The Study

The carbohydrate-responsive element-binding protein (ChREBP) is a transcription factor known to translocate into the nucleus of liver cells in response to high glucose level in order to activate the expression of several genes coding for many enzymes involved in glycolysis, a metabolic pathway using glucose (a simple form of carbohydrate) in order to produce energy for the body, and lipogenesis, a metabolic pathway that converts acetyl-CoA, an intermediate product of glycolysis generated in the presence of an excess of glucose in the liver, into fatty acids. The latter pathway allows the body to store energy derived from an excessive intake of carbohydrate into body fats. The action of ChREBP in the liver is independent of insulin effects and accounts for more than half of de novo fat synthesis in the liver.

This study looked at the effects of a high sucrose (HS) and high fat (HF) diets on rat’s liver metabolism and the interaction of ChREBP with other proteins leading to either its activation or inactivation.

Methods

This study used 5 to 10 week-old male rats living in a temperature- and light-controlled environment. They were either fed with a high-sucrose (HS) (60% sucrose, 20% casein, 15% cellulose, 2.5% vitamins, and 2.5% minerals) or a high-fat (HF) diet (31% casein, 31% cellulose, 3% peanut oil, 27% lard, 2.5% vitamins, 2.5% minerals, and 3% corn oil). Subsequent molecular experiments were performed using liver cells harvested from the livers of those rats.

Results

As expected, ChREBP was more likely to be localized within the nucleus of cells derived from HS-fed rats than of cells derived from HF-fed rats, confirming that the translocation of ChREBP to the nucleus responds to the intake of carbohydrates. However, experiments suggest that the precise molecular mechanisms involved in the translocation of ChREBP into the nucleus of liver cells in response to carbohydrates is far more complex than previously thought and involves interactions with many different other molecules. Those detailed interactions will not be discussed here, as they are out of the scope of this summary.

Interestingly, the results also suggest that, in the context of ketosis, ketone bodies and the nucleotide adenosine monophosphate (AMP) act together in order to inhibit the translocation of ChREBP into the nucleus, which consequently also inhibit the lipogenesis in the liver. Lowering of the blood glucose level was also observed in that particular case.

Conclusion

Taken together, these results suggest that ketogenic diets might be used in the treatment of diabetes, obesity and over-weight individuals.

 

Study Editor

Marie-Christine Brotherton holds a Ph.D. in Cellular and Molecular Biology with specific expertise in Parasitology, Proteomics, Drug Resistance and Genomics. She also holds a MBA with a major in Corporate Social and Environmental Responsibility. She has strong experience with the scientific publication process, including author guidelines requirements, as well as with the medical and social/environmental fields. She can be reached by email at marie-christine.brotherton.1@ulaval.ca

Citation

Sato, S., Jung, H., Nakagawa, T., Pawlosky, R., Takeshima, T., Lee, W. R., … & MacMillan, J. B. (2016). Metabolite Regulation of Nuclear Localization of Carbohydrate Response Element-binding Protein (ChREBP). Role of AMP as an Allosteric Inhibitor. Journal of Biological Chemistry, jbc-M115.