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

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

Authors :
Shogo Sato
Hunmin Jung
Jef K. De Brabander
Robert J. Pawlosky
Tomomi Takeshima
Kosaku Uyeda
Wan Ru Lee
R. Max Wynn
Tsutomu Nakagawa
Benjamin P. Tu
Richard L. Veech
John B. MacMillan
Haruhiko Sakiyama
Sunil Laxman
Source :
Journal of Biological Chemistry. 291:10515-10527
Publication Year :
2016
Publisher :
Elsevier BV, 2016.

Abstract

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.

Details

ISSN :
00219258
Volume :
291
Database :
OpenAIRE
Journal :
Journal of Biological Chemistry
Accession number :
edsair.doi...........3dfdb42ed720359e944bee4a3edd0891
Full Text :
https://doi.org/10.1074/jbc.m115.708982