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Adaptive and maladaptive roles for ChREBP in the liver and pancreatic islets

2021; Elsevier BV; Volume: 296; Linguagem: Inglês

10.1016/j.jbc.2021.100623

1083-351X

Liora S. Katz, Sharon Baumel-Alterzon, Donald K. Scott, Mark A. Herman,

Diet, Metabolism, and Disease

Excessive sugar consumption is a contributor to the worldwide epidemic of cardiometabolic disease. Understanding mechanisms by which sugar is sensed and regulates metabolic processes may provide new opportunities to prevent and treat these epidemics. Carbohydrate Responsive-Element Binding Protein (ChREBP) is a sugar-sensing transcription factor that mediates genomic responses to changes in carbohydrate abundance in key metabolic tissues. Carbohydrate metabolites activate the canonical form of ChREBP, ChREBP-alpha, which stimulates production of a potent, constitutively active ChREBP isoform called ChREBP-beta. Carbohydrate metabolites and other metabolic signals may also regulate ChREBP activity via posttranslational modifications including phosphorylation, acetylation, and O-GlcNAcylation that can affect ChREBP's cellular localization, stability, binding to cofactors, and transcriptional activity. In this review, we discuss mechanisms regulating ChREBP activity and highlight phenotypes and controversies in ChREBP gain- and loss-of-function genetic rodent models focused on the liver and pancreatic islets. Excessive sugar consumption is a contributor to the worldwide epidemic of cardiometabolic disease. Understanding mechanisms by which sugar is sensed and regulates metabolic processes may provide new opportunities to prevent and treat these epidemics. Carbohydrate Responsive-Element Binding Protein (ChREBP) is a sugar-sensing transcription factor that mediates genomic responses to changes in carbohydrate abundance in key metabolic tissues. Carbohydrate metabolites activate the canonical form of ChREBP, ChREBP-alpha, which stimulates production of a potent, constitutively active ChREBP isoform called ChREBP-beta. Carbohydrate metabolites and other metabolic signals may also regulate ChREBP activity via posttranslational modifications including phosphorylation, acetylation, and O-GlcNAcylation that can affect ChREBP's cellular localization, stability, binding to cofactors, and transcriptional activity. In this review, we discuss mechanisms regulating ChREBP activity and highlight phenotypes and controversies in ChREBP gain- and loss-of-function genetic rodent models focused on the liver and pancreatic islets. Sugar consumption in the form of sucrose or high-fructose corn syrup has increased markedly in recent decades (1Piernas C. Popkin B.M. Food portion patterns and trends among U.S. children and the relationship to total eating occasion size, 1977-2006.J. Nutr. 2011; 141: 1159-1164Crossref PubMed Scopus (0) Google Scholar, 2Brownell K.D. Farley T. Willett W.C. Popkin B.M. Chaloupka F.J. Thompson J.W. Ludwig D.S. The public health and economic benefits of taxing sugar-sweetened beverages.N. 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Complex mechanisms and systems have evolved to sense carbohydrate consumption and regulate its metabolism and storage to meet our bodies' long-term energetic and synthetic demands. Increases in circulating glucose following consumption of starch and sugar potently stimulate secretion of insulin from pancreatic beta-cells to coordinate systemic glucose homeostasis. Insulin increases glucose uptake in the muscle and adipose tissue for storage as glycogen and triglyceride, respectively. Insulin also suppresses glucose production by the liver and supports macromolecular anabolic programs such as protein synthesis throughout the body. Whereas glucose-mediated insulin secretion serves to integrate carbohydrate use systemically and maintain euglycemia, additional sugar-sensing systems exist within most cells to fine-tune cellular and tissue metabolic programs and responses independently of hormonal cues. In key metabolic cell types and tissues such as enterocytes, which are directly exposed to ingested nutrients, and the liver where ingested nutrients are delivered from the gut via the portal vein, these cellular nutrient-sensing mechanisms have further evolved to play key roles in the regulation of organ and systemic metabolism complementary to hormonal systems. Indeed, observations that high glucose levels in cell culture media regulated expression of glycolytic enzymes in isolated hepatocytes independently of insulin signaling led to the search for factors that mediated this cell autonomous metabolic regulation (12Yamashita H. Takenoshita M. Sakurai M. Bruick R.K. Henzel W.J. Shillinglaw W. Arnot D. Uyeda K. A glucose-responsive transcription factor that regulates carbohydrate metabolism in the liver.Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 9116-9121Crossref PubMed Scopus (486) Google Scholar). In 2001, Dr Kosaku Uyeda and colleagues discovered Carbohydrate Responsive-Element Binding Protein (ChREBP, also known as Mlxipl or MondoB), as the key factor that is activated by carbohydrate metabolites and transactivates genomic programs including glycolytic and lipogenic genes involved in the response to dietary and circulating sugars (12Yamashita H. Takenoshita M. Sakurai M. Bruick R.K. Henzel W.J. Shillinglaw W. Arnot D. Uyeda K. A glucose-responsive transcription factor that regulates carbohydrate metabolism in the liver.Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 9116-9121Crossref PubMed Scopus (486) Google Scholar, 13Iizuka K. Bruick R.K. Liang G. Horton J.D. Uyeda K. Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis.Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 7281-7286Crossref PubMed Scopus (516) Google Scholar). ChREBP has since been identified as a member of the Mondo family of basic helix-loop-helix transcription factors, which mediate an evolutionarily conserved and essential carbohydrate-sensing function across Animalia including Drosophila (14Li M.V. Chang B. Imamura M. Poungvarin N. Chan L. Glucose-dependent transcriptional regulation by an evolutionarily conserved glucose-sensing module.Diabetes. 2006; 55: 1179-1189Crossref PubMed Scopus (126) Google Scholar, 15Havula E. Teesalu M. Hyötyläinen T. Seppälä H. Hasygar K. Auvinen P. Orešič M. Sandmann T. Hietakangas V. Mondo/ChREBP-Mlx-regulated transcriptional network is essential for dietary sugar tolerance in Drosophila.PLoS Genet. 2013; 9e1003438Crossref PubMed Scopus (61) Google Scholar). ChREBP is a specialized member of this family found in mammals and expressed at high levels in key metabolic tissues including the liver, white and brown adipose tissue, pancreatic islet cells, small intestine, and kidney with lower level expression in other tissues including skeletal muscle (13Iizuka K. Bruick R.K. Liang G. Horton J.D. Uyeda K. Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis.Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 7281-7286Crossref PubMed Scopus (516) Google Scholar). MondoA (also known as Mlxip) is a glucose-sensing ChREBP homologue expressed ubiquitously in mammalian tissues and may fine-tune carbohydrate metabolism in these "non-metabolic" cell types (16Billin A.N. Eilers A.L. Coulter K.L. Logan J.S. Ayer D.E. MondoA, a novel basic helix-loop-helix-leucine zipper transcriptional activator that constitutes a positive branch of a max-like network.Mol. Cell. 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The ability of ChREBP and other Mondo family members to bind DNA and transactivate gene expression in response to carbohydrate metabolites requires dimerization with Max-like protein x (Mlx), another member of this transcription factor family (19Stoeckman A.K. Ma L. Towle H.C. Mlx is the functional heteromeric partner of the carbohydrate response element-binding protein in glucose regulation of lipogenic enzyme genes.J. Biol. Chem. 2004; 279: 15662-15669Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar). 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Our knowledge of the tissue-specific transcriptional targets and associated cellular and physiological mechanisms by which ChREBP mediates its pleiotropic metabolic effects remains poorly defined. In this review, we will discuss both adaptive and maladaptive functions of ChREBP in metabolic physiology guided by results in tissue-specific genetic gain- and loss-of-function models. We will limit our discussion to the role of ChREBP in the liver and pancreatic beta cells. Important roles for ChREBP have also been established in the intestine and white and brown adipose tissue. These aspects have been reviewed elsewhere recently (30Ortega-Prieto P. Postic C. Carbohydrate sensing through the transcription factor ChREBP.Front. Genet. 2019; 10: 472Crossref PubMed Scopus (37) Google Scholar, 31Abdul-Wahed A. Guilmeau S. Postic C. Sweet sixteenth for ChREBP: Established roles and future goals.Cell Metab. 2017; 26: 324-341Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). We will focus on controversies and outstanding issues arising out of these genetic models that will be important to resolve through additional investigation. Resolution of these controversies will be essential to focus future work on identifying specific ChREBP targets and pathways that may be leveraged to prevent and treat cardiometabolic disease. ChREBP senses carbohydrate metabolites and regulates downstream cellular processes including metabolic pathways and cell proliferation via its effects on gene expression. As such, its activity is tightly regulated depending upon the status of carbohydrate fuel availability. The precise carbohydrate metabolites and the mechanisms by which these metabolites regulate ChREBP transcriptional activity remain controversial. An early model suggested that ChREBP transcriptional activity was primarily regulated by an effect of the pentose-phosphate metabolite, xylulose-5-phosphate, to activate a protein phosphatase and dephosphorylate ChREBP at cAMP-dependent protein kinase phosphorylation sites (12Yamashita H. Takenoshita M. Sakurai M. Bruick R.K. Henzel W.J. Shillinglaw W. Arnot D. Uyeda K. A glucose-responsive transcription factor that regulates carbohydrate metabolism in the liver.Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 9116-9121Crossref PubMed Scopus (486) Google Scholar, 32Kabashima T. Kawaguchi T. Wadzinski B.E. Uyeda K. Xylulose 5-phosphate mediates glucose-induced lipogenesis by xylulose 5-phosphate-activated protein phosphatase in rat liver.Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 5107-5112Crossref PubMed Scopus (282) Google Scholar). This dephosphorylation was proposed to cause ChREBP's translocation into the nucleus and activation of its transcriptional targets. However, glucose responsiveness persists in mutant forms of ChREBP that cannot be phosphorylated by cAMP-dependent protein kinase (33Tsatsos N.G. Towle H.C. Glucose activation of ChREBP in hepatocytes occurs via a two-step mechanism.Biochem. Biophys. Res. Commun. 2006; 340: 449-456Crossref PubMed Scopus (64) Google Scholar). Moreover, mutant forms of ChREBP that are constitutively localized to the nucleus also retain carbohydrate responsiveness (34Davies M.N. O'Callaghan B.L. Towle H.C. Glucose activates ChREBP by increasing its rate of nuclear entry and relieving repression of its transcriptional activity.J. Biol. Chem. 2008; 283: 24029-24038Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar). Thus, nuclear localization, per se, is insufficient to activate ChREBP. As an alternative model, carbohydrate metabolites might directly bind and activate ChREBP through allosteric effects on the ChREBP protein itself. Glucose-6-phosphate (G6P) is the prime candidate for this activity (35Dentin R. Tomas-Cobos L. Foufelle F. Leopold J. Girard J. Postic C. Ferré P. Glucose 6-phosphate, rather than xylulose 5-phosphate, is required for the activation of ChREBP in response to glucose in the liver.J. Hepatol. 2012; 56: 199-209Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 36Li M.V. Chen W. Harmancey R.N. Nuotio-Antar A.M. Imamura M. Saha P. Taegtmeyer H. Chan L. Glucose-6-phosphate mediates activation of the carbohydrate responsive binding protein (ChREBP).Biochem. Biophys. Res. Commun. 2010; 395: 395-400Crossref PubMed Scopus (77) Google Scholar). The potential importance of G6P is supported by evidence that this metabolite also likely activates the ChREBP homologue, MondoA (17Stoltzman C.A. Peterson C.W. Breen K.T. Muoio D.M. Billin A.N. Ayer D.E. Glucose sensing by MondoA:Mlx complexes: A role for hexokinases and direct regulation of thioredoxin-interacting protein expression.Proc. Natl. Acad. Sci. U. S. A. 2008; 105: 6912-6917Crossref PubMed Scopus (169) Google Scholar). Other metabolites are also implicated (37Arden C. Tudhope S.J. Petrie J.L. Al-Oanzi Z.H. Cullen K.S. Lange A.J. Towle H.C. Agius L. Fructose 2,6-bisphosphate is essential for glucose-regulated gene transcription of glucose-6-phosphatase and other ChREBP target genes in hepatocytes.Biochem. J. 2012; 443: 111-123Crossref PubMed Scopus (65) Google Scholar). The potential role of G6P as an allosteric regulator of ChREBP activity is supported by identification of five evolutionarily conserved "mondo conserved regions" (MCR) in the N-terminus of ChREBP and its Mondo homologues that comprise a "glucose-sensing module" composed of a "low-glucose inhibitory domain" (LID) and a "glucose-response activation conserved element" (14Li M.V. Chang B. Imamura M. Poungvarin N. 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Imamura M. Poungvarin N. Chan L. Glucose-dependent transcriptional regulation by an evolutionarily conserved glucose-sensing module.Diabetes. 2006; 55: 1179-1189Crossref PubMed Scopus (126) Google Scholar). While allosteric activation of ChREBP might be required for its carbohydrate-sensing function, posttranslational modifications of ChREBP may alter protein stability, subcellular localization, protein–DNA or protein–protein interactions, all of which may alter the efficiency by which ChREBP transcribes its gene targets (32Kabashima T. Kawaguchi T. Wadzinski B.E. Uyeda K. Xylulose 5-phosphate mediates glucose-induced lipogenesis by xylulose 5-phosphate-activated protein phosphatase in rat liver.Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 5107-5112Crossref PubMed Scopus (282) Google Scholar, 33Tsatsos N.G. Towle H.C. Glucose activation of ChREBP in hepatocytes occurs via a two-step mechanism.Biochem. Biophys. Res. 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