Integrated Expression Profiling and Genome-Wide Analysis of ChREBP Targets Reveals the Dual Role for ChREBP in Glucose-Regulated Gene Expression

Jeong, Yun Seung; Kim, Deokhoon; Lee, Yong Seok; Kim, Ha Jung; Han, Jung Youn; Im, Seung Soon; Chong, Hansook Kim; Kwon, Je Keun; Cho, Yun Ho; Kim, Woo Kyung; Osborne, Timothy F.; Horton, Jay D.; Jun, Hee-Sook; Ahn, Yeon Soon; Ahn, Sung Min; Young, Jung Han

doi:10.1371/journal.pone.0022544

Cited by 134 publications

(135 citation statements)

References 48 publications

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“…3B). In contrast to the findings in HepG2 cells (35) and INS1 cells (34, 36), we did not find recruitment of ChREBP to the TXNIP gene promoter (Fig. 3B).…”

Section: Resultscontrasting

confidence: 99%

Glucose Induces Protein Targeting to Glycogen in Hepatocytes by Fructose 2,6-Bisphosphate-Mediated Recruitment of MondoA to the Promoter

Petrie

Al‐Oanzi

Arden

et al. 2013

Molecular and Cellular Biology

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dIn the liver, a high glucose concentration activates transcription of genes encoding glucose 6-phosphatase and enzymes for glycolysis and lipogenesis by elevation in phosphorylated intermediates and recruitment of the transcription factor ChREBP (carbohydrate response element binding protein) and its partner, Mlx, to gene promoters. A proposed function for this mechanism is intracellular phosphate homeostasis. In extrahepatic tissues, MondoA, the paralog of ChREBP, partners with Mlx in transcriptional induction by glucose. We tested for glucose induction of regulatory proteins of the glycogenic pathway in hepatocytes and identified the glycogen-targeting proteins, G L and PTG (protein targeting to glycogen), as being encoded by Mlx-dependent glucose-inducible genes. PTG induction by glucose was MondoA dependent but ChREBP independent and was enhanced by forced elevation of fructose 2,6-bisphosphate and by additional xylitol-derived metabolites. It was counteracted by selective depletion of fructose 2,6-bisphosphate with a bisphosphatase-active kinase-deficient variant of phosphofructokinase 2/fructosebisphosphatase 2, which prevented translocation of MondoA to the nucleus and recruitment to the PTG promoter. We identify a novel role for MondoA in the liver and demonstrate that elevated fructose 2,6-bisphosphate is essential for recruitment of MondoA to the PTG promoter. Phosphometabolite activation of MondoA and ChREBP and their recruitment to target genes is consistent with a mechanism for gene regulation to maintain intracellular phosphate homeostasis.

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“…3B). In contrast to the findings in HepG2 cells (35) and INS1 cells (34, 36), we did not find recruitment of ChREBP to the TXNIP gene promoter (Fig. 3B).…”

Section: Resultscontrasting

confidence: 99%

Glucose Induces Protein Targeting to Glycogen in Hepatocytes by Fructose 2,6-Bisphosphate-Mediated Recruitment of MondoA to the Promoter

Petrie

Al‐Oanzi

Arden

et al. 2013

Molecular and Cellular Biology

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“…Our results also showed a positive correlation of blood glucose and HbA1c with circulating betatrophin in T2DM in subgroups treated with insulin and having higher BMI which is supported by the results of Fu et al (2014) [66]. Glucose through activating carbohydrate response element binding protein may control the promoter of betatrophin gene [71,72]. Therefore, a positive relationship between betatrophin, blood glucose and HbA1c in T2DM is not unexpected.…”

Section: Discussionsupporting

confidence: 84%

Circulating Betatrophin and Hepatocyte Growth Factor in Type 2 Diabetic Patients: Their Relationship With Disease Prognosis

Alduraywish

2017

J Endocrinol Metab

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Background: In Saudi Arabia, diabetes established itself as an epidemic that necessitates dissection of its predisposing factors and pathogenesis to set appropriate preventive measures. In a cross-sectional study, relationships between plasma betatrophin (BetaT) and hepatocyte growth factor (HGF) on one side, and, glycemic control, lipogram, anthropometric indices, treatment and prognosis on the other side were assessed in Saudi patients with type 2 diabetes mellitus (T2DM) vs. healthy controls.

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“…Indeed, a selective enrichment in their lipid products (i.e., MUFA) ( Figure 2G) was observed upon ChREBP overexpression in liver under both standard and HFDs. Interestingly, both SCD1 and Elovl6 were identified among 700 other direct target genes of ChREBP in a genome-wide scale analysis performed in HepG2 cells using ChIP sequencing (53).…”

Section: Discussionmentioning

confidence: 99%

The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans

Benhamed¹,

Denechaud²,

Lemoine³

et al. 2012

J. Clin. Invest.

342

317

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Nonalcoholic fatty liver disease (NAFLD) is associated with all features of the metabolic syndrome. Although deposition of excess triglycerides within liver cells, a hallmark of NAFLD, is associated with a loss of insulin sensitivity, it is not clear which cellular abnormality arises first. We have explored this in mice overexpressing carbohydrate responsive element-binding protein (ChREBP). On a standard diet, mice overexpressing ChREBP remained insulin sensitive, despite increased expression of genes involved in lipogenesis/fatty acid esterification and resultant hepatic steatosis (simple fatty liver). Lipidomic analysis revealed that the steatosis was associated with increased accumulation of monounsaturated fatty acids (MUFAs). In primary cultures of mouse hepatocytes, ChREBP overexpression induced expression of stearoyl-CoA desaturase 1 (Scd1), the enzyme responsible for the conversion of saturated fatty acids (SFAs) into MUFAs. SFA impairment of insulin-responsive Akt phosphorylation was therefore rescued by the elevation of Scd1 levels upon ChREBP overexpression, whereas pharmacological or shRNA-mediated reduction of Scd1 activity decreased the beneficial effect of ChREBP on Akt phosphorylation. Importantly, ChREBP-overexpressing mice fed a high-fat diet showed normal insulin levels and improved insulin signaling and glucose tolerance compared with controls, despite having greater hepatic steatosis. Finally, ChREBP expression in liver biopsies from patients with nonalcoholic steatohepatitis was increased when steatosis was greater than 50% and decreased in the presence of severe insulin resistance. Together, these results demonstrate that increased ChREBP can dissociate hepatic steatosis from insulin resistance, with beneficial effects on both glucose and lipid metabolism.

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Integrated Expression Profiling and Genome-Wide Analysis of ChREBP Targets Reveals the Dual Role for ChREBP in Glucose-Regulated Gene Expression

Cited by 134 publications

References 48 publications

Glucose Induces Protein Targeting to Glycogen in Hepatocytes by Fructose 2,6-Bisphosphate-Mediated Recruitment of MondoA to the Promoter

Glucose Induces Protein Targeting to Glycogen in Hepatocytes by Fructose 2,6-Bisphosphate-Mediated Recruitment of MondoA to the Promoter

Circulating Betatrophin and Hepatocyte Growth Factor in Type 2 Diabetic Patients: Their Relationship With Disease Prognosis

The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans

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