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Related Concept Videos

cAMP-dependent Protein Kinase Pathways01:25

cAMP-dependent Protein Kinase Pathways

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Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
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Multicellular organisms contain a variety of structurally and functionally distinct cell types, but the DNA in all the cells originated from the same parent cells. The differences in the cells can be attributed to the differential gene expression. Liver cells, whose functions include detoxification of blood, production of bile to metabolize fats, and synthesis of proteins essential for metabolism, must express a specific set of genes to perform their functions. Gene expression also varies with...
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Pyruvate is the end product of glycolysis, where glucose is oxidized to pyruvate, simultaneously reducing NAD+ to NADH. Two molecules of ATP are also produced by substrate-level phosphorylation.
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Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
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Pyruvate Oxidation01:15

Pyruvate Oxidation

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After glycolysis, the charged pyruvate molecules enter the mitochondria via active transport and undergo three enzymatic reactions. These reactions ensure that pyruvate can enter the next metabolic pathway so that energy stored in the pyruvate molecules can be harnessed by the cells.
First, the enzyme pyruvate dehydrogenase removes the carboxyl group from pyruvate and releases it as carbon dioxide. The stripped molecule is then oxidized and releases electrons, which are then picked up by NAD+...
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Regulation of the Unfolded Protein Response01:31

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Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
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Updated: Sep 21, 2025

Isolation of Primary Mouse Hepatocytes for Nascent Protein Synthesis Analysis by Non-radioactive L-azidohomoalanine Labeling Method
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Pyruvate Upregulates Hepatic FGF21 Expression by Activating PDE and Inhibiting cAMP-Epac-CREB Signaling Pathway.

Yan-Yan Zhao1, Li-Jun Zhang1, Xiang-Yan Liang1

  • 1Institute of Basic Medical Sciences, Xi'an Medical University, Xi'an 710021, China.

International Journal of Molecular Sciences
|May 28, 2022
PubMed
Summary
This summary is machine-generated.

Pyruvate boosts fibroblast growth factor 21 (FGF21) production in liver cells by lowering cyclic AMP (cAMP) and inhibiting the cAMP-Epac-CREB pathway. This reveals a new mechanism regulating FGF21, a key metabolic hormone.

Keywords:
CREBFGF21PDEcAMPhepatocytespyruvate

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Area of Science:

  • Metabolic regulation
  • Hormone signaling
  • Cellular metabolism

Background:

  • Fibroblast growth factor 21 (FGF21) is a hormone regulating glucose and lipid metabolism.
  • FGF21 expression is influenced by cellular metabolic stress.
  • The role of pyruvate, a central metabolite, in hepatic FGF21 regulation was unclear.

Purpose of the Study:

  • To investigate the effect of pyruvate on FGF21 expression and secretion in hepatocytes.
  • To elucidate the signaling pathways involved in pyruvate-mediated FGF21 regulation.

Main Methods:

  • Gene and protein expression analysis of FGF21 in human (HepG2) and mouse (AML12) hepatocytes in vitro.
  • In vivo studies in mice treated with pyruvate.
  • Measurement of intracellular cAMP levels, PDE activity, and CREB phosphorylation.

Main Results:

  • Pyruvate significantly increased FGF21 expression and secretion in hepatocytes.
  • Pyruvate elevated phosphodiesterase (PDE) activity, reduced cAMP levels, and decreased CREB phosphorylation.
  • Inhibition of Epac and CREB pathways upregulated FGF21, diminishing pyruvate's effect.

Conclusions:

  • Pyruvate upregulates hepatic FGF21 expression by activating PDEs, which reduces cAMP levels.
  • This process inhibits the cAMP-Epac-CREB signaling pathway, leading to increased FGF21 production.
  • Pyruvate represents a novel regulator of FGF21 in hepatocytes.