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A schematic of the de novo lipogenesis pathway is shown. Direct targets of ChREBP identified by ChIP-seq are indicated in boldface type. GKRP, glucokinase regulatory protein; G6Pase, glucose-6-phosphatase, catalytic subunit; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; PKLR, pyruvate kinase, liver and RBC; PCK1, phosphoenolpyruvate carboxykinase1; LDH, lactate dehydrogenase A; DCT, dicarboxylate transporter; PDK2, pyruvate dehydrogenase kinase isozyme2; PDH, pyruvate dehydrogenase; SDHAP3, succinate dehydrogenase complex, subunit A; FASN, fatty acid synthase; SCD1, stearoyl-CoA desaturase 1; GPD1, glycerol-3-phosphate dehydrogenase 1 (soluble); MOGAT2, monoacylglycerol O-acyltransferase 2; DGAT2, diacylglycerol O-acyltransferase homolog 2.
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The carbohydrate response element binding protein (ChREBP), a basic helix-loop-helix/leucine zipper transcription factor, plays a critical role in the control of lipogenesis in the liver. To identify the direct targets of ChREBP on a genome-wide scale and provide more insight into the mechanism by which ChREBP regulates glucose-responsive gene expr...
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Extensive studies in Arabidopsis and rice have demonstrated that Subgroup-A members of the bZIP transcription factor family play important roles in plant responses to multiple abiotic stresses. Although common wheat (Triticum aestivum) is one of the most widely cultivated and consumed food crops in the world, there are limited investigations into S...
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... Mondo-Mlx binds to the ChoRE (carbohydrate response element) motif as heterodimers to regulate most of the global glucose-induced transcriptional responses and many of their target genes involved in carbohydrate, lipid, and amino acid metabolism [29][30][31][32][33][34][35][36]. These target genes include Phosphofructokinase 2 (PFK2), Aldehyde dehydrogenase type III (Adh III), Glucose-6-phosphate dehydrogenase (G6PD), FAS, ACC, GS2, and so on in flies [29][30][31][32][33][34]36,37]. ...
... Mondo-Mlx binds to the ChoRE (carbohydrate response element) motif as heterodimers to regulate most of the global glucose-induced transcriptional responses and many of their target genes involved in carbohydrate, lipid, and amino acid metabolism [29][30][31][32][33][34][35][36]. These target genes include Phosphofructokinase 2 (PFK2), Aldehyde dehydrogenase type III (Adh III), Glucose-6-phosphate dehydrogenase (G6PD), FAS, ACC, GS2, and so on in flies [29][30][31][32][33][34]36,37]. Meanwhile, Mondo-Mlx regulates sugar transport GLUT and the carbohydrate digestion gene Amy-p [33]. ...
... As one of the three major nutrient types, fatty acids can not only provide energy for organisms but are also the raw materials for synthesizing other substances. ChREBP-Mlx in mammals and flies regulate transcription of the lipogenic genes ACC and FAS [29][30][31]33,36,37]. When RNAi was performed for Mlx or Mondo in BmNs cells, the expression of ACC was decreased, which is the rate-limiting enzyme in the fatty acid synthesis pathway (Figure 3a). ...
Bombyx mori was domesticated from Bombyx mandarina. The long-term domestication of the silkworm has brought about many remarkable changes to its body size and cocoon shell weight. However, the molecular mechanism underlying the improvement in the economic characteristics of this species during domestication remains unclear. In this study, we found that a transposable element (TE)—Bm1—was present in the upstream regulatory region of the Mlx (Max-like protein X) gene in wild silkworms but not in all domesticated silkworms. The absence of Bm1 caused an increase in the promoter activity and mRNA content of Mlx. Mlx and its partner Mondo belong to the bHLHZ transcription factors family and regulate nutrient metabolism. RNAi of Mlx and Mondo decreased the expression and promoter activity of glucose metabolism-related genes (trehalose transport (Tret), phosphofructokinase (PFK), and pyruvate kinase (PK)), lipogenic genes (Acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS)), and glutamine synthesis gene (Glutamine synthase 2, (GS2)). Furthermore, the transgenic overexpression of Mlx and Mondo in the fat body of silkworms increased the larval body size, cocoon shell weight, and egg number, but the silencing of the two genes resulted in the opposite phenotypes. Our results reveal the molecular mechanism of Mlx selection during domestication and its successful use in the molecular breeding of Bombyx mori.
... Fasting suppresses ChREBP activation, whereas refeeding with a high-carbohydrate diet stimulates ChREBP expression and activity [53,54]. ChREBP directly regulates KLF10 expression by binding to ChoRE in the KLF10 promoter region [55,56]. KLF10 deletion increases the activity of ChREBP target genes in the liver, while KLF10 overexpression inhibits ChREBP target genes. ...
Fibrosis, characterized by excessive extracellular matrix accumulation, disrupts normal tissue architecture, causes organ dysfunction, and contributes to numerous chronic diseases. This review focuses on Krüppel-like factor 10 (KLF10), a transcription factor significantly induced by transforming growth factor-β (TGF-β), and its role in fibrosis pathogenesis and progression across various tissues. KLF10, initially identified as TGF-β-inducible early gene-1 (TIEG1), is involved in key biological processes including cell proliferation, differentiation, apoptosis, and immune responses. Our analysis investigated KLF10 gene and protein structures, interaction partners, and context-dependent functions in fibrotic diseases. This review highlights recent findings that underscore KLF10 interaction with pivotal signaling pathways, such as TGF-β, and the modulation of gene expression in fibrotic tissues. We examined the dual role of KLF10 in promoting and inhibiting fibrosis depending on tissue type and fibrotic context. This review also discusses the therapeutic potential of targeting KLF10 in fibrotic diseases, based on its regulatory role in key pathogenic mechanisms. By consolidating current research, this review aims to enhance the understanding of the multifaceted role of KLF10 in fibrosis and stimulate further research into its potential as a therapeutic target in combating fibrotic diseases.
... ChREBP has been established to be a key transcription factor in adipogenesis induced by glucose in hepatocytes, 3T3-L1 cells, and rat adipocytes (Burgess et al., 2008;Herman et al., 2012;Iizuka et al., 2012). Glucose stimulated ChREBP expression and activated its transcriptional activity through the intermediate glucose-6-phosphate, and thus regulated the expressions of target genes, including Txnip and ACC1 (Jeong et al., 2011;McFerrin and Atchley, 2012). In the present study, the adipogenesis was significantly stimulated, and the expressions of ChREBP and Txnip were upregulated in porcine adipocytes when treated with high glucose. ...
To explore the functions of Txnip and its mechanism in adipocyte differentiation, the preadipocytes were isolated from subcutaneous adipose tissue of three-day-old piglets and induced into adipogenic differentiation. The expression of Txnip and ChREBP was silenced, and the Txnip overexpression was achieved in the cells with transfection of the recombinant lentivirus strategies. Txnip silencing promoted the differentiation of porcine preadipocytes and PPARγ expression, and a PPARγ inhibitor reduced this facilitation. Instead, Txnip overexpression exerted a suppressive effect on the cell differentiation and PPARγ expression, and the PPARγ agonist offset this inhibition. High glucose stimulated the preadipocyte differentiation and expressions of ChREBP and Txnip. In contrast, Txnip expression was reduced by ChREBP silencing, suggesting glucose-regulated Txnip expression through the mediation of ChREBP. Moreover, the expressions of ChREBP and Glut4 induced by high glucose and glucose uptake of the cells were reduced by Txnip-overexpression, but increased by Txnip silencing, while these changes of Txnip did not alter their expressions under low glucose. Collectively, Txnip could be an inhibitor of porcine preadipocyte differentiation, which attenuated the adipogenesis through the negative feedback regulation on PPARγ. Txnip impaired the induction of glucose on the preadipocyte differentiation through decreasing Glut4 expression and glucose uptake and subsequent decrease of the expression and transcriptional activity of ChREBP.
Keywords:
adipose tissue; lipid; pig
... The complement of ChREBP transcriptional targets that regulates these diverse traits is incompletely understood. To date, ChIP-Seq assays have implicated thousands of genes as ChREBP targets (10,11). It is well established that ChREBP regulates glycolysis and fructolysis, hepatic and adipose lipogenesis, and hepatic glucose production via regulation of key enzymes involved in these metabolic pathways (4,(12)(13)(14). ...
Carbohydrate Responsive Element-Binding Protein (ChREBP) is a carbohydrate sensing transcription factor that regulates both adaptive and maladaptive genomic responses in coordination of systemic fuel homeostasis. Genetic variants in the ChREBP locus associate with diverse metabolic traits in humans, including circulating lipids. To identify novel ChREBP-regulated hepatokines that contribute to its systemic metabolic effects, we integrated ChREBP ChIP-seq analysis in mouse liver with human genetic and genomic data for lipid traits and identified Hepatocyte Growth Factor Activator (HGFAC) as a promising ChREBP-regulated candidate in mice and humans. HGFAC is a protease that activates the pleiotropic hormone Hepatocyte Growth Factor (HGF). We demonstrate that HGFAC KO mice have phenotypes concordant with putative loss-of-function variants in human HGFAC. Moreover, in gain- and loss-of-function genetic mouse models, we demonstrate that HGFAC enhances lipid and glucose homeostasis, which may be mediated in part through actions to activate hepatic PPARγ activity. Together, our studies show that ChREBP mediates an adaptive response to overnutrition via activation of HGFAC in the liver to preserve glucose and lipid homeostasis.
... Mlx Network target genes, while overlapping with those regulated by the Myc Network, are both fewer in number and have been reported to be more functionally restricted [65][66][67]. They tend to encode enzymes involved in carbohydrate and lipid metabolism; mitochondrial and ribosomal proteins and factors that regulate translational initiation, elongation and termination [21,33,50,[57][58][59][60]63,[65][66][67][68][69][70][71][72][73][74][75][76][77][78]. Together these findings indicate that, via selective, cytoplasmic-nuclear partitioning, sharing of Mxd1,4 and Mnt and binding to both common and unique target genes, this "Extended Myc Network" cross-talks, while simultaneously communicating with and responding to the metabolic cues needed to support energy-intensive processes such as translation and proliferation [43,[50][51][52]56,[77][78][79][80][81][82][83][84][85]. ...
Among the first discovered and most prominent cellular oncogenes is MYC, which encodes a bHLH-ZIP transcription factor (Myc) that both activates and suppresses numerous genes involved in proliferation, energy production, metabolism and translation. Myc belongs to a small group of bHLH-ZIP transcriptional regulators (the Myc Network) that includes its obligate heterodimerization partner Max and six “Mxd proteins” (Mxd1-4, Mnt and Mga) each of which heterodimerizes with Max and largely oppose Myc’s functions. More recently, a second group of bHLH-ZIP proteins (the Mlx Network) has emerged. It is comprised of the Myc-like factors ChREBP and MondoA, which, in association with the Max-like member Mlx, regulate smaller and more functionally restricted sets of target genes, some of which are shared with Myc. Opposing ChREBP and MondoA are heterodimers comprised of Mlx and Mxd1, Mxd4 and Mnt, which also structurally and operationally link the two Networks. We discuss here the functions of these “Extended Myc Network” members with particular emphasis on the roles played by Max, Mlx and Mxd proteins in suppressing normal and neoplastic growth. These roles are complex due to the temporally- and tissue-restricted expression of Extended Myc Network proteins in normal cells, their regulation of both common and unique target genes and, in some cases, their functional redundancy.
... The expression of the mammalian stearoyl-CoA desaturase (SCD) genes is repressed by the satiety hormone leptin and is activated by insulin (Waters and Ntambi, 1994), dietary cholesterol (Garg et al., 1988), saturated fat or sugar (Miyazaki et al., 2004), and TFs including SREBP (Tabor et al., 1998(Tabor et al., , 1999, ChREBP (Jeong et al., 2011), nuclear transcription factor-Y (NF-Y) (Yao et al., 2016), liver X receptor (LXR) (Zhang et al., 2014) and the cofactor PGC-1 (Lin et al., 2005). The stearoyl-CoA desaturase or 'Desat' class of lipid metabolic enzymes has not previously been shown to function in cardiac lipotoxicity but plays an important role in lipogenesis and is essential for the flexibility and utility of acyl chain substituents in phospholipids, TG and other complex lipids. ...
Diets high in carbohydrates are associated with type 2 diabetes and its comorbidities, including hyperglycemia, hyperlipidemia, obesity, hepatic steatosis and cardiovascular disease. We use a high-sugar diet to study the pathophysiology of diet-induced metabolic disease in Drosophila melanogaster. High-sugar diets produce hyperglycemia, obesity, insulin resistance, and cardiomyopathy in flies along with ectopic accumulation of toxic lipids, or lipotoxicity. Stearoyl-CoA desaturase 1 is an enzyme that contributes to long-chain fatty acid metabolism by introducing a double bond into the acyl chain. Knockdown of stearoyl-CoA desaturase 1 in the fat body reduced lipogenesis and exacerbated pathophysiology in flies reared on high-sugar diets. These flies exhibited dyslipidemia and growth deficiency in addition to defects in cardiac and gut function. We assessed the lipidome of these flies using tandem mass spectrometry to provide insight into the relationship between potentially lipotoxic species and type 2 diabetes-like pathophysiology. Oleic acid supplementation is able to rescue a variety of phenotypes produced by stearoyl-CoA desaturase 1 RNAi, including fly weight, triglyceride storage, gut development, and cardiac failure. Taken together, these data suggest a protective role for monounsaturated fatty acids in diet-induced metabolic disease phenotypes.
... There is a carbohydrate response element-binding proteinβ (ChREBP-β) binding site 2.5 kb upstream of the BDK transcriptional start site (Jeong et al., 2011). Furthermore, adenovirus ChREBP-β treatment for 7 days upregulates BDK transcripts (∼50%) in rat liver (White et al., 2018). ...
Branched-chain amino acids (BCAAs) are critical for skeletal muscle and whole-body anabolism and energy homeostasis. They also serve as signaling molecules, for example, being able to activate mammalian/mechanistic target of rapamycin complex 1 (mTORC1). This has implication for macronutrient metabolism. However, elevated circulating levels of BCAAs and of their ketoacids as well as impaired catabolism of these amino acids (AAs) are implicated in the development of insulin resistance and its sequelae, including type 2 diabetes, cardiovascular disease, and of some cancers, although other studies indicate supplements of these AAs may help in the management of some chronic diseases. Here, we first reviewed the catabolism of these AAs especially in skeletal muscle as this tissue contributes the most to whole body disposal of the BCAA. We then reviewed emerging mechanisms of control of enzymes involved in regulating BCAA catabolism. Such mechanisms include regulation of their abundance by microRNA and by post translational modifications such as phosphorylation, acetylation, and ubiquitination. We also reviewed implications of impaired metabolism of BCAA for muscle and whole-body metabolism. We comment on outstanding questions in the regulation of catabolism of these AAs, including regulation of the abundance and post-transcriptional/post-translational modification of enzymes that regulate BCAA catabolism, as well the impact of circadian rhythm, age and mTORC1 on these enzymes. Answers to such questions may facilitate emergence of treatment/management options that can help patients suffering from chronic diseases linked to impaired metabolism of the BCAAs.
... De manière intéressante, la surexpression hépatique de SIK2 en parallèle de celle de p300, protège le foie d'une accumulation excessive d'acides gras tandis que son inhibition chez des souris invalidées spécifiquement pour SIK2 dans le foie favorise le développement d'une stéatose hépatique, d'une résistance à l'insuline et d'une inflammation (Bricambert et al., 2010). On sait également aujourd'hui que ChREBP peut jouer le rôle de répresseur transcriptionnel (Jeong et al., 2011). Dans l'hépatocyte, le recrutement de ChREBP sur le promoteur de la PEPCK inhibe son expression en réponse au glucose. ...
La prévalence du développement du carcinome hépatocellulaire (CHC) est en constante augmentation dans les sociétés occidentales. Ainsi, au fil de cette décennie, cette forme de cancer du foie est devenue la quatrième cause de mortalité par cancer dans le monde, en raison notamment d’un diagnostic tardif et d’une résistance aux traitements classique de chimiothérapie. Chez l'homme, l’initiation et le développement d'un CHC est particulièrement corrélée à l'augmentation du nombre de patients atteints du syndrome métabolique (obésité, diabète, stéatose hépatique). Dans ce contexte, il est désormais bien décrit que les tumeurs présentent une reprogrammation de leur activité métabolique qui favorise la progression du cancer. En raison de son rôle central dans le contrôle du métabolisme des glucides et des lipides dans le foie, nous avons émis l'hypothèse que le facteur de transcription sensible au glucose ChREBP (Carbohydrate Responsive Element Binding Protein), jouant un rôle clé dans la régulation du métabolisme des lipides dans le foie, pourrait jouer un rôle clé dans les étapes d’initiation et de développement du CHC. Pour répondre à cette question, ChREBP a été surexprimé de manière stable dans le foie de souris C57BL6/J en utilisant la technique non virale de transfert de gêne par transposition appelée «Sleeping beauty». Nos résultats montrent pour la première fois qu'une augmentation de l'activité transactivatrice de ChREBP dans l'hépatocyte est suffisante à elle seule pour initier le développement d'un CHC de mauvais pronostic chez la souris. D'un point de vue moléculaire, ChREBP exerce ses effets proprolifératifs et pro-oncogéniques sur l’hépatocyte en stimulant l'activité de la voie de signalisation PI3K/AKT, dans un mécanisme dépendant de la régulation transcriptionnelle de la sous unité régulatrice p85α de la PI3K. De plus, l’augmentation de l’activité de ChREBP favorise la réorientation du métabolisme du glucose et de la glutamine vers des voies anaboliques de synthèse de novo de lipide et de nucléotide nécessaires au soutien de la prolifération des cellules tumorales. Dans ce contexte, nous démontrons pour la première fois que l'activité de ChREBP est systématiquement augmentée dans 10 cohortes indépendantes de CHC chez l’homme. Finalement, d'un point de vue thérapeutique, nos travaux ont caractérisé un nouvel inhibiteur pharmacologique de ChREBP permettant de diminuer la prolifération cellulaire, le développement tumoral et de manière plus importante de sensibiliser les cellules cancéreuses hépatiques au sorafenib qui représente de nos le traitement de référence utilisé chez l’homme dans le cadre de la lutte contre le CHC. En conclusion, nos travaux ont identifié un nouveau mécanisme de la carcinogenèse hépatique, impliquant le facteur de transcription ChREBP. Au vu denos résultats, ChREBP constitue une cible thérapeutique de choix pour le développement de nouvelles stratégies de traitement au CHC.
... The b isoform is expressed at extremely low levels; however, its transcriptional activity is much more potent than that of the a isoform. [36] ChREBP is abundantly expressed in both liver and intestine, [37,38] and regulates transcription of many genes involved in monocarbohydrate transport, glycolysis, fructolysis, and de novo lipogenesis (DNL), [37,[39][40][41] thereby contributing to glucose and lipid homeostasis. The target genes regulated by ChREBP are very extensive with different physiological significance. ...
Excessive consumption of fructose, the sweetest of all naturally occurring carbohydrates, has been linked to worldwide epidemics of metabolic diseases in humans, and it is considered an independent risk factor for cardiovascular diseases. We provide an overview about the features of fructose metabolism, as well as potential mechanisms by which excessive fructose intake is associated with the pathogenesis of metabolic diseases both in humans and rodents. To accomplish this aim, we focus on illuminating the cellular and molecular mechanisms of fructose metabolism as well as its signaling effects on metabolic and cardiovascular homeostasis in health and disease, highlighting the role of carbohydrate-responsive element-binding protein in regulating fructose metabolism.
... In the mouse liver, KLF10 is a circadian clock-controlled transcription factor that regulates genes implicated in glucose and lipid metabolism [22]. Moreover, the levels of KLF10 are increased in primary mouse hepatocytes upon glucose treatment by the carbohydrate response element-binding protein (ChREBP), which is another major transcription factor that regulates various genes involved in glucose and lipid metabolism [23][24][25][26]. The levels of KLF10 are increased in the mouse models of diabetes and obesity, and its gene variants exhibit a mild correlation with the development of type 2 diabetes [27,28]. ...
Liver fibrosis is a consequence of chronic liver injury associated with chronic viral infection, alcohol abuse, and nonalcoholic fatty liver. The evidence from clinical and animal studies indicates that transforming growth factor-β (TGF-β) signaling is associated with the development of liver fibrosis. Krüppel-like factor 10 (KLF10) is a transcription factor that plays a significant role in TGF-β-mediated cell growth, apoptosis, and differentiation. In recent studies, it has been reported to be associated with glucose homeostasis and insulin resistance. In the present study, we investigated the role of KLF10 in the progression of liver disease upon a high-sucrose diet (HSD) in mice. Wild type (WT) and Klf10 knockout (KO) mice were fed either a control chow diet or HSD (50% sucrose) for eight weeks. Klf10 KO mice exhibited significant hepatic steatosis, inflammation, and liver injury upon HSD feeding, whereas the WT mice exhibited mild hepatic steatosis with no apparent liver injury. The livers of HSD-fed Klf10 KO mice demonstrated significantly increased endoplasmic reticulum stress, oxidative stress, and proinflammatory cytokines. Klf10 deletion led to the development of sucrose-induced hepatocyte cell death both in vivo and in vitro. Moreover, it significantly increased fibrogenic gene expression and collagen accumulation in the liver. Increased liver fibrosis was accompanied by increased phosphorylation and nuclear localization of Smad3. Here, we demonstrate that HSD-fed mice develop a severe liver injury in the absence of KLF10 due to the hyperactivation of the endoplasmic reticulum stress response and CCAAT/enhance-binding protein homologous protein (CHOP)-mediated apoptosis of hepatocytes. The current study suggests that KLF10 plays a protective role against the progression of hepatic steatosis into liver fibrosis in a lipogenic state.
