Elsevier

Molecular Metabolism

Volume 11, May 2018, Pages 104-112
Molecular Metabolism

Original Article
E2F1 promotes hepatic gluconeogenesis and contributes to hyperglycemia during diabetes

https://doi.org/10.1016/j.molmet.2018.02.011Get rights and content
Under a Creative Commons license
open access

Highlights

  • Genetic manipulation of the CDK4-RB1-E2F1 pathway in hepatocytes results in changes in gluconeogenic gene expression and glucose production.

  • Overexpression of E2F1 promotes gluconeogenesis in primary hepatocytes and in liver.

  • E2F1 mRNA levels are increased in the livers of diabetic patients and correlate with PCK1 gene expression.

  • Genetic depletion and pharmacological inhibition of E2F1 reduces hyperglycemia in diabetic mice.

Abstract

Objective

Aberrant hepatic glucose production contributes to the development of hyperglycemia and is a hallmark of type 2 diabetes. In a recent study, we showed that the transcription factor E2F1, a component of the cell cycle machinery, contributes to hepatic steatosis through the transcriptional regulation of key lipogenic enzymes. Here, we investigate if E2F1 contributes to hyperglycemia by regulating hepatic gluconeogenesis.

Methods

We use different genetic models to investigate if E2F1 regulates gluconeogenesis in primary hepatocytes and in vivo. We study the impact of depleting E2F1 or inhibiting E2F1 activity in diabetic mouse models to evaluate if this transcription factor contributes to hyperglycemia during insulin resistance. We analyze E2F1 mRNA levels in the livers of human diabetic patients to assess the relevance of E2F1 in human pathophysiology.

Results

Lack of E2F1 impaired gluconeogenesis in primary hepatocytes. Conversely, E2F1 overexpression increased glucose production in hepatocytes and in mice. Several genetic models showed that the canonical CDK4-RB1-E2F1 pathway is directly involved in this regulation. E2F1 mRNA levels were increased in the livers from human diabetic patients and correlated with the expression of the gluconeogenic enzyme Pck1. Genetic invalidation or pharmacological inhibition of E2F1 improved glucose homeostasis in diabetic mouse models.

Conclusions

Our study unveils that the transcription factor E2F1 contributes to mammalian glucose homeostasis by directly controlling hepatic gluconeogenesis. Together with our previous finding that E2F1 promotes hepatic steatosis, the data presented here show that E2F1 contributes to both hyperlipidemia and hyperglycemia in diabetes, suggesting that specifically targeting E2F1 in the liver could be an interesting strategy for therapies against type 2 diabetes.

Keywords

Gluconeogenesis
E2F1
Liver metabolism
Hyperglycemia
Diabetes
Cell cycle regulators

Abbreviations

PCK1
Phosphoenolpyruvate carboxykinase 1
G6PC
glucose-6-phosphatase G6PC
PTT
Pyruvate tolerance test
CDK4
cyclin–cyclin-dependent kinase 4
PKA
protein kinase A
cAMP
Cyclic adenosine monophosphate
PPARGC1A
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
FOXO1
Forkhead box protein O1
CREB
cAMP response element-binding protein
HFD
high fat diet
FAO
fatty acid oxidation

Cited by (0)

6

Present address: Institut des Maladie Metaboliques et Cardiovasculaires, INSERM UMR1048, 1 Avenue Poulhès, Toulouse, France.

7

Authorship: AG and PDD contributed equally to this work.