberrant signaling through various FGF receptors.In both humans and mice, the fibroblast growth factor (FGF) family is composed of 22 structurally related proteins that can be divided into several subfamilies (1). The endocrine FGF subfamily, which function as metabolic regulators (2-5), is composed of FGF19, FGF21, and FGF23 in humans and FGF15, FGF21, and FGF23 in mice. Mouse (m)Fgf15 is an ortholog for human (h)FGF19 (6). Both mFGF15 and hFGF19 are expressed in the distal small intestine. Their secretion into the circulation is induced by bile acid, and after reaching the liver via the portal vein they suppress a key liver enzyme involved in bile acid biosynthesis, thereby closing a feedback loop regulating bile acid homeostasis (7). hFGF19/mFGF15 also reportedly contributes to the regulation of blood glucose levels, along with other metabolic regulators, including FGF21 and insulin (8 -11).Endocrine FGFs act via receptor tyrosine kinases but also require the presence of a co-receptor, alphaKlotho (KLA) 4 or betaKlotho (KLB) (12). In humans, FGF23 signaling via several FGF receptor (FGFR) subtypes is thought to specifically require KLA, whereas hFGF19 and FGF21 reportedly require . But other studies have shown that KLA can also act as a co-receptor for hFGF19 (15). It has thus been unclear how the receptor specificity of hFGF19 is achieved, or even what its precise receptor specificity is. Results from Fgf15 knockout mice suggest that mFGFR4 is the sole functional receptor for mFGF15 (7).Moreover, the potential applicability of hFGF19 to the treatment of metabolic diseases such as diabetes (8 -11) has prompted attempts to develop protocols for its clinical application, but these have been discouraged by the finding that transgenic mice expressing high le...

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Direct effects of FGF21 on glucose uptake in human skeletal muscle: implications for type 2 diabetes and obesity

Mashili

Austin

Deshmukh

et al. 2011

Diabetes Metabolism Res

194

144

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Plasma FGF21 is increased in T2D patients, and positively correlated with fasting insulin and BMI. However, FGF21 has direct effects in enhancing skeletal muscle glucose uptake, providing additional points of regulation that may contribute to the beneficial effects of FGF21 on glucose homeostasis. Whether increased plasma FGF21 in T2D is a compensatory mechanism to increase glucose metabolism remains to be determined.

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Relevant use of Klotho in FGF19 subfamily signaling system in vivo

Cited by 137 publications

References 34 publications

Fibroblast Growth Factor 21 Induces Glucose Transporter-1 Expression through Activation of the Serum Response Factor/Ets-Like Protein-1 in Adipocytes

Fibroblast Growth Factor 21 Induces Glucose Transporter-1 Expression through Activation of the Serum Response Factor/Ets-Like Protein-1 in Adipocytes

Sulfated Glycosaminoglycans Are Required for Specific and Sensitive Fibroblast Growth Factor (FGF) 19 Signaling via FGF Receptor 4 and betaKlotho

Direct effects of FGF21 on glucose uptake in human skeletal muscle: implications for type 2 diabetes and obesity

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