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Pyruvate Upregulates Hepatic FGF21 Expression by Activating PDE and Inhibiting cAMP–Epac–CREB Signaling Pathway

Fibroblast growth factor 21 (FGF21) functions as a polypeptide hormone to regulate glucose and lipid metabolism, and its expression is regulated by cellular metabolic stress. Pyruvate is an important intermediate metabolite that acts as a key hub for cellular fuel metabolism. However, the effect of...

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Autores principales: Zhao, Yan-Yan, Zhang, Li-Jun, Liang, Xiang-Yan, Zhang, Xiao-Chun, Chang, Jin-Rui, Shi, Man, Liu, Huan, Zhou, Ying, Sun, Zhuo, Zhao, Yu-Feng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9141208/
https://www.ncbi.nlm.nih.gov/pubmed/35628302
http://dx.doi.org/10.3390/ijms23105490
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author Zhao, Yan-Yan
Zhang, Li-Jun
Liang, Xiang-Yan
Zhang, Xiao-Chun
Chang, Jin-Rui
Shi, Man
Liu, Huan
Zhou, Ying
Sun, Zhuo
Zhao, Yu-Feng
author_facet Zhao, Yan-Yan
Zhang, Li-Jun
Liang, Xiang-Yan
Zhang, Xiao-Chun
Chang, Jin-Rui
Shi, Man
Liu, Huan
Zhou, Ying
Sun, Zhuo
Zhao, Yu-Feng
author_sort Zhao, Yan-Yan
collection PubMed
description Fibroblast growth factor 21 (FGF21) functions as a polypeptide hormone to regulate glucose and lipid metabolism, and its expression is regulated by cellular metabolic stress. Pyruvate is an important intermediate metabolite that acts as a key hub for cellular fuel metabolism. However, the effect of pyruvate on hepatic FGF21 expression and secretion remains unknown. Herein, we examined the gene expression and protein levels of FGF21 in human hepatoma HepG2 cells and mouse AML12 hepatocytes in vitro, as well as in mice in vivo. In HepG2 and AML12 cells, pyruvate at concentrations above 0.1 mM significantly increased FGF21 expression and secretion. The increase in cellular cAMP levels by adenylyl cyclase activation, phosphodiesterase (PDE) inhibition and 8-Bromo-cAMP administration significantly restrained pyruvate-stimulated FGF21 expression. Pyruvate significantly increased PDE activities, reduced cAMP levels and decreased CREB phosphorylation. The inhibition of exchange protein directed activated by cAMP (Epac) and cAMP response element binding protein (CREB) upregulated FGF21 expression, upon which pyruvate no longer increased FGF21 expression. The increase in plasma pyruvate levels in mice induced by the intraperitoneal injection of pyruvate significantly increased FGF21 gene expression and PDE activity with a reduction in cAMP levels and CREB phosphorylation in the mouse liver compared with the control. In conclusion, pyruvate activates PDEs to reduce cAMP and then inhibits the cAMP–Epac–CREB signaling pathway to upregulate FGF21 expression in hepatocytes.
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spelling pubmed-91412082022-05-28 Pyruvate Upregulates Hepatic FGF21 Expression by Activating PDE and Inhibiting cAMP–Epac–CREB Signaling Pathway Zhao, Yan-Yan Zhang, Li-Jun Liang, Xiang-Yan Zhang, Xiao-Chun Chang, Jin-Rui Shi, Man Liu, Huan Zhou, Ying Sun, Zhuo Zhao, Yu-Feng Int J Mol Sci Article Fibroblast growth factor 21 (FGF21) functions as a polypeptide hormone to regulate glucose and lipid metabolism, and its expression is regulated by cellular metabolic stress. Pyruvate is an important intermediate metabolite that acts as a key hub for cellular fuel metabolism. However, the effect of pyruvate on hepatic FGF21 expression and secretion remains unknown. Herein, we examined the gene expression and protein levels of FGF21 in human hepatoma HepG2 cells and mouse AML12 hepatocytes in vitro, as well as in mice in vivo. In HepG2 and AML12 cells, pyruvate at concentrations above 0.1 mM significantly increased FGF21 expression and secretion. The increase in cellular cAMP levels by adenylyl cyclase activation, phosphodiesterase (PDE) inhibition and 8-Bromo-cAMP administration significantly restrained pyruvate-stimulated FGF21 expression. Pyruvate significantly increased PDE activities, reduced cAMP levels and decreased CREB phosphorylation. The inhibition of exchange protein directed activated by cAMP (Epac) and cAMP response element binding protein (CREB) upregulated FGF21 expression, upon which pyruvate no longer increased FGF21 expression. The increase in plasma pyruvate levels in mice induced by the intraperitoneal injection of pyruvate significantly increased FGF21 gene expression and PDE activity with a reduction in cAMP levels and CREB phosphorylation in the mouse liver compared with the control. In conclusion, pyruvate activates PDEs to reduce cAMP and then inhibits the cAMP–Epac–CREB signaling pathway to upregulate FGF21 expression in hepatocytes. MDPI 2022-05-14 /pmc/articles/PMC9141208/ /pubmed/35628302 http://dx.doi.org/10.3390/ijms23105490 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zhao, Yan-Yan
Zhang, Li-Jun
Liang, Xiang-Yan
Zhang, Xiao-Chun
Chang, Jin-Rui
Shi, Man
Liu, Huan
Zhou, Ying
Sun, Zhuo
Zhao, Yu-Feng
Pyruvate Upregulates Hepatic FGF21 Expression by Activating PDE and Inhibiting cAMP–Epac–CREB Signaling Pathway
title Pyruvate Upregulates Hepatic FGF21 Expression by Activating PDE and Inhibiting cAMP–Epac–CREB Signaling Pathway
title_full Pyruvate Upregulates Hepatic FGF21 Expression by Activating PDE and Inhibiting cAMP–Epac–CREB Signaling Pathway
title_fullStr Pyruvate Upregulates Hepatic FGF21 Expression by Activating PDE and Inhibiting cAMP–Epac–CREB Signaling Pathway
title_full_unstemmed Pyruvate Upregulates Hepatic FGF21 Expression by Activating PDE and Inhibiting cAMP–Epac–CREB Signaling Pathway
title_short Pyruvate Upregulates Hepatic FGF21 Expression by Activating PDE and Inhibiting cAMP–Epac–CREB Signaling Pathway
title_sort pyruvate upregulates hepatic fgf21 expression by activating pde and inhibiting camp–epac–creb signaling pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9141208/
https://www.ncbi.nlm.nih.gov/pubmed/35628302
http://dx.doi.org/10.3390/ijms23105490
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