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

Sato S, Jung H, Nakagawa T, Pawlosky R, Takeshima T, Lee WR, Sakiyama H, Laxman S, Wynn RM, Tu BP, MacMillan JB, De Brabander JK, Veech RL, Uyeda K
J Biol Chem 291 10515-27 (2016)
Cited: 40 times
EuropePMC logo PMID: 26984404

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.

Reviews - 5f74 mentioned but not cited (1)

  1. Modulators of 14-3-3 Protein-Protein Interactions. Stevers LM, Sijbesma E, Botta M, MacKintosh C, Obsil T, Landrieu I, Cau Y, Wilson AJ, Karawajczyk A, Eickhoff J, Davis J, Hann M, O'Mahony G, Doveston RG, Brunsveld L, Ottmann C. J Med Chem 61 3755-3778 (2018)

Articles - 5f74 mentioned but not cited (4)

  1. Metabolite Regulation of Nuclear Localization of Carbohydrate-response Element-binding Protein (ChREBP): ROLE OF AMP AS AN ALLOSTERIC INHIBITOR. Sato S, Jung H, Nakagawa T, Pawlosky R, Takeshima T, Lee WR, Sakiyama H, Laxman S, Wynn RM, Tu BP, MacMillan JB, De Brabander JK, Veech RL, Uyeda K. J Biol Chem 291 10515-10527 (2016)
  2. Structure-based evolution of a promiscuous inhibitor to a selective stabilizer of protein-protein interactions. Sijbesma E, Visser E, Plitzko K, Thiel P, Milroy LG, Kaiser M, Brunsveld L, Ottmann C. Nat Commun 11 3954 (2020)
  3. Functional mapping of the 14-3-3 hub protein as a guide to design 14-3-3 molecular glues. Somsen BA, Craenmehr FWB, Liu WW, Koops AA, Pennings MAM, Visser EJ, Ottmann C, Cossar PJ, Brunsveld L. Chem Sci 13 13122-13131 (2022)
  4. What Makes a Good Protein-Protein Interaction Stabilizer: Analysis and Application of the Dual-Binding Mechanism. Chen SY, Zacharias M. ACS Cent Sci 9 969-979 (2023)


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  6. Carbohydrate Sensing Through the Transcription Factor ChREBP. Ortega-Prieto P, Postic C. Front Genet 10 472 (2019)
  7. The Role of Carbohydrate Response Element Binding Protein in Intestinal and Hepatic Fructose Metabolism. Iizuka K. Nutrients 9 E181 (2017)
  8. The Metformin Mechanism on Gluconeogenesis and AMPK Activation: The Metabolite Perspective. Agius L, Ford BE, Chachra SS. Int J Mol Sci 21 3240 (2020)
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  11. Glucose-6 Phosphate, A Central Hub for Liver Carbohydrate Metabolism. Rajas F, Gautier-Stein A, Mithieux G. Metabolites 9 E282 (2019)
  12. Recent insights into the role of ChREBP in intestinal fructose absorption and metabolism. Lee HJ, Cha JY. BMB Rep 51 429-436 (2018)
  13. Multifaceted Role of AMPK in Viral Infections. Bhutta MS, Gallo ES, Borenstein R. Cells 10 1118 (2021)
  14. 14-3-3: A Case Study in PPI Modulation. Ballone A, Centorrino F, Ottmann C. Molecules 23 E1386 (2018)
  15. Glucose-Sensing Transcription Factor MondoA/ChREBP as Targets for Type 2 Diabetes: Opportunities and Challenges. Song Z, Yang H, Zhou L, Yang F. Int J Mol Sci 20 E5132 (2019)
  16. The Protective Role of the Carbohydrate Response Element Binding Protein in the Liver: The Metabolite Perspective. Agius L, Chachra SS, Ford BE. Front Endocrinol (Lausanne) 11 594041 (2020)
  17. From Food to Genes: Transcriptional Regulation of Metabolism by Lipids and Carbohydrates. Bravo-Ruiz I, Medina MÁ, Martínez-Poveda B. Nutrients 13 1513 (2021)
  18. Insulin-Responsive Transcription Factors. Thiel G, Guethlein LA, Rössler OG. Biomolecules 11 1886 (2021)
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  20. The Role of Mondo Family Transcription Factors in Nutrient-Sensing and Obesity. Ke H, Luan Y, Wu S, Zhu Y, Tong X. Front Endocrinol (Lausanne) 12 653972 (2021)
  21. Mechanisms linking gut microbial metabolites to insulin resistance. Jang HR, Lee HY. World J Diabetes 12 730-744 (2021)
  22. The Roles of Carbohydrate Response Element Binding Protein in the Relationship between Carbohydrate Intake and Diseases. Iizuka K. Int J Mol Sci 22 12058 (2021)
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  1. Retinol saturase coordinates liver metabolism by regulating ChREBP activity. Heidenreich S, Witte N, Weber P, Goehring I, Tolkachov A, von Loeffelholz C, Döcke S, Bauer M, Stockmann M, Pfeiffer AFH, Birkenfeld AL, Pietzke M, Kempa S, Muenzner M, Schupp M. Nat Commun 8 384 (2017)
  2. Hepatic Carbohydrate Response Element Binding Protein Activation Limits Nonalcoholic Fatty Liver Disease Development in a Mouse Model for Glycogen Storage Disease Type 1a. Lei Y, Hoogerland JA, Bloks VW, Bos T, Bleeker A, Wolters H, Wolters JC, Hijmans BS, van Dijk TH, Thomas R, van Weeghel M, Mithieux G, Houtkooper RH, de Bruin A, Rajas F, Kuipers F, Oosterveer MH. Hepatology 72 1638-1653 (2020)
  3. 15N detection harnesses the slow relaxation property of nitrogen: Delivering enhanced resolution for intrinsically disordered proteins. Chhabra S, Fischer P, Takeuchi K, Dubey A, Ziarek JJ, Boeszoermenyi A, Mathieu D, Bermel W, Davey NE, Wagner G, Arthanari H. Proc Natl Acad Sci U S A 115 E1710-E1719 (2018)
  4. The glucose-sensing transcription factor ChREBP is targeted by proline hydroxylation. Heidenreich S, Weber P, Stephanowitz H, Petricek KM, Schütte T, Oster M, Salo AM, Knauer M, Goehring I, Yang N, Witte N, Schumann A, Sommerfeld M, Muenzner M, Myllyharju J, Krause E, Schupp M. J Biol Chem 295 17158-17168 (2020)
  5. Carbohydrate response element binding protein (ChREBP) modulates the inflammatory response of mesangial cells in response to glucose. Chen Y, Wang YJ, Zhao Y, Wang JC. Biosci Rep 38 BSR20180767 (2018)
  6. An Overview of the Mechanism of Penthorum chinense Pursh on Alcoholic Fatty Liver. Zhao X, Li L, Zhou M, Liu M, Deng Y, He L, Guo C, Li Y. Evid Based Complement Alternat Med 2020 4875764 (2020)
  7. A high throughput screen for pharmacological inhibitors of the carbohydrate response element. You S, Bollong MJ. Sci Data 10 676 (2023)
  8. ChREBP deficiency prevents high sucrose diet-induced obesity through reducing sucrase expression. Sakiyama H, Li L, Inoue M, Eguchi H, Yoshihara D, Fujiwara N, Suzuki K. J Clin Biochem Nutr 71 221-228 (2022)
  9. Identification of heat shock protein family A member 5 (HSPA5) targets involved in nonalcoholic fatty liver disease. Rehati A, Abuduaini B, Liang Z, Chen D, He F. Genes Immun 24 124-129 (2023)


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