Regulating Lipogenesis during Ketosis

By Evan Gassaway

Paper: Metabolic regulation of Nucleo-cytosolic Trafficking of Carbohydrate Response Element-binding Protein (ChREBP): Role of Ketone Bodies

http://www.jbc.org/content/288/39/28368

ChREBP (carbohydrate response element-binding protein) is known to be a transcription factor of great importance in the conversion of excess carbohydrate into fat. It is also known that ChREBP responds to changes in levels of glucose, which is to be expected given its function. But a very important piece of information is missing here: how does this protein respond to changes in glucose concentration? This is a very important question that research by Nakagawa et. al. (

Proposed nuclear/cytosolic trafficking pathways of ChREBP.   J. Biol. Chem. 2013;288:28368
Proposed nuclear/cytosolic trafficking pathways of ChREBP.
J. Biol. Chem. 2013;288:28368

) answers very well by establishing the role of ketone bodies (β-hydroxybutyrate and acetoacetate) in regulating the localization of ChREBP through its association with a 14-3-3β protein.
The use of both in vivo and in vitro experimentation, pull down assays and Isothermal Titration Calorimetry, and HPLC for the separation of protein-free liver cell extracts allowed the authors to pinpoint the compounds responsible for activating the ChREBP:14-3-3β interaction. The authors used HPLC to isolate fractions from the protein free liver extracts of rats on a variety of diets (starved, high sucrose, high fat, and a normal diet) and found, as would be expected, the highest level of interaction promoting compounds in the starved rats. These compounds where then identified using β-hydroxybutyrate dehydrogenase and GC-MS, and it was shown that they were indeed the ketone bodies β-hydroxybutyrate and acetoacetate. The experimentation that was used to determine this was thorough and quite clever, almost as clever as the system of regulation itself.