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Title: Metabolite Regulation of Nuclear Localization of Carbohydrate-response Element-binding Protein (ChREBP): Role of AMP as an Allosteric Inhibitor

Journal Article · · Journal of Biological Chemistry
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  1. Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
  2. National Inst. on Alcohol Abuse and Alcoholism, Bethesda, MD (United States)
  3. Univ. of Texas Southwestern Medical Center, Dallas, TX (United States); Dallas Veterans Affairs Medical Center, Dallas, TX (United States)
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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. As a result, AMP and ketone bodies together can therefore inhibit lipogenesis by restricting localization of ChREBP to the cytoplasm during periods of ketosis.

Research Organization:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER); Dept. of Veterans Affairs; Robert A. Welch Foundation
Grant/Contract Number:
AC02-06CH11357; I-1720; I-1422
OSTI ID:
1256357
Journal Information:
Journal of Biological Chemistry, Vol. 291, Issue 20; ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular BiologyCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 46 works
Citation information provided by
Web of Science

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Cited By (7)

15 N detection harnesses the slow relaxation property of nitrogen: Delivering enhanced resolution for intrinsically disordered proteins journal February 2018
The Role of Carbohydrate Response Element Binding Protein in Intestinal and Hepatic Fructose Metabolism journal February 2017
Stearoyl-CoA Desaturase 1 as a Therapeutic Target for the Treatment of Cancer journal July 2019
Carbohydrate Sensing Through the Transcription Factor ChREBP journal June 2019
Carbohydrate response element binding protein (ChREBP) modulates the inflammatory response of mesangial cells in response to glucose journal December 2018
Treatment of nonalcoholic fatty liver disease: role of AMPK journal October 2016
Regulation and Metabolic Significance of De Novo Lipogenesis in Adipose Tissues journal September 2018

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
allosteric regulation
AMP
glucose metabolism
hepatocyte
lipogenesis
ChREBP
ketogenesis
glucose sensing
nuclear localization