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Hepatic glucose sensing and integrative pathways in the liver

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Abstract

The hepatic glucose-sensing system is a functional network of enzymes and transcription factors that is critical for the maintenance of energy homeostasis and systemic glycemia. Here we review the recent literature on its components and metabolic actions. Glucokinase (GCK) is generally considered as the initial postprandial glucose-sensing component, which acts as the gatekeeper for hepatic glucose metabolism and provides metabolites that activate the transcription factor carbohydrate response element binding protein (ChREBP). Recently, liver receptor homolog 1 (LRH-1) has emerged as an upstream regulator of the central GCK–ChREBP axis, with a critical role in the integration of hepatic intermediary metabolism in response to glucose. Evidence is also accumulating that O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) and acetylation can act as glucose-sensitive modifications that may contribute to hepatic glucose sensing by targeting regulatory proteins and the epigenome. Further elucidation of the components and functional roles of the hepatic glucose-sensing system may contribute to the future treatment of liver diseases associated with deregulated glucose sensors.

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Abbreviations

Acetyl-CoA:

Acetyl-coenzyme A

ACL:

ATP citrate lyase

ChoRE:

Carbohydrate response element

ChREBP:

Carbohydrate response element binding protein

CREB:

Cyclic AMP-responsive element binding protein

CRTC2:

cAMP-regulated transcriptional co-activator 2

F2:

6bisP, fructose-2,6-bisphosphate

F6P:

Fructose-6-phosphate

FOXA2:

Forkhead box protein A2

FOXO1:

Forkhead box protein O1

FXR:

Farnesoid x receptor

G6P:

Glucose-6-phosphate

G6Pc:

Glucose-6-phosphatase

G6Pt:

Glucose-6-phosphate transporter

GCK:

Glucokinase

GCKR:

GCK regulatory protein

GLUT:

Glucose transporter

GSD-1:

Glycogen storage disease type 1

HDAC:

Histone deacetylase

HIF-1:

Hypoxia-inducible factor 1

HK:

Hexokinase

HNF-4:

Hepatocyte nuclear factor 4

KAT:

Lysine acetyltransferase

KLF-6:

Kruppel-like factor 6

LRH-1:

Liver receptor homolog 1

LXR:

Liver x receptor

Mlx:

Max-like protein X

MLXIP:

Mlx interacting protein

MLXIPL:

Max-like protein X interacting protein-like

OGA:

O-GlcNAcase

O-GlcNAcylation:

O-linked β-N-acetylglucosaminylation

OGT:

O-GlcNAc transferase

PGC-1α:

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha

PPARγ:

Peroxisome proliferator activated receptor gamma

SREBP-1c:

Sterol regulatory binding protein-1c

T2D:

Type 2 diabetes

TCA:

Tricarboxylic acid

TCFE3:

Transcription factor E3

UDP-GlcNAc:

UDP-N-acetylglucosamine

UTP:

Uridine triphosphate

X5P:

Xylulose-5-phosphate

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Acknowledgments

We thank Albert K. Groen for reading and commenting on the manuscript. The work in the laboratory of the authors is supported by the Ecole Polytechnique Fédérale de Lausanne (EPFL), the Swiss National Science Foundation, the Swiss Cancer League and the University Medical Center Groningen (UMCG).

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  1. Department of Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, 9713 GZ, Groningen, The Netherlands

    Maaike H. Oosterveer

  2. Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland

    Kristina Schoonjans

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  1. Maaike H. Oosterveer
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Correspondence to Kristina Schoonjans.

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Oosterveer, M.H., Schoonjans, K. Hepatic glucose sensing and integrative pathways in the liver. Cell. Mol. Life Sci. 71, 1453–1467 (2014). https://doi.org/10.1007/s00018-013-1505-z

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