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Tissue Specific Effects of Dietary Carbohydrates and Obesity on ChREBPα and ChREBPβ Expression

  • Original Article
  • Published:
Lipids

Abstract

Carbohydrate response element binding protein (ChREBP) regulates insulin-independent de novo lipogenesis. Recently, a novel ChREBPβ isoform was identified. The purpose of the current study was to define the effect of dietary carbohydrates (CHO) and obesity on the transcriptional activity of ChREBP isoforms and their respective target genes. Mice were subjected to fasting-refeeding of high-CHO diets. In all three CHO-refeeding groups, mice failed to induce ChREBPα, yet ChREBPβ increased 10- to 20-fold. High-fat fed mice increased hepatic ChREBPβ mRNA expression compared to chow-fed along with increased protein expression. To better assess the independent effect of fructose on ChREBPα/β activity, HepG2 cells were treated with fructose ± a fructose-1,6-bisphosphatase inhibitor to suppress gluconeogenesis. Fructose treatment in the absence of gluconeogenesis resulted in increased ChREBP activity. To confirm the existence of ChREBPβ in human tissue, primary hepatocytes were incubated with high-glucose and the expression of ChREBPα and -β was determined. As with the animal models, glucose induced ChREBPβ expression while ChREBPα was decreased. Taken together, ChREBPβ is more responsive to changes in dietary CHO availability than the -α isoform. Diet-induced obesity increases basal expression of ChREBPβ, which may increase the risk of developing hepatic steatosis, and fructose-induced activation is independent of gluconeogenesis.

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Abbreviations

ChREBP:

Carbohydrate response element binding protein

CHO:

Carbohydrates

DNL:

De novo lipogenesis

TG:

Triglycerides

NAFLD:

Non-alcoholic fatty liver disease

LID:

Low-glucose inhibitory domain

GNG:

Gluconeogenesis

IPGTT:

Intraperitoneal glucose tolerance tests

RNAP2:

RNA polymerase II

PCR:

Polymerase chain reaction

FBPase-1:

Fructose-1,6-bisphosphatase

DMEM:

Dulbecco’s modified Eagle’s medium

RPMI:

Roswell Park Memorial Institute medium

cDNA:

Complementary DNA

SEM:

Standard error of the mean

L-PK:

Liver pyruvate kinase

SCD-1:

Stearoyl-CoA desaturase-1

FOXO1:

Forkhead box protein O1

PGC-1α:

Peroxisome proliferator-activated receptor gamma coactivator-1α

PEPCK:

Phosphoenolpyruvate carboxykinase

G6Pase:

Glucose-6-phosphatase

mRNA:

Messenger RNA

LG:

Low glucose

HG:

High glucose

LF:

Low fructose

HF:

High fructose

ACCα:

Acetyl-CoA carboxylase-α

FASN:

Fatty acid synthase

TXNIP:

Thioredoxin-interacting protein

KHK:

Ketohexokinase

HFD:

High-fat diet

UnT:

Untreated

X5P:

Xylulose-5-phosphate

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Acknowledgments

A.D.S. prepared the manuscript and conducted mouse and cell experiments; R.P.S., N.M.K., J.T.L., D.N.D., and R.L.J. assisted in manuscript preparation and conducted primary hepatocyte studies; C.M.P. prepared the manuscript, conducted, and directed studies. This research was supported by Grant (133505) from the Canadian Institutes of Health Research (CIHR). R.L.J. is a CIHR New Investigator.

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Authors and Affiliations

  1. Department of Nutritional Sciences, Texas Tech University, Lubbock, TX, 79409, USA

    Alexis D. Stamatikos

  2. Department of Agricultural, Food and Nutritional Sciences, Alberta Diabetes Institute, University of Alberta, Edmonton, AB, T6G 2S2, Canada

    Robin P. da Silva & René L. Jacobs

  3. Department of Surgery, Surgical-Medical Research Institute, University of Alberta, Edmonton, AB, T6G 2S2, Canada

    Jamie T. Lewis, Donna N. Douglas & Norman M. Kneteman

  4. Department of Food Science & Technology, University of Georgia, 100 Cedar St., Athens, GA, 30602, USA

    Chad M. Paton

  5. Department of Foods & Nutrition, University of Georgia, Athens, GA, USA

    Chad M. Paton

Authors
  1. Alexis D. Stamatikos
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  2. Robin P. da Silva
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  3. Jamie T. Lewis
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Correspondence to Chad M. Paton.

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Stamatikos, A.D., da Silva, R.P., Lewis, J.T. et al. Tissue Specific Effects of Dietary Carbohydrates and Obesity on ChREBPα and ChREBPβ Expression. Lipids 51, 95–104 (2016). https://doi.org/10.1007/s11745-015-4090-0

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