Metabolite Regulation of Nuclear Localization of Carbohydrate-response Element-binding Protein (ChREBP)

The carbohydrate-response element-binding protein (ChREBP) is a glucose-responsive transcription factor that plays an essential role in converting excess carbohydrate to fat storage in the liver. In response to glucose levels, ChREBP is regulated by nuclear/cytosol trafficking via interaction with 1...

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Veröffentlicht in:The Journal of biological chemistry 2016-05, Vol.291 (20), p.10515-10527
Hauptverfasser: Sato, Shogo, Jung, Hunmin, Nakagawa, Tsutomu, Pawlosky, Robert, Takeshima, Tomomi, Lee, Wan-Ru, Sakiyama, Haruhiko, Laxman, Sunil, Wynn, R. Max, Tu, Benjamin P., MacMillan, John B., De Brabander, Jef K., Veech, Richard L., Uyeda, Kosaku
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Sprache:eng
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Zusammenfassung:The carbohydrate-response element-binding protein (ChREBP) is a glucose-responsive transcription factor that plays an essential role in converting excess carbohydrate to fat storage in the liver. In response to glucose levels, ChREBP is regulated by nuclear/cytosol trafficking via interaction with 14-3-3 proteins, CRM-1 (exportin-1 or XPO-1), or importins. Nuclear localization of ChREBP was rapidly inhibited when incubated in branched-chain α-ketoacids, saturated and unsaturated fatty acids, or 5-aminoimidazole-4-carboxamide ribonucleotide. Here, we discovered that protein-free extracts of high fat-fed livers contained, in addition to ketone bodies, a new metabolite, identified as AMP, which specifically activates the interaction between ChREBP and 14-3-3. The crystal structure showed that AMP binds directly to the N terminus of ChREBP-α2 helix. Our results suggest that AMP inhibits the nuclear localization of ChREBP through an allosteric activation of ChREBP/14-3-3 interactions and not by activation of AMPK. AMP and ketone bodies together can therefore inhibit lipogenesis by restricting localization of ChREBP to the cytoplasm during periods of ketosis.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M115.708982