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J Biol Chem. 2016 May 13;291(20):10515-27. doi: 10.1074/jbc.M115.708982. Epub 2016 Mar 16.

Metabolite Regulation of Nuclear Localization of Carbohydrate-response Element-binding Protein (ChREBP): ROLE OF AMP AS AN ALLOSTERIC INHIBITOR.

Author information

1
From the Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390.
2
the National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-8115, and.
3
From the Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, the Dallas Veterans Affairs Medical Center, Dallas, Texas 75216 kuyeda@utsouthwestern.edu.

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.

KEYWORDS:

AMP; ChREBP; allosteric regulation; glucose metabolism; glucose sensing; hepatocyte; ketogenesis; lipogenesis; nuclear localization

PMID:
26984404
PMCID:
PMC4865902
DOI:
10.1074/jbc.M115.708982
[Indexed for MEDLINE]
Free PMC Article

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