Metabolite regulation of nuclear localization of carbohydrate-response element-binding protein (ChREBP)

Role of amp as an allosteric inhibitor

Shogo Sato, Hunmin Jung, Tsutomu Nakagawa, Robert Pawlosky, Tomomi Takeshima, Wan Ru Lee, Haruhiko Sakiyama, Sunil Laxman, R. Max Wynn, Benjamin P. Tu, John B. MacMillan, Jef K. De Brabander, Richard L. Veech, Kosaku Uyeda

Research output: Contribution to journalArticle

20 Citations (Scopus)

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 branchedchain 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.

Original languageEnglish (US)
Pages (from-to)10515-10527
Number of pages13
JournalJournal of Biological Chemistry
Volume291
Issue number20
DOIs
StatePublished - May 13 2016

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Response Elements
Metabolites
Carrier Proteins
Carbohydrates
Adenosine Monophosphate
14-3-3 Proteins
Ketone Bodies
Liver
Chemical activation
Fats
Karyopherins
Ribonucleotides
Glucose
Lipogenesis
Ketosis
AMP-Activated Protein Kinases
Unsaturated Fatty Acids
Cytosol
Cytoplasm
Transcription Factors

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Metabolite regulation of nuclear localization of carbohydrate-response element-binding protein (ChREBP) : Role of amp as an allosteric inhibitor. / 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.

In: Journal of Biological Chemistry, Vol. 291, No. 20, 13.05.2016, p. 10515-10527.

Research output: Contribution to journalArticle

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. / Metabolite regulation of nuclear localization of carbohydrate-response element-binding protein (ChREBP) : Role of amp as an allosteric inhibitor. In: Journal of Biological Chemistry. 2016 ; Vol. 291, No. 20. pp. 10515-10527.
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