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Logo of jbcThe Journal of Biological Chemistry
J Biol Chem. 2013 September 27; 288(39): 28368.
PMCID: PMC3784754

Ketone Bodies Inhibit Fat Synthesis by Localizing Transcription Factor to Cytoplasm♦

Metabolite Regulation of Nucleo-cytosolic Trafficking of Carbohydrate Response Element-binding Protein (ChREBP). Role of Ketone Bodies

♦ See referenced article, J. Biol. Chem. 2013, 288, 28358–28367

The carbohydrate response element-binding protein (ChREBP) is a transcription factor involved in the conversion of excess carbohydrate into storage fat in liver. As glucose levels change, ChREBP gets shuttled between the nucleus and the cytoplasm by 14-3-3 proteins and importins. A team led by Kosaku Uyeda at the University of Texas Southwestern Medical Center at Dallas and the Dallas Veterans Affairs Medical Center demonstrated that protein-free extracts of mouse liver, from either starved and or high fat-fed animals, contained the ketone bodies β-hydroxybutyrate and acetoacetate. The metabolites promoted ChREBP localization in the cytoplasm by activating the ChREBP/14-3-3 interaction while inhibiting the ChREBP/importin α interaction. The authors conclude, “These observations show that ketone bodies play an important role in the regulation of ChREBP activity by restricting ChREBP localization to the cytoplasm, thus inhibiting fat synthesis during periods of ketosis.”

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Proposed nuclear/cytosolic trafficking pathways of ChREBP. In response to high glucose, phosphorylated inactive ChREBP is dephosphorylated by xylulose 5-phosphate (Xu5P)-activated PP2A and translocates into the nucleus through interactions with importins α and β. ChREBP is further dephosphorylated in the nucleus and induces transcription of L-type pyruvate kinase (L-PK) and lipogenic genes. A decrease in glucose concentration results in inactivation of ChREBP by phosphorylation by PKA and complex formation with 14-3-3 and CRM-1, followed by translocation to the cytosol.

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