Glucose activation of ChREBP in hepatocytes occurs via a two-step mechanism

Tsatsos, Nikolas G.; Towle, Howard C.

doi:10.1016/j.bbrc.2005.12.029

Cited by 71 publications

(66 citation statements)

References 26 publications

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“…33 Specifically, a diet rich in glucose has been shown to activate hepatic ChREBP in animal models leading to an increased expression of enzymes involved in the formation of triglycerides. 34,35 In this study, we confirmed these results and showed an elevated mRNA expression of ChREBP associated with increased levels of FAS and triglycerides in the liver of mice fed a 30% glucose solution. It is interesting that, such changes were not found in the livers of mice fed glucose concomitantly treated with tropisetron further, suggesting that tropisetron may prevent the metabolism of glucose into triglycerides in the liver.…”

Section: Discussionsupporting

confidence: 85%

Treatment with the 5-HT3 antagonist tropisetron modulates glucose-induced obesity in mice

et al. 2009

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Objective: Sugar consumption has increased markedly over the last few decades and parallels the dramatic increase in overweight and obesity. Data obtained from animal studies suggest that the intestinal serotonergic system and herein particularly the serotonin receptor 3 (5-HT3R) may be involved in sugar detection and short-term control of food intake. Using a mouse model, we tested the hypothesis that blocking 5-HT3R prevents the development of sugar-induced obesity. Design: For 8 weeks, C57BL/J6 mice were offered either water containing 30% glucose or plain water in addition to normal chow. The effect of oral treatment with the 5-HT3R antagonist, tropisetron (0.2 mg kg À1 body weight), on body weight and caloric intake was studied. Results: Total caloric intake and weight gain were significantly increased in mice fed glucose compared with the control group. Tropisetron treatment reduced intestinal motility and almost completely blocked weight gain associated with glucose feeding; however, total caloric intake was not affected. The effect of tropisetron was not associated with a decreased expression of the intestinal and hepatic glucose transporters, SGLT1 (sodium-dependent glucose cotransporter) and Glut2 (glucose transporter 2); instead, the expression of these transporters was slightly increased by the 5-HT3R antagonist. However, expressions of carbohydrate responsive element binding protein and fatty acid synthase, as well as triglyceride levels in the liver were only enhanced in mice fed glucose, but remained unchanged at the level of the control group when mice were treated concomitantly with tropisetron. At the same time, b-hydroxybutyrate dehydrogenase mRNA expression and plasma levels of ketone bodies were significantly increased. Conclusion: Our results suggest that 5-HT3R is a new target for the modulation of hepatic glucose metabolism and for the prevention of obesity.

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Section: Discussionsupporting

confidence: 85%

Treatment with the 5-HT3 antagonist tropisetron modulates glucose-induced obesity in mice

et al. 2009

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“…ChREBP is transcribed as either a fulllength ChREBP-α (864 residues), which is cytoplasmic at low glucose and activated by high glucose which causes translocation to the nucleus, recruitment to target genes and transcriptional activation, or as a shorter ChREBP-β isoform (lacking the first 117-residues at the N-terminus), that is constitutively active at low glucose (75) . Several aspects of the post-transcriptional regulation of ChREBP-α have been explored, including covalent modification by phosphorylation (8,(76)(77)(78) , O-GlcNAc-modification (79,80) and acetylation (81) ; mutational studies for mapping of the N-terminal glucose sensory domain and 14-3-3 binding sites (82)(83)(84) , and identification of putative metabolites that mediate the response to high glucose. The proposed metabolites include: G6P (85,86) , xylulose 5-P (8) , the regulatory metabolite F2,6P 2 ( 43,87) , ketone bodies (88) and the product of the hexosamine pathway UDP-N-acetylglucosamine (79,80) which is the substrate for O-GlcNAc-modification of proteins.…”

Section: Effects Of Fructose On Hepatic Phosphate Ester Inorganic Phmentioning

confidence: 99%

Dietary carbohydrate and control of hepatic gene expression: mechanistic links from ATP and phosphate ester homeostasis to the carbohydrate-response element-binding protein

Agius

2015

Proc. Nutr. Soc.

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Type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) are associated with elevated hepatic glucose production and fatty acid synthesis (de novolipogenesis (DNL)). High carbohydrate diets also increase hepatic glucose production and lipogenesis. The carbohydrate-response element-binding protein (ChREBP, encoded byMLXIPL) is a transcription factor with a major role in the hepatic response to excess dietary carbohydrate. Because its target genes include pyruvate kinase (PKLR) and enzymes of lipogenesis, it is regarded as a key regulator for conversion of dietary carbohydrate to lipid for energy storage. An alternative hypothesis for ChREBP function is to maintain hepatic ATP homeostasis by restraining the elevation of phosphate ester intermediates in response to elevated glucose. This is supported by the following evidence: (i) A key stimulus for ChREBP activation and induction of its target genes is elevation of phosphate esters; (ii) target genes of ChREBP include key negative regulators of the hexose phosphate ester pool (GCKR,G6PC,SLC37A4) and triose phosphate pool (PKLR); (iii) ChREBP knock-down models have elevated hepatic hexose phosphates and triose phosphates and compromised ATP phosphorylation potential; (iv) gene defects inG6PCandSLC37A4and common variants ofMLXIPL,GCKRandPKLRin man are associated with elevated hepatic uric acid production (a marker of ATP depletion) or raised plasma uric acid levels. It is proposed that compromised hepatic phosphate homeostasis is a contributing factor to the elevated hepatic glucose production and lipogenesis that associate with type 2 diabetes, NAFLD and excess carbohydrate in the diet.

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“…However, some groups have reported evidence against such a phosphorylation/dephosphorylation mechanism. Despite lacking phosphorylation sites by PKA, a S196A/T666A mutant of ChREBP retains glucose responsiveness and cAMP-dependent inhibition of ACC promoter transactivity [24]. Nevertheless, the ChREBP protein contains a glucose-sensing module that mediates its glucose responsiveness (Fig.…”

Section: Regulation Of Chrebp Transcriptional Activitymentioning

confidence: 99%

ChREBP: A Glucose-activated Transcription Factor Involved in the Development of Metabolic Syndrome

2008

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Abstract. Excess carbohydrate intake leads to fat accumulation and insulin resistance. Glucose and insulin coordinately regulate de novo lipogenesis from glucose in the liver, and insulin activates several transcription factors including SREBP1c and LXR, while those activated by glucose remain unknown. Recently, a carbohydrate response element binding protein (ChREBP), which binds to the carbohydrate response element (ChoRE) in the promoter of rat liver type pyruvate kinase (LPK), has been identified. The target genes of ChREBP are involved in glycolysis, lipogenesis, and gluconeogenesis. Although the regulation of ChREBP remains unknown in detail, the transactivity of ChREBP is partly regulated by a phosphorylation/dephosphorylation mechanism. During fasting, protein kinase A and AMP-activated protein kinase phosphorylate ChREBP and inactivate its transactivity. During feeding, xylulose-5-phosphate in the hexose monophosphate pathway activates protein phosphatase 2A, which dephosphorylates ChREBP and activates its transactivity. ChREBP controls 50% of hepatic lipogenesis by regulating glycolytic and lipogenic gene expression. In ChREBP -/-mice, liver triglyceride content is decreased and liver glycogen content is increased compared to wild-type mice. These results indicate that ChREBP can regulate metabolic gene expression to convert excess carbohydrate into triglyceride rather than glycogen. Furthermore, complete inhibition of ChREBP in ob/ob mice reduces the effects of the metabolic syndrome such as obesity, fatty liver, and glucose intolerance. Thus, further clarification of the physiological role of ChREBP may be useful in developing treatments for the metabolic syndrome.

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Glucose activation of ChREBP in hepatocytes occurs via a two-step mechanism

Cited by 71 publications

References 26 publications

Treatment with the 5-HT3 antagonist tropisetron modulates glucose-induced obesity in mice

Treatment with the 5-HT3 antagonist tropisetron modulates glucose-induced obesity in mice

Dietary carbohydrate and control of hepatic gene expression: mechanistic links from ATP and phosphate ester homeostasis to the carbohydrate-response element-binding protein

ChREBP: A Glucose-activated Transcription Factor Involved in the Development of Metabolic Syndrome

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