Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis

Iizuka, Katsumi; Bruick, Richard K.; Liang, Guosheng; Horton, Jay D.; Uyeda, Kosaku

doi:10.1073/pnas.0401516101

Cited by 662 publications

(750 citation statements)

References 18 publications

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“…Recently, mice deleted for the ChREBP gene have been generated (23). These mice are viable but display a complex pattern of metabolic abnormalities.…”

Section: Discussionmentioning

confidence: 99%

“…Third, ChREBP shuttles between the cytoplasm and nucleus in a glucose-responsive manner in hepatocytes (31). Fourth, mice in which the ChREBP gene has been disrupted or hepatocytes treated with siRNA to reduce ChREBP expression do not induce lipogenic gene expression in response to carbohydrate feeding or glucose, respectively (23,43). Fifth, hepatocytes prepared from ChREBP knock-out mice do not support a glucose response when transfected with a ChoRE-containing promoter, but this response can be restored by the addition of a ChREBP expression vector (44).…”

Section: Discussionmentioning

confidence: 99%

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Direct Role of ChREBP·Mlx in Regulating Hepatic Glucose-responsive Genes

Tsatsos

Towle

2005

Journal of Biological Chemistry

163

141

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Enzymes required for de novo lipogenesis are induced in mammalian liver after a meal high in carbohydrates. In addition to insulin, increased glucose metabolism initiates an intracellular signaling pathway that transcriptionally regulates genes encoding lipogenic enzymes. A cis-acting sequence, the carbohydrate response element (ChoRE), has been found in the promoter region of several of these genes. ChREBP (carbohydrate response element-binding protein) was recently identified as a candidate transcription factor in the glucose-signaling pathway. We reported that ChREBP requires the heterodimeric partner Max-like factor X (Mlx) to bind to ChoRE sequences. In this study we provide further evidence to support a direct role of Mlx in glucose signaling in the liver. We constructed two different dominant negative forms of Mlx that could dimerize with ChREBP but block its binding to DNA. When introduced into hepatocytes, both dominant negative forms of Mlx inhibited the glucose response of a transfected ChoRE-containing promoter. The glucose response was rescued by adding exogenous wild type Mlx or ChREBP, but not MondoA, a paralog of ChREBP that can also form a heterodimer with Mlx. Furthermore, dominant negative Mlx blocked the induction of glucose-responsive genes from their natural chromosomal context under high glucose conditions. In contrast, genes induced by the insulin and thyroid hormone-signaling pathways were unaffected by dominant negative Mlx. Mlx was present in the glucoseresponsive complex of liver nuclear extract from which ChREBP was purified. In conclusion, Mlx is an obligatory partner of ChREBP in regulating lipogenic enzyme genes in liver.

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“…Recently, mice deleted for the ChREBP gene have been generated (23). These mice are viable but display a complex pattern of metabolic abnormalities.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Direct Role of ChREBP·Mlx in Regulating Hepatic Glucose-responsive Genes

Tsatsos

Towle

2005

Journal of Biological Chemistry

163

141

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“…Although both of these processes are controlled by insulin, the intermediary regulatory mechanisms appear to be separate. The conversion of carbohydrates to fatty acids is orchestrated by the transcription factors sterol regulatory element binding protein 1 (SREBP1c) and carbohydrate response element binding protein (ChREBP), which promote the transcription of enzymes required for de novo lipogenesis in response to insulin (21,25). Genetic disruption of the SREBP pathway markedly reduces fatty acid synthesis in liver (26), but does not prevent up-regulation of ANGPTL8 with refeeding (14).…”

Section: Discussionmentioning

confidence: 99%

Mice lacking ANGPTL8 (Betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis

Wang

Quagliarini²,

Gusarova

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

290

354

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Angiopoietin-like protein (ANGPTL)8 (alternatively called TD26, RIFL, Lipasin, and Betatrophin) is a newly recognized ANGPTL family member that has been implicated in both triglyceride (TG) and glucose metabolism. Hepatic overexpression of ANGPTL8 causes hypertriglyceridemia and increased insulin secretion. Here we examined the effects of inactivating Angptl8 on TG and glucose metabolism in mice. Angptl8 knockout (Angptl8 −/− ) mice gained weight more slowly than wild-type littermates due to a selective reduction in adipose tissue accretion. Plasma levels of TGs of the Angptl8 −/− mice were similar to wild-type animals in the fasted state but paradoxically decreased after refeeding. The lower TG levels were associated with both a reduction in very low density lipoprotein secretion and an increase in lipoprotein lipase (LPL) activity. Despite the increase in LPL activity, the uptake of very low density lipoprotein-TG is markedly reduced in adipose tissue but preserved in hearts of fed Angptl8 −/− mice. Taken together, these data indicate that ANGPTL8 plays a key role in the metabolic transition between fasting and refeeding; it is required to direct fatty acids to adipose tissue for storage in the fed state. Finally, glucose and insulin tolerance testing revealed no alterations in glucose homeostasis in mice fed either a chow or high fat diet. Thus, although absence of ANGPTL8 profoundly disrupts TG metabolism, we found no evidence that it is required for maintenance of glucose homeostasis.

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“…So far ChREBP has mainly been found to act as a glucose-stimulated transcriptional activator of glycolytic and lipogenic genes in hepatocytes (17)(18)(19)(20)(21) and in pancreatic ␤-cells (22,23). Recently, however, it was reported that ChREBP acts as a negative regulator of the ARNT/HIF-1␣ gene (56).…”

Section: Discussionmentioning

confidence: 99%

ChREBP Mediates Glucose Repression of Peroxisome Proliferator-activated Receptor α Expression in Pancreatic β-Cells

Boergesen

Poulsen

Schmidt

et al. 2011

Journal of Biological Chemistry

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The primary function of pancreatic ␤-cells is to continuously secrete an appropriate amount of insulin in response to the concentration of glucose and other nutrients in the blood. This process requires constant metabolic adjustment within the ␤-cell, which not only involves rapid changes in the post-translational state of key metabolic enzymes but also includes regulation of metabolic gene expression at the transcriptional level.

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Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis

Cited by 662 publications

References 18 publications

Direct Role of ChREBP·Mlx in Regulating Hepatic Glucose-responsive Genes

Direct Role of ChREBP·Mlx in Regulating Hepatic Glucose-responsive Genes

Mice lacking ANGPTL8 (Betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis

ChREBP Mediates Glucose Repression of Peroxisome Proliferator-activated Receptor α Expression in Pancreatic β-Cells

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