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

Ma, Lin; Tsatsos, Nikolas G.; Towle, Howard C.

doi:10.1074/jbc.m413063200

Cited by 165 publications

(152 citation statements)

References 48 publications

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“…Recombinant Adenovirus-Recombinant adenoviruses expressing ChREBP and MLX␤ were obtained from H. Towle, University of Minnesota, Minneapolis, MN (19). The adenoviruses were constructed using the pAdenoVator-CMV5-IRES-GFP.…”

Section: Methodsmentioning

confidence: 99%

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Regulation of Rat Hepatic L-Pyruvate Kinase Promoter Composition and Activity by Glucose, n-3 Polyunsaturated Fatty Acids, and Peroxisome Proliferator-activated Receptor-α Agonist

Christian

Jump

2006

Journal of Biological Chemistry

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Carbohydrate regulatory element-binding protein (ChREBP), MAX-like factor X (MLX), and hepatic nuclear factor-4␣ (HNF-4␣) are key transcription factors involved in the glucose-mediated induction of hepatic L-type pyruvate kinase (L-PK) gene transcription. n-3 polyunsaturated fatty acids (PUFA) and WY14643 (peroxisome proliferatoractivated receptor ␣ (PPAR␣) agonist) interfere with glucose-stimulated L-PK gene transcription in vivo and in rat primary hepatocytes. Feeding rats a diet containing n-3 PUFA or WY14643 suppressed hepatic mRNA L-PK but did not suppress hepatic ChREBP or HNF-4␣ nuclear abundance. Hepatic MLX nuclear abundance, however, was suppressed by n-3 PUFA but not WY14643. In rat primary hepatocytes, glucose-stimulated accumulation of mRNA LPK and L-PK promoter activity correlated with increased ChREBP nuclear abundance. This treatment also increased L-PK promoter occupancy by RNA polymerase II (RNA pol II), acetylated histone H3 (Ac-H3), and acetylated histone H4 (Ac-H4) but did not significantly impact L-PK promoter occupancy by ChREBP or HNF-4␣. Inhibition of L-PK promoter activity by n-3 PUFA correlated with suppressed RNA pol II, Ac-H3, and Ac-H4 occupancy on the L-PK promoter. Although n-3 PUFA transiently suppressed ChREBP and MLX nuclear abundance, this treatment did not impact ChREBP-LPK promoter interaction. HNF4␣-LPK promoter interaction was transiently suppressed by n-3 PUFA. Inhibition of L-PK promoter activity by WY14643 correlated with a transient decline in ChREBP nuclear abundance and decreased Ac-H4 interaction with the L-PK promoter. WY14643, however, had no impact on MLX nuclear abundance or HNF4␣-LPK promoter interaction. Although overexpressed ChREBP or HNF-4␣ did not relieve n-3 PUFA suppression of L-PK gene expression, overexpressed MLX fully abrogated n-3 PUFA suppression of L-PK promoter activity and mRNA L-PK abundance. Overexpressed ChREBP, but not MLX, relieved the WY14643 inhibition of L-PK. In conclusion, n-3 PUFA and WY14643/PPAR␣ target different transcription factors to control L-PK gene transcription. MLX, the heterodimer partner for ChREBP, has emerged as a novel target for n-3 PUFA regulation.The glycolytic enzyme, liver-type pyruvate kinase (L-PK), 2 plays a key role in hepatic glucose and lipid metabolism (1). Phosphorylation and allosteric factors acutely regulate L-PK enzyme activity, whereas hormones and nutrients chronically control the abundance of L-PK protein by regulating L-PK gene transcription. Excess glucose consumption induces glycolysis, L-PK activity, de novo lipogenesis, and lipid storage, whereas n-3 polyunsaturated fatty acids (n-3 PUFA) inhibit these metabolic events (2, 3). L-PK gene transcription is induced by insulin-stimulated glucose metabolism (4) and inhibited by n-3 PUFA and activators of PPAR␣ (WY14643), protein kinase A, and AMP kinase (AMPK) (5-8).Key cis-regulatory elements controlling L-PK gene transcription are located between Ϫ197 and Ϫ125 bp upstream of the transcription start site (Fig. 1). Two basic helix-loop-helix transcri...

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Section: Methodsmentioning

confidence: 99%

“…Fatty-acid synthase and S14 are two well established glucose-and fatty acid-regulated genes (4,19,28). The effect of overexpressed ChREBP and MLX on glucose and fatty acid on control of mRNA FAS and mRNA S14 was compared with the effect on mRNA LPK (Fig.…”

Section: Mechanisms Controlling L-pk Promoter Activitymentioning

confidence: 99%

Regulation of Rat Hepatic L-Pyruvate Kinase Promoter Composition and Activity by Glucose, n-3 Polyunsaturated Fatty Acids, and Peroxisome Proliferator-activated Receptor-α Agonist

Christian

Jump

2006

Journal of Biological Chemistry

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“…To further investigate the molecular mechanisms involved in repression of PPAR␣ expression by glucose in ␤-cells, we decided to evaluate the role of Mlx, which is the functional heterodimeric partner of ChREBP when mediating glucose-induced gene activation (20,27,28). Knockdown of Mlx by siRNA reduces Mlx mRNA levels by 70 -80% (Fig.…”

Section: Chrebp Knockdown Blunts Glucose Repression Of Ppar␣ Expressimentioning

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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“…The COOH-terminal region, called WBSCR14 max-like protein x [Mlx] C-tail (14) or dimerization and cytoplasmic localization domain (15), dimerizes with Mlx, which is essential for DNA binding and contributes to cytoplasmic retention of MondoA (9,14,15). Despite the striking similarity among Mondo proteins, two cAMP-dependent protein kinase (PKA) phosphorylation sites considered essential for glucose responsiveness of ChREBP are not conserved in other Mondo proteins (16,17), whose physiological function remains unknown.…”

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confidence: 99%

Glucose-Dependent Transcriptional Regulation by an Evolutionarily Conserved Glucose-Sensing Module

et al. 2006

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We report here a novel mechanism for glucose-mediated activation of carbohydrate response element binding protein (ChREBP), a basic helix-loop-helix/leucine zipper (bHLH/ZIP) transcription factor of Mondo family that binds to carbohydrate response element in the promoter of some glucose-regulated genes and activates their expression upon glucose stimulation. Structure-function analysis of ChREBP in a highly glucose-sensitive system using GAL4-ChREBP fusion constructs revealed a glucose-sensing module (GSM) that mediates glucose responsiveness of ChREBP. GSM is conserved among Mondo family members; MondoA, a mammalian paralog of unknown function, and the GSM region of a Drosophila homolog were also found to be glucose responsive. GSM is composed of a low-glucose inhibitory domain (LID) and a glucose-response activation conserved element (GRACE). We have identified a new mechanism accounting for glucose responsiveness of ChREBP that involves specific inhibition of the transactivation activity of GRACE by LID under low glucose concentration and reversal of this inhibition by glucose in an orientation-sensitive manner. The intramolecular inhibition and its release by glucose is a regulatory mechanism that is independent of changes of subcellular localization or DNA binding activity, events that also appear to be involved in glucose responsiveness. This evolutionally conserved mechanism may play an essential role in glucose-responsive gene regulation.

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

Cited by 165 publications

References 48 publications

Regulation of Rat Hepatic L-Pyruvate Kinase Promoter Composition and Activity by Glucose, n-3 Polyunsaturated Fatty Acids, and Peroxisome Proliferator-activated Receptor-α Agonist

Regulation of Rat Hepatic L-Pyruvate Kinase Promoter Composition and Activity by Glucose, n-3 Polyunsaturated Fatty Acids, and Peroxisome Proliferator-activated Receptor-α Agonist

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

Glucose-Dependent Transcriptional Regulation by an Evolutionarily Conserved Glucose-Sensing Module

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