44 results on '"Dentin R"'
Search Results
2. Loss of intestinal ChREBP impairs absorption of dietary sugars and prevents glycemic excursion curves
- Author
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Charifi, W, primary, Fauveau, V, additional, Francese, L, additional, Grosfeld, A, additional, Le Gall, M, additional, Ourabah, S, additional, Ellero-Simatos, S, additional, Viel, T, additional, Cauzac, M, additional, Gueddouri, D, additional, Benhamed, F, additional, Tavitian, B, additional, Dentin, R, additional, Burnol, AF, additional, Postic, C, additional, and Guilmeau, S, additional
- Published
- 2021
- Full Text
- View/download PDF
3. Transcriptional control of hepatic fatty acid synthesis in liver: A role for ChREBP
- Author
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Postic, C., Denechaud, P., Robichon, C., Guinez, C., Behnamed, F., Dentin, R., and Girard, J.
- Published
- 2008
4. Role of the liver in the control of carbohydrate and lipid homeostasis
- Author
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Postic, C, Dentin, R, and Girard, J
- Published
- 2004
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5. L’expression d’une forme active de ChREBP conduit à la réinduction de la lipogenèse dans un modèle animal de déficience en LXR et SREBP-1c
- Author
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Poupeau, A., Rayah-Benhamed, F., Dentin, R., Guillou, Hervé, Girard , .J., Postic, C., Toxicologie Intégrative & Métabolisme (ToxAlim-TIM), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Saisissez le nom du laboratoire, du service ou du département., Ville service., and ProdInra, Migration
- Subjects
[SDV] Life Sciences [q-bio] ,[SDV]Life Sciences [q-bio] ,ComputingMilieux_MISCELLANEOUS - Abstract
National audience
- Published
- 2011
6. Dysregulated CRTC1 activity is a novel component of PGE2 signaling that contributes to colon cancer growth
- Author
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Schumacher, Y, primary, Aparicio, T, additional, Ourabah, S, additional, Baraille, F, additional, Martin, A, additional, Wind, P, additional, Dentin, R, additional, Postic, C, additional, and Guilmeau, S, additional
- Published
- 2015
- Full Text
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7. 119 ROLE OF ChREBP IN LIVER ALCOHOLIC STEATOSIS DEVELOPMENT
- Author
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Marmier, S., primary, Dentin, R., additional, Loterstazjn, S., additional, and Postic, C., additional
- Published
- 2013
- Full Text
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8. P08 Implication de l’histone déméthylase phf2 au développement de la stéatose hépatique au court de physiopathologie de l’obésité et du diabète de type 2
- Author
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Bricambert, J., primary, Postic, C., additional, Girard, J., additional, and Dentin, R., additional
- Published
- 2012
- Full Text
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9. O38 La O-glycosylation du facteur de transcription ChREBP stimule son activité transactivatrice et participe au développement de la stéatose hépatique
- Author
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Guinez, C., primary, Rayah, F., additional, Dubuquoy, C., additional, Dentin, R., additional, Michalski, J.C., additional, Lefebvre, T., additional, Girard, J., additional, and Postic, C., additional
- Published
- 2010
- Full Text
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10. PO25 Contribution de la sérine/thréonine kinase SIK2 dans le développement de la stéatose hépatique induite par les régulateurs transcriptionnels p300 et ChREBP
- Author
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Miranda, J., primary, Benhamed, F., additional, Girard, J., additional, Postic, C., additional, and Dentin, R., additional
- Published
- 2010
- Full Text
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11. PO26 L’expression d’une forme active de ChREBP conduit à la réinduction de la lipogenèse hépatique dans un modèle de déficience en LXR et SREBP-1c
- Author
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Poupeau, A., primary, Rayah-Benhamed, F., additional, Dentin, R., additional, Lobaccaro, J.M., additional, Girard, J., additional, and Postic, C., additional
- Published
- 2010
- Full Text
- View/download PDF
12. PO40 Contribution du facteur de transcription ChREBP au développement de la stéatose hépatique induite par le fructose
- Author
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Benhamed Rayah, F., primary, Dentin, R., additional, Girard, J., additional, and Postic, C., additional
- Published
- 2010
- Full Text
- View/download PDF
13. Polyunsaturated fatty acids suppress glycolytic and lipogenic genes through the inhibition of ChREBP nuclear protein translocation
- Author
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Dentin, R., primary
- Published
- 2005
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14. Glucose metabolism via hepatic glucokinase (GK) is necessary for the induction of glycolytic and lipogenic gene expression: Implication of carbohydrate responsive element binding protein (ChREBP)
- Author
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Dentin, R., Pegorier, Y. P., Rayah, F., Foufelle, F., Pascal Ferre, Magnuson, M. A., Girard, J. R., and Postic, C.
15. Iron Boosts Antitumor Type 1 T-cell Responses and Anti-PD1 Immunotherapy.
- Author
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Porte S, Audemard-Verger A, Wu C, Durand A, Level T, Giraud L, Lombès A, Germain M, Pierre R, Saintpierre B, Lambert M, Auffray C, Peyssonnaux C, Goldwasser F, Vaulont S, Alves-Guerra MC, Dentin R, Lucas B, and Martin B
- Subjects
- Animals, Mice, Humans, Cell Line, Tumor, Mice, Inbred C57BL, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Interferon-gamma metabolism, Female, Th1 Cells immunology, Neoplasms immunology, Neoplasms therapy, Neoplasms drug therapy, Iron metabolism, Immunotherapy methods, Programmed Cell Death 1 Receptor antagonists & inhibitors
- Abstract
Cancers only develop if they escape immunosurveillance, and the success of cancer immunotherapies relies in most cases on their ability to restore effector T-cell functions, particularly IFNγ production. Revolutionizing the treatment of many cancers, immunotherapies targeting immune checkpoints such as PD1 can increase survival and cure patients. Unfortunately, although immunotherapy has greatly improved the prognosis of patients, not all respond to anti-PD1 immunotherapy, making it crucial to identify alternative treatments that could be combined with current immunotherapies to improve their effectiveness. Here, we show that iron supplementation significantly boosts T-cell responses in vivo and in vitro. The boost was associated with a metabolic reprogramming of T cells in favor of lipid oxidation. We also found that the "adjuvant" effect of iron led to a marked slowdown of tumor cell growth after tumor cell line transplantation in mice. Specifically, our results suggest that iron supplementation promotes antitumor responses by increasing IFNγ production by T cells. In addition, iron supplementation improved the efficacy of anti-PD1 cancer immunotherapy in mice. Finally, our study suggests that, in patients with cancer, the quality and efficacy of the antitumor response following anti-PD1 immunotherapy may be modulated by plasma ferritin levels. In summary, our results suggest the benefits of iron supplementation on the reactivation of antitumor responses and support the relevance of a fruitful association between immunotherapy and iron supplementation., (©2024 American Association for Cancer Research.)
- Published
- 2024
- Full Text
- View/download PDF
16. The transcription factor ChREBP Orchestrates liver carcinogenesis by coordinating the PI3K/AKT signaling and cancer metabolism.
- Author
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Benichou E, Seffou B, Topçu S, Renoult O, Lenoir V, Planchais J, Bonner C, Postic C, Prip-Buus C, Pecqueur C, Guilmeau S, Alves-Guerra MC, and Dentin R
- Subjects
- Humans, Transcription Factors genetics, Transcription Factors metabolism, Proto-Oncogene Proteins c-akt metabolism, Phosphatidylinositol 3-Kinases metabolism, Signal Transduction, Carcinogenesis, Cell Proliferation, Cell Line, Tumor, Carcinoma, Hepatocellular metabolism, Liver Neoplasms metabolism
- Abstract
Cancer cells integrate multiple biosynthetic demands to drive unrestricted proliferation. How these cellular processes crosstalk to fuel cancer cell growth is still not fully understood. Here, we uncover the mechanisms by which the transcription factor Carbohydrate responsive element binding protein (ChREBP) functions as an oncogene during hepatocellular carcinoma (HCC) development. Mechanistically, ChREBP triggers the expression of the PI3K regulatory subunit p85α, to sustain the activity of the pro-oncogenic PI3K/AKT signaling pathway in HCC. In parallel, increased ChREBP activity reroutes glucose and glutamine metabolic fluxes into fatty acid and nucleic acid synthesis to support PI3K/AKT-mediated HCC growth. Thus, HCC cells have a ChREBP-driven circuitry that ensures balanced coordination between PI3K/AKT signaling and appropriate cell anabolism to support HCC development. Finally, pharmacological inhibition of ChREBP by SBI-993 significantly suppresses in vivo HCC tumor growth. Overall, we show that targeting ChREBP with specific inhibitors provides an attractive therapeutic window for HCC treatment., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
17. UCP2 silencing restrains leukemia cell proliferation through glutamine metabolic remodeling.
- Author
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Sancerni T, Renoult O, Luby A, Caradeuc C, Lenoir V, Croyal M, Ransy C, Aguilar E, Postic C, Bertho G, Dentin R, Prip-Buus C, Pecqueur C, and Alves-Guerra MC
- Subjects
- Humans, Uncoupling Protein 2 genetics, Uncoupling Protein 2 metabolism, Malates, Cell Proliferation, Tricarboxylic Acids, Lipids, Glutamine metabolism, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics
- Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy derived from early T cell progenitors. Since relapsed T-ALL is associated with a poor prognosis improving initial treatment of patients is essential to avoid resistant selection of T-ALL. During initiation, development, metastasis and even in response to chemotherapy, tumor cells face strong metabolic challenges. In this study, we identify mitochondrial UnCoupling Protein 2 (UCP2) as a tricarboxylic acid (TCA) cycle metabolite transporter controlling glutamine metabolism associated with T-ALL cell proliferation. In T-ALL cell lines, we show that UCP2 expression is controlled by glutamine metabolism and is essential for their proliferation. Our data show that T-ALL cell lines differ in their substrate dependency and their energetic metabolism (glycolysis and oxidative). Thus, while UCP2 silencing decreases cell proliferation in all leukemia cells, it also alters mitochondrial respiration of T-ALL cells relying on glutamine-dependent oxidative metabolism by rewiring their cellular metabolism to glycolysis. In this context, the function of UCP2 in the metabolite export of malate enables appropriate TCA cycle to provide building blocks such as lipids for cell growth and mitochondrial respiration. Therefore, interfering with UCP2 function can be considered as an interesting strategy to decrease metabolic efficiency and proliferation rate of leukemia cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sancerni, Renoult, Luby, Caradeuc, Lenoir, Croyal, Ransy, Aguilar, Postic, Bertho, Dentin, Prip-Buus, Pecqueur and Alves-Guerra.)
- Published
- 2022
- Full Text
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18. ChREBPβ is dispensable for the control of glucose homeostasis and energy balance.
- Author
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Recazens E, Tavernier G, Dufau J, Bergoglio C, Benhamed F, Cassant-Sourdy S, Marques MA, Caspar-Bauguil S, Brion A, Monbrun L, Dentin R, Ferrier C, Leroux M, Denechaud PD, Moro C, Concordet JP, Postic C, Mouisel E, and Langin D
- Subjects
- Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors biosynthesis, Cells, Cultured, Diabetes Mellitus, Type 2 metabolism, Diabetes Mellitus, Type 2 pathology, Female, Male, Mice, Mice, Inbred C57BL, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics, Blood Glucose metabolism, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2 genetics, Energy Metabolism genetics, Gene Expression Regulation, RNA genetics
- Abstract
Impaired glucose metabolism is observed in obesity and type 2 diabetes. Glucose controls gene expression through the transcription factor ChREBP in liver and adipose tissues. Mlxipl encodes 2 isoforms: ChREBPα, the full-length form (translocation into the nucleus is under the control of glucose), and ChREBPβ, a constitutively nuclear shorter form. ChREBPβ gene expression in white adipose tissue is strongly associated with insulin sensitivity. Here, we investigated the consequences of ChREBPβ deficiency on insulin action and energy balance. ChREBPβ-deficient male and female C57BL6/J and FVB/N mice were produced using CRISPR/Cas9-mediated gene editing. Unlike global ChREBP deficiency, lack of ChREBPβ showed modest effects on gene expression in adipose tissues and the liver, with variations chiefly observed in brown adipose tissue. In mice fed chow and 2 types of high-fat diets, lack of ChREBPβ had moderate effects on body composition and insulin sensitivity. At thermoneutrality, ChREBPβ deficiency did not prevent the whitening of brown adipose tissue previously reported in total ChREBP-KO mice. These findings revealed that ChREBPβ is dispensable for metabolic adaptations to nutritional and thermic challenges.
- Published
- 2022
- Full Text
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19. Cooperation Between the NRF2 Pathway and Oncogenic β-catenin During HCC Tumorigenesis.
- Author
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Savall M, Senni N, Lagoutte I, Sohier P, Dentin R, Romagnolo B, Perret C, and Bossard P
- Abstract
CTNNB1 (catenin beta 1)-mutated hepatocellular carcinomas (HCCs) account for a large proportion of human HCCs. They display high levels of respiratory chain activity. As metabolism and redox balance are closely linked, tumor cells must maintain their redox status during these metabolic alterations. We investigated the redox balance of these HCCs and the feasibility of targeting this balance as an avenue for targeted therapy. We assessed the expression of the nuclear erythroid 2 p45-related factor 2 (NRF2) detoxification pathway in an annotated human HCC data set and reported an enrichment of the NRF2 program in human HCCs with CTNNB1 mutations, largely independent of NFE2L2 (nuclear factor, erythroid 2 like 2) or KEAP1 (Kelch-like ECH-associated protein 1) mutations. We then used mice with hepatocyte-specific oncogenic β-catenin activation to evaluate the redox status associated with β-catenin activation in preneoplastic livers and tumors. We challenged them with various oxidative stressors and observed that the β-catenin pathway activation increased transcription of Nfe2l2, which protects β-catenin-activated hepatocytes from oxidative damage and supports tumor development. Moreover, outside of its effects on reactive oxygen species scavenging, we found out that Nrf2 itself contributes to the metabolic activity of β-catenin-activated cells. We then challenged β-catenin activated tumors pharmacologically to create a redox imbalance and found that pharmacological inactivation of Nrf2 was sufficient to considerably decrease the progression of β-catenin-dependent HCC development. Conclusion: These results demonstrate cooperation between oncogenic β-catenin signaling and the NRF2 pathway in CTNNB1-mediated HCC tumorigenesis, and we provide evidence for the relevance of redox balance targeting as a therapeutic strategy in CTNNB1-mutated HCC., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.)
- Published
- 2021
- Full Text
- View/download PDF
20. The absence of hepatic glucose-6 phosphatase/ChREBP couple is incompatible with survival in mice.
- Author
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Rajas F, Dentin R, Cannella Miliano A, Silva M, Raffin M, Levavasseur F, Gautier-Stein A, Postic C, and Mithieux G
- Subjects
- Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics, Glucose metabolism, Glucose-6-Phosphatase metabolism, Glucose-6-Phosphate metabolism, Hepatocytes metabolism, Hydrolysis, Lipids physiology, Liver pathology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Non-alcoholic Fatty Liver Disease physiopathology, Non-alcoholic Fatty Liver Disease prevention & control, Phosphoric Monoester Hydrolases genetics, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Lipid Metabolism physiology, Phosphoric Monoester Hydrolases metabolism
- Abstract
Objective: Glucose production in the blood requires the expression of glucose-6 phosphatase (G6Pase), a key enzyme that allows glucose-6 phosphate (G6P) hydrolysis into free glucose and inorganic phosphate. We previously reported that the hepatic suppression of G6Pase leads to G6P accumulation and to metabolic reprogramming in hepatocytes from liver G6Pase-deficient mice (L.G6pc
-/- ). Interestingly, the activity of the transcription factor carbohydrate response element-binding protein (ChREBP), central for de novo lipid synthesis, is markedly activated in L.G6pc-/- mice, which consequently rapidly develop NAFLD-like pathology. In the current work, we assessed whether a selective deletion of ChREBP could prevent hepatic lipid accumulation and NAFLD initiation in L.G6pc-/- mice., Methods: We generated liver-specific ChREBP (L.Chrebp-/- )- and/or G6Pase (L.G6pc-/- )-deficient mice using a Cre-lox strategy in B6.SACreERT2 mice. Mice were fed a standard chow diet or a high-fat diet for 10 days. Markers of hepatic metabolism and cellular stress were analysed in the liver of control, L. G6pc-/- , L. Chrebp-/- and double knockout (i.e., L.G6pc-/- .Chrebp-/- ) mice., Results: We observed that there was a dramatic decrease in lipid accumulation in the liver of L.G6pc-/- .Chrebp-/- mice. At the mechanistic level, elevated G6P concentrations caused by lack of G6Pase are rerouted towards glycogen synthesis. Importantly, this exacerbated glycogen accumulation, leading to hepatic water retention and aggravated hepatomegaly. This caused animal distress and hepatocyte damage, characterised by ballooning and moderate fibrosis, paralleled with acute endoplasmic reticulum stress., Conclusions: Our study reveals the crucial role of the ChREBP-G6Pase duo in the regulation of G6P-regulated pathways in the liver., (Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.)- Published
- 2021
- Full Text
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21. UCP2 Deficiency Increases Colon Tumorigenesis by Promoting Lipid Synthesis and Depleting NADPH for Antioxidant Defenses.
- Author
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Aguilar E, Esteves P, Sancerni T, Lenoir V, Aparicio T, Bouillaud F, Dentin R, Prip-Buus C, Ricquier D, Pecqueur C, Guilmeau S, and Alves-Guerra MC
- Subjects
- Aged, Aged, 80 and over, Animals, Carcinogenesis metabolism, Colon metabolism, Colon pathology, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Glycolysis, Humans, Intestine, Small metabolism, Intestine, Small pathology, Male, Mice, Mice, Inbred C57BL, Middle Aged, Uncoupling Protein 2 genetics, Carcinogenesis genetics, Colorectal Neoplasms metabolism, Lipogenesis, NADP metabolism, Oxidative Stress, Uncoupling Protein 2 metabolism
- Abstract
Colorectal cancer (CRC) is associated with metabolic and redox perturbation. The mitochondrial transporter uncoupling protein 2 (UCP2) controls cell proliferation in vitro through the modulation of cellular metabolism, but the underlying mechanism in tumors in vivo remains unexplored. Using murine intestinal cancer models and CRC patient samples, we find higher UCP2 protein levels in tumors compared to their non-tumoral counterparts. We reveal the tumor-suppressive role of UCP2 as its deletion enhances colon and small intestinal tumorigenesis in AOM/DSS-treated and Apc
Min/+ mice, respectively, and correlates with poor survival in the latter model. Mechanistically, UCP2 loss increases levels of oxidized glutathione and proteins in tumors. UCP2 deficiency alters glycolytic pathways while promoting phospholipid synthesis, thereby limiting the availability of NADPH for buffering oxidative stress. We show that UCP2 loss renders colon cells more prone to malignant transformation through metabolic reprogramming and perturbation of redox homeostasis and could favor worse outcomes in CRC., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2019
- Full Text
- View/download PDF
22. The histone demethylase Phf2 acts as a molecular checkpoint to prevent NAFLD progression during obesity.
- Author
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Bricambert J, Alves-Guerra MC, Esteves P, Prip-Buus C, Bertrand-Michel J, Guillou H, Chang CJ, Vander Wal MN, Canonne-Hergaux F, Mathurin P, Raverdy V, Pattou F, Girard J, Postic C, and Dentin R
- Subjects
- Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Cells, Cultured, Enzyme Activation, Glucose metabolism, Glutathione biosynthesis, Humans, Liver pathology, Male, Methylation, Mice, Mice, Inbred C57BL, Mice, Knockout, Nuclear Proteins genetics, Oxidative Stress genetics, Oxidative Stress physiology, Pentose Phosphate Pathway physiology, Promoter Regions, Genetic genetics, Transcription Factors genetics, Demethylation, Histone Demethylases metabolism, Histones metabolism, Homeodomain Proteins metabolism, NF-E2-Related Factor 2 metabolism, Non-alcoholic Fatty Liver Disease pathology, Nuclear Proteins metabolism, Obesity pathology, Transcription Factors metabolism
- Abstract
Aberrant histone methylation profile is reported to correlate with the development and progression of NAFLD during obesity. However, the identification of specific epigenetic modifiers involved in this process remains poorly understood. Here, we identify the histone demethylase Plant Homeodomain Finger 2 (Phf2) as a new transcriptional co-activator of the transcription factor Carbohydrate Responsive Element Binding Protein (ChREBP). By specifically erasing H3K9me2 methyl-marks on the promoter of ChREBP-regulated genes, Phf2 facilitates incorporation of metabolic precursors into mono-unsaturated fatty acids, leading to hepatosteatosis development in the absence of inflammation and insulin resistance. Moreover, the Phf2-mediated activation of the transcription factor NF-E2-related factor 2 (Nrf2) further reroutes glucose fluxes toward the pentose phosphate pathway and glutathione biosynthesis, protecting the liver from oxidative stress and fibrogenesis in response to diet-induced obesity. Overall, our findings establish a downstream epigenetic checkpoint, whereby Phf2, through facilitating H3K9me2 demethylation at specific gene promoters, protects liver from the pathogenesis progression of NAFLD.
- Published
- 2018
- Full Text
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23. A Specific ChREBP and PPARα Cross-Talk Is Required for the Glucose-Mediated FGF21 Response.
- Author
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Iroz A, Montagner A, Benhamed F, Levavasseur F, Polizzi A, Anthony E, Régnier M, Fouché E, Lukowicz C, Cauzac M, Tournier E, Do-Cruzeiro M, Daujat-Chavanieu M, Gerbal-Chalouin S, Fauveau V, Marmier S, Burnol AF, Guilmeau S, Lippi Y, Girard J, Wahli W, Dentin R, Guillou H, and Postic C
- Subjects
- Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Cells, Cultured, Female, Fibroblast Growth Factors genetics, Hepatocytes metabolism, Male, Mice, Mice, Inbred C57BL, Nuclear Proteins genetics, PPAR alpha genetics, Response Elements, Transcription Factors genetics, Fibroblast Growth Factors metabolism, Glucose metabolism, Nuclear Proteins metabolism, PPAR alpha metabolism, Transcription Factors metabolism
- Abstract
While the physiological benefits of the fibroblast growth factor 21 (FGF21) hepatokine are documented in response to fasting, little information is available on Fgf21 regulation in a glucose-overload context. We report that peroxisome-proliferator-activated receptor α (PPARα), a nuclear receptor of the fasting response, is required with the carbohydrate-sensitive transcription factor carbohydrate-responsive element-binding protein (ChREBP) to balance FGF21 glucose response. Microarray analysis indicated that only a few hepatic genes respond to fasting and glucose similarly to Fgf21. Glucose-challenged Chrebp
-/- mice exhibit a marked reduction in FGF21 production, a decrease that was rescued by re-expression of an active ChREBP isoform in the liver of Chrebp-/- mice. Unexpectedly, carbohydrate challenge of hepatic Pparα knockout mice also demonstrated a PPARα-dependent glucose response for Fgf21 that was associated with an increased sucrose preference. This blunted response was due to decreased Fgf21 promoter accessibility and diminished ChREBP binding onto Fgf21 carbohydrate-responsive element (ChoRE) in hepatocytes lacking PPARα. Our study reports that PPARα is required for the ChREBP-induced glucose response of FGF21., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2017
- Full Text
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24. Integration of ChREBP-Mediated Glucose Sensing into Whole Body Metabolism.
- Author
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Baraille F, Planchais J, Dentin R, Guilmeau S, and Postic C
- Subjects
- Adipose Tissue metabolism, Adipose Tissue pathology, Animals, Diabetes Mellitus, Type 2 metabolism, Diabetes Mellitus, Type 2 pathology, Fatty Acids metabolism, Humans, Insulin Resistance, Liver metabolism, Liver pathology, Neoplasms metabolism, Neoplasms pathology, Non-alcoholic Fatty Liver Disease metabolism, Non-alcoholic Fatty Liver Disease pathology, Protein Isoforms, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Energy Metabolism, Glucose metabolism, Signal Transduction
- Abstract
Since glucose is the principal energy source for most cells, many organisms have evolved numerous and sophisticated mechanisms to sense glucose and respond to it appropriately. In this context, cloning of the carbohydrate responsive element binding protein has unraveled a critical molecular link between glucose metabolism and transcriptional reprogramming induced by glucose. In this review, we detail major findings that have advanced our knowledge of glucose sensing., (©2015 Int. Union Physiol. Sci./Am. Physiol. Soc.)
- Published
- 2015
- Full Text
- View/download PDF
25. Novel role for carbohydrate responsive element binding protein in the control of ethanol metabolism and susceptibility to binge drinking.
- Author
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Marmier S, Dentin R, Daujat-Chavanieu M, Guillou H, Bertrand-Michel J, Gerbal-Chaloin S, Girard J, Lotersztajn S, and Postic C
- Subjects
- Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Disease Susceptibility, Male, Mice, Mice, Inbred C57BL, Binge Drinking etiology, Ethanol metabolism, Nuclear Proteins physiology, Transcription Factors physiology
- Abstract
Unlabelled: Carbohydrate responsive element binding protein (ChREBP) is central for de novo fatty acid synthesis under physiological conditions and in the context of nonalcoholic fatty liver disease. We explored its contribution to alcohol-induced steatosis in a mouse model of binge drinking as acute ethanol (EtOH) intoxication has become an alarming health problem. Within 6 hours, ChREBP acetylation and its recruitment onto target gene promoters were increased in liver of EtOH-fed mice. Acetylation of ChREBP was dependent on alcohol metabolism because inhibition of alcohol dehydrogenase (ADH) activity blunted ChREBP EtOH-induced acetylation in mouse hepatocytes. Transfection of an acetylation-defective mutant of ChREBP (ChREBP(K672A) ) in HepG2 cells impaired the stimulatory effect of EtOH on ChREBP activity. Importantly, ChREBP silencing in the liver of EtOH-fed mice prevented alcohol-induced triglyceride accumulation through an inhibition of the lipogenic pathway but also led, unexpectedly, to hypothermia, increased blood acetaldehyde concentrations, and enhanced lethality. This phenotype was associated with impaired hepatic EtOH metabolism as a consequence of reduced ADH activity. While the expression and activity of the NAD(+) dependent deacetylase sirtuin 1, a ChREBP-negative target, were down-regulated in the liver of alcohol-fed mice, they were restored to control levels upon ChREBP silencing. In turn, ADH acetylation was reduced, suggesting that ChREBP regulates EtOH metabolism and ADH activity through its direct control of sirtuin 1 expression. Indeed, when sirtuin 1 activity was rescued by resveratrol pretreatment in EtOH-treated hepatocytes, a significant decrease in ADH protein content and/or acetylation was observed., Conclusion: our study describes a novel role for ChREBP in EtOH metabolism and unravels its protective effect against severe intoxication in response to binge drinking., (© 2015 by the American Association for the Study of Liver Diseases.)
- Published
- 2015
- Full Text
- View/download PDF
26. Novel insights into ChREBP regulation and function.
- Author
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Filhoulaud G, Guilmeau S, Dentin R, Girard J, and Postic C
- Subjects
- Animals, Apoptosis, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors chemistry, Cell Proliferation, Humans, Insulin Resistance, Insulin-Secreting Cells cytology, Muscle, Skeletal metabolism, Phosphorylation, Protein Processing, Post-Translational, Protein Structure, Tertiary, Response Elements, Adipose Tissue metabolism, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Glycolysis, Insulin-Secreting Cells metabolism, Lipogenesis, Liver metabolism, Models, Biological
- Abstract
Glucose is an energy source that also controls the expression of key genes involved in energetic metabolism through the glucose-signaling transcription factor carbohydrate response element-binding protein (ChREBP). ChREBP has recently emerged as a central regulator of glycolysis and de novo fatty acid synthesis in liver, but new evidence shows that it plays a broader and crucial role in various processes, ranging from glucolipotoxicity to apoptosis and/or proliferation in specific cell types. However, several aspects of ChREBP activation by glucose metabolites are currently controversial, as well as the effects of activating or inhibiting ChREBP, on insulin sensitivity, which might depend on genetic, dietary or environmental factors. Thus, much remains to be elucidated. Here, we summarize our current understanding of the regulation and function of this fascinating transcription factor., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
- Full Text
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27. Hidden variant of ChREBP in fat links lipogenesis to insulin sensitivity.
- Author
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Dentin R, Langin D, and Postic C
- Abstract
The ChREBP transcription factor is regulated by glucose and plays a role in insulin sensitivity, but the mechanism underlying these effects remains unclear. In a recent Nature article, Herman et al. (2012) show that a shorter ChREBP isoform (ChREBP-β) links glucose transport to lipogenesis in white adipose tissue., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
- Full Text
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28. Glucose 6-phosphate, rather than xylulose 5-phosphate, is required for the activation of ChREBP in response to glucose in the liver.
- Author
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Dentin R, Tomas-Cobos L, Foufelle F, Leopold J, Girard J, Postic C, and Ferré P
- Subjects
- Active Transport, Cell Nucleus, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors chemistry, Glucosephosphate Dehydrogenase antagonists & inhibitors, Glucosephosphate Dehydrogenase genetics, Glucosephosphate Dehydrogenase metabolism, Hep G2 Cells, Hepatocytes drug effects, Hepatocytes metabolism, Humans, Lipogenesis, Models, Biological, Pentose Phosphate Pathway, Phosphorylation, Protein Phosphatase 2 metabolism, RNA, Small Interfering genetics, Transcription, Genetic, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Glucose pharmacology, Glucose-6-Phosphate metabolism, Liver drug effects, Liver metabolism, Pentosephosphates metabolism
- Abstract
Background & Aims: In liver, the glucose-responsive transcription factor ChREBP plays a critical role in converting excess carbohydrates into triglycerides through de novo lipogenesis. Although the importance of ChREBP in glucose sensing and hepatic energy utilization is strongly supported, the mechanism driving its activation in response to glucose in the liver is not fully understood. Indeed, the current model of ChREBP activation, which depends on Serine 196 and Threonine 666 dephosphorylation, phosphatase 2A (PP2A) activity, and xylulose 5-phosphate (X5P) as a signaling metabolite, has been challenged., Methods: We inhibited PP2A activity in HepG2 cells through the overexpression of SV40 small t antigen and addressed the importance of ChREBP dephosphorylation on Ser-196 using a phospho-specific antibody. To identify the exact nature of the metabolite signal required for ChREBP activity in liver, we focused on the importance of G6P synthesis in liver cells, through the modulation of glucose 6-phosphate dehydrogenase (G6PDH) activity, the rate-limiting enzyme of the pentose phosphate pathway in hepatocytes, and in HepG2 cells using both adenoviral and siRNA approaches., Results: In contrast to the current proposed model, our study reports that PP2A activity is dispensable for ChREBP activation in response to glucose and that dephosphorylation on Ser-196 is not sufficient to promote ChREBP nuclear translocation in the absence of a rise in glucose metabolism. By deciphering the respective roles of G6P and X5P as signaling metabolites, our study reveals that G6P produced by GK, but not X5P, is essential for both ChREBP nuclear translocation and transcriptional activity in response to glucose in liver cells., Conclusions: Altogether, our study, by reporting that G6P is the glucose-signaling metabolite, challenges the PP2A/X5P-dependent model currently described for ChREBP activation in response to glucose in liver., (Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
- Published
- 2012
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29. cis-9,trans-11,cis-15 and cis-9,trans-13,cis-15 CLNA mixture activates PPARα in HEK293 and reduces triacylglycerols in 3T3-L1 cells.
- Author
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Miranda J, Lasa A, Fernández-Quintela A, García-Marzo C, Ayo J, Dentin R, and Portillo MP
- Subjects
- 3T3-L1 Cells, Acetyltransferases genetics, Acetyltransferases metabolism, Adipocytes drug effects, Adipocytes enzymology, Adipocytes metabolism, Animals, Fatty Acid Synthases genetics, Fatty Acid Synthases metabolism, Gene Expression, HEK293 Cells, Humans, Lipoprotein Lipase genetics, Lipoprotein Lipase metabolism, Mice, PPAR alpha agonists, PPAR gamma agonists, PPAR gamma genetics, PPAR gamma metabolism, Stereoisomerism, Sterol Esterase genetics, Sterol Esterase metabolism, Sterol Regulatory Element Binding Protein 1 genetics, Sterol Regulatory Element Binding Protein 1 metabolism, Triglycerides metabolism, PPAR alpha metabolism, alpha-Linolenic Acid pharmacology
- Abstract
Scientific research is constantly working to find new molecules that are effective in preventing excessive accumulation of body fat. The aim of the present work was to assess the potential agonism on PPARα and PPARγ of a conjugated linolenic acid (CLNA) isomer mixture, consisting of two CLNA isomers (cis-9,trans-11,cis-15 and cis-9,trans-13,cis-15). Secondly, we aimed to analyze the effects of this mixture on triacylglycerol accumulation in 3T3-L1 mature adipocytes. Luciferase transactivation assay was used to analyze whether the CLNA mixture activated PPARs. The expression of several enzymes and transcriptional factors involved in the main metabolic pathways that control triacylglycerol accumulation in adipocytes was assessed by real time RT-PCR in 3T3-L1 adipocytes treated for 20 h with the CLNA mixture. The mixture activated PPRE in cells with PPARα receptor over-expression, but not those with PPARγ over-expression. Decreased triacylglycerol was found in treated adipocytes. The lowest dose (10 μM) increased HSL expression and the highest dose (100 μM) increased ATGL gene expression. The other genes analyzed remained unchanged. The hypothesis of an anti-obesity action of the analyzed CLNA mixture, based on increased lipid mobilization in adipose tissue, can be proposed.
- Published
- 2011
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30. O-GlcNAcylation increases ChREBP protein content and transcriptional activity in the liver.
- Author
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Guinez C, Filhoulaud G, Rayah-Benhamed F, Marmier S, Dubuquoy C, Dentin R, Moldes M, Burnol AF, Yang X, Lefebvre T, Girard J, and Postic C
- Subjects
- Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Cell Line, Cells, Cultured, Chromatin Immunoprecipitation, Fatty Liver enzymology, Fatty Liver genetics, Hep G2 Cells, Hepatocytes metabolism, Humans, Immunoblotting, Immunoprecipitation, Liver enzymology, Male, Mice, Mice, Inbred C57BL, N-Acetylglucosaminyltransferases genetics, Nuclear Proteins genetics, Protein Binding, Transcription Factors genetics, beta-N-Acetylhexosaminidases genetics, beta-N-Acetylhexosaminidases metabolism, Fatty Liver metabolism, Liver metabolism, N-Acetylglucosaminyltransferases metabolism, Nuclear Proteins metabolism, Transcription Factors metabolism
- Abstract
Objective: Carbohydrate-responsive element-binding protein (ChREBP) is a key transcription factor that mediates the effects of glucose on glycolytic and lipogenic genes in the liver. We have previously reported that liver-specific inhibition of ChREBP prevents hepatic steatosis in ob/ob mice by specifically decreasing lipogenic rates in vivo. To better understand the regulation of ChREBP activity in the liver, we investigated the implication of O-linked β-N-acetylglucosamine (O-GlcNAc or O-GlcNAcylation), an important glucose-dependent posttranslational modification playing multiple roles in transcription, protein stabilization, nuclear localization, and signal transduction., Research Design and Methods: O-GlcNAcylation is highly dynamic through the action of two enzymes: the O-GlcNAc transferase (OGT), which transfers the monosaccharide to serine/threonine residues on a target protein, and the O-GlcNAcase (OGA), which hydrolyses the sugar. To modulate ChREBP(OG) in vitro and in vivo, the OGT and OGA enzymes were overexpressed or inhibited via adenoviral approaches in mouse hepatocytes and in the liver of C57BL/6J or obese db/db mice., Results: Our study shows that ChREBP interacts with OGT and is subjected to O-GlcNAcylation in liver cells. O-GlcNAcylation stabilizes the ChREBP protein and increases its transcriptional activity toward its target glycolytic (L-PK) and lipogenic genes (ACC, FAS, and SCD1) when combined with an active glucose flux in vivo. Indeed, OGT overexpression significantly increased ChREBP(OG) in liver nuclear extracts from fed C57BL/6J mice, leading in turn to enhanced lipogenic gene expression and to excessive hepatic triglyceride deposition. In the livers of hyperglycemic obese db/db mice, ChREBP(OG) levels were elevated compared with controls. Interestingly, reducing ChREBP(OG) levels via OGA overexpression decreased lipogenic protein content (ACC, FAS), prevented hepatic steatosis, and improved the lipidic profile of OGA-treated db/db mice., Conclusions: Taken together, our results reveal that O-GlcNAcylation represents an important novel regulation of ChREBP activity in the liver under both physiological and pathophysiological conditions.
- Published
- 2011
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31. Salt-inducible kinase 2 links transcriptional coactivator p300 phosphorylation to the prevention of ChREBP-dependent hepatic steatosis in mice.
- Author
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Bricambert J, Miranda J, Benhamed F, Girard J, Postic C, and Dentin R
- Subjects
- Acetylation, Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Binding Sites genetics, Cells, Cultured, Disease Models, Animal, Fatty Acids metabolism, Fatty Liver genetics, Fatty Liver metabolism, Fatty Liver pathology, Fatty Liver prevention & control, Gene Knockdown Techniques, Hepatocytes metabolism, Humans, Inflammation etiology, Insulin Resistance, Mice, Mice, Transgenic, Non-alcoholic Fatty Liver Disease, Phosphorylation, Promoter Regions, Genetic, Protein Serine-Threonine Kinases antagonists & inhibitors, Protein Serine-Threonine Kinases genetics, Pyruvate Kinase genetics, p300-CBP Transcription Factors chemistry, Nuclear Proteins metabolism, Protein Serine-Threonine Kinases metabolism, Transcription Factors metabolism, p300-CBP Transcription Factors metabolism
- Abstract
Obesity and type 2 diabetes are associated with increased lipogenesis in the liver. This results in fat accumulation in hepatocytes, a condition known as hepatic steatosis, which is a form of nonalcoholic fatty liver disease (NAFLD), the most common cause of liver dysfunction in the United States. Carbohydrate-responsive element-binding protein (ChREBP), a transcriptional activator of glycolytic and lipogenic genes, has emerged as a major player in the development of hepatic steatosis in mice. However, the molecular mechanisms enhancing its transcriptional activity remain largely unknown. In this study, we have identified the histone acetyltransferase (HAT) coactivator p300 and serine/threonine kinase salt-inducible kinase 2 (SIK2) as key upstream regulators of ChREBP activity. In cultured mouse hepatocytes, we showed that glucose-activated p300 acetylated ChREBP on Lys672 and increased its transcriptional activity by enhancing its recruitment to its target gene promoters. SIK2 inhibited p300 HAT activity by direct phosphorylation on Ser89, which in turn decreased ChREBP-mediated lipogenesis in hepatocytes and mice overexpressing SIK2. Moreover, both liver-specific SIK2 knockdown and p300 overexpression resulted in hepatic steatosis, insulin resistance, and inflammation, phenotypes reversed by SIK2/p300 co-overexpression. Finally, in mouse models of type 2 diabetes and obesity, low SIK2 activity was associated with increased p300 HAT activity, ChREBP hyperacetylation, and hepatic steatosis. Our findings suggest that inhibition of hepatic p300 activity may be beneficial for treating hepatic steatosis in obesity and type 2 diabetes and identify SIK2 activators and specific p300 inhibitors as potential targets for pharmaceutical intervention.
- Published
- 2010
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32. Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis.
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Zhang EE, Liu Y, Dentin R, Pongsawakul PY, Liu AC, Hirota T, Nusinow DA, Sun X, Landais S, Kodama Y, Brenner DA, Montminy M, and Kay SA
- Subjects
- Animals, Cells, Cultured, Cyclic AMP Response Element-Binding Protein physiology, Male, Mice, Mice, Inbred C57BL, Receptors, G-Protein-Coupled physiology, Circadian Rhythm physiology, Cryptochromes physiology, Cyclic AMP physiology, Gluconeogenesis, Liver metabolism, Signal Transduction physiology
- Abstract
During fasting, mammals maintain normal glucose homeostasis by stimulating hepatic gluconeogenesis. Elevations in circulating glucagon and epinephrine, two hormones that activate hepatic gluconeogenesis, trigger the cAMP-mediated phosphorylation of cAMP response element-binding protein (Creb) and dephosphorylation of the Creb-regulated transcription coactivator-2 (Crtc2)--two key transcriptional regulators of this process. Although the underlying mechanism is unclear, hepatic gluconeogenesis is also regulated by the circadian clock, which coordinates glucose metabolism with changes in the external environment. Circadian control of gene expression is achieved by two transcriptional activators, Clock and Bmal1, which stimulate cryptochrome (Cry1 and Cry2) and Period (Per1, Per2 and Per3) repressors that feed back on Clock-Bmal1 activity. Here we show that Creb activity during fasting is modulated by Cry1 and Cry2, which are rhythmically expressed in the liver. Cry1 expression was elevated during the night-day transition, when it reduced fasting gluconeogenic gene expression by blocking glucagon-mediated increases in intracellular cAMP concentrations and in the protein kinase A-mediated phosphorylation of Creb. In biochemical reconstitution studies, we found that Cry1 inhibited accumulation of cAMP in response to G protein-coupled receptor (GPCR) activation but not to forskolin, a direct activator of adenyl cyclase. Cry proteins seemed to modulate GPCR activity directly through interaction with G(s)α. As hepatic overexpression of Cry1 lowered blood glucose concentrations and improved insulin sensitivity in insulin-resistant db/db mice, our results suggest that compounds that enhance cryptochrome activity may provide therapeutic benefit to individuals with type 2 diabetes.
- Published
- 2010
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33. Adipocyte CREB promotes insulin resistance in obesity.
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Qi L, Saberi M, Zmuda E, Wang Y, Altarejos J, Zhang X, Dentin R, Hedrick S, Bandyopadhyay G, Hai T, Olefsky J, and Montminy M
- Subjects
- Activating Transcription Factor 3 genetics, Activating Transcription Factor 3 metabolism, Adenylate Kinase metabolism, Adipocytes cytology, Adipocytes pathology, Adiponectin metabolism, Animals, Cells, Cultured, Cyclic AMP Response Element-Binding Protein genetics, Diabetes Mellitus, Type 2 metabolism, Diabetes Mellitus, Type 2 physiopathology, Disease Progression, Fatty Liver metabolism, Fatty Liver pathology, Gluconeogenesis physiology, Glucose Transporter Type 4 genetics, Glucose Transporter Type 4 metabolism, Hepatocytes cytology, Hepatocytes metabolism, Humans, Liver cytology, Liver metabolism, Liver pathology, Mice, Mice, Obese, Mice, Transgenic, Muscle, Skeletal cytology, Muscle, Skeletal metabolism, Obesity metabolism, Transcription Factors metabolism, Adipocytes metabolism, Cyclic AMP Response Element-Binding Protein metabolism, Insulin Resistance physiology, Obesity physiopathology
- Abstract
Increases in adiposity trigger metabolic and inflammatory changes that interfere with insulin action in peripheral tissues, culminating in beta cell failure and overt diabetes. We found that the cAMP Response Element Binding protein (CREB) is activated in adipose cells under obese conditions, where it promotes insulin resistance by triggering expression of the transcriptional repressor ATF3 and thereby downregulating expression of the adipokine hormone adiponectin as well as the insulin-sensitive glucose transporter 4 (GLUT4). Transgenic mice expressing a dominant-negative CREB transgene in adipocytes displayed increased whole-body insulin sensitivity in the contexts of diet-induced and genetic obesity, and they were protected from the development of hepatic steatosis and adipose tissue inflammation. These results indicate that adipocyte CREB provides an early signal in the progression to type 2 diabetes.
- Published
- 2009
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34. A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange.
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Liu Y, Dentin R, Chen D, Hedrick S, Ravnskjaer K, Schenk S, Milne J, Meyers DJ, Cole P, Yates J 3rd, Olefsky J, Guarente L, and Montminy M
- Subjects
- Acetylation, Animals, CREB-Binding Protein metabolism, Cell Line, Transformed, Cyclic AMP Response Element-Binding Protein metabolism, Enzyme Inhibitors pharmacology, Forkhead Box Protein O1, Forkhead Transcription Factors metabolism, Gene Expression Regulation drug effects, Heterocyclic Compounds, 4 or More Rings pharmacology, Humans, Liver metabolism, Male, Mice, Mice, Knockout, Nuclear Proteins metabolism, Resveratrol, Sirtuin 1, Sirtuins genetics, Sirtuins metabolism, Stilbenes pharmacology, Trans-Activators metabolism, Transcription Factors, Ubiquitin-Protein Ligases metabolism, p300-CBP Transcription Factors metabolism, Fasting physiology, Gluconeogenesis physiology
- Abstract
During early fasting, increases in skeletal muscle proteolysis liberate free amino acids for hepatic gluconeogenesis in response to pancreatic glucagon. Hepatic glucose output diminishes during the late protein-sparing phase of fasting, when ketone body production by the liver supplies compensatory fuel for glucose-dependent tissues. Glucagon stimulates the gluconeogenic program by triggering the dephosphorylation and nuclear translocation of the CREB regulated transcription coactivator 2 (CRTC2; also known as TORC2), while parallel decreases in insulin signalling augment gluconeogenic gene expression through the dephosphorylation and nuclear shuttling of forkhead box O1 (FOXO1). Here we show that a fasting-inducible switch, consisting of the histone acetyltransferase p300 and the nutrient-sensing deacetylase sirtuin 1 (SIRT1), maintains energy balance in mice through the sequential induction of CRTC2 and FOXO1. After glucagon induction, CRTC2 stimulated gluconeogenic gene expression by an association with p300, which we show here is also activated by dephosphorylation at Ser 89 during fasting. In turn, p300 increased hepatic CRTC2 activity by acetylating it at Lys 628, a site that also targets CRTC2 for degradation after its ubiquitination by the E3 ligase constitutive photomorphogenic protein (COP1). Glucagon effects were attenuated during late fasting, when CRTC2 was downregulated owing to SIRT1-mediated deacetylation and when FOXO1 supported expression of the gluconeogenic program. Disrupting SIRT1 activity, by liver-specific knockout of the Sirt1 gene or by administration of a SIRT1 antagonist, increased CRTC2 activity and glucose output, whereas exposure to SIRT1 agonists reduced them. In view of the reciprocal activation of FOXO1 and its coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha, encoded by Ppargc1a) by SIRT1 activators, our results illustrate how the exchange of two gluconeogenic regulators during fasting maintains energy balance.
- Published
- 2008
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35. Hepatic glucose sensing via the CREB coactivator CRTC2.
- Author
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Dentin R, Hedrick S, Xie J, Yates J 3rd, and Montminy M
- Subjects
- Amino Acid Substitution, Animals, Blood Glucose metabolism, Cell Nucleus metabolism, Cells, Cultured, Cyclic AMP Response Element-Binding Protein metabolism, Cytoplasm metabolism, Diabetes Mellitus metabolism, Glycosylation, Glycosyltransferases metabolism, Hepatocytes metabolism, Humans, Insulin metabolism, Male, Mice, Mice, Inbred C57BL, Phosphorylation, RNA Interference, Signal Transduction, Trans-Activators genetics, Transcription Factors, beta-N-Acetylhexosaminidases metabolism, Gluconeogenesis, Glucose metabolism, Liver metabolism, Trans-Activators metabolism
- Abstract
Chronic hyperglycemia contributes to the development of diabetes-associated complications. Increases in the concentration of circulating glucose activate the hexosamine biosynthetic pathway (HBP) and promote the O-glycosylation of proteins by O-glycosyl transferase (OGT). We show that OGT triggered hepatic gluconeogenesis through the O-glycosylation of the transducer of regulated cyclic adenosine monophosphate response element-binding protein (CREB) 2 (TORC2 or CRTC2). CRTC2 was O-glycosylated at sites that normally sequester CRTC2 in the cytoplasm through a phosphorylation-dependent mechanism. Decreasing amounts of O-glycosylated CRTC2 by expression of the deglycosylating enzyme O-GlcNAcase blocked effects of glucose on gluconeogenesis, demonstrating the importance of the HBP in the development of glucose intolerance.
- Published
- 2008
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36. Role of ChREBP in hepatic steatosis and insulin resistance.
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Denechaud PD, Dentin R, Girard J, and Postic C
- Subjects
- Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Liver metabolism, Mice, Mice, Inbred Strains, Nuclear Proteins metabolism, Transcription Factors metabolism, Fatty Liver physiopathology, Insulin Resistance, Nuclear Proteins physiology, Transcription Factors physiology
- Abstract
Non-alcoholic fatty liver disease is tightly associated with insulin resistance, type 2 diabetes and obesity, but the molecular links between hepatic fat accumulation and insulin resistance are not fully identified. Excessive accumulation of triglycerides (TG) is one the main characteristics of non-alcoholic fatty liver disease and fatty acids utilized for the synthesis of TG in liver are available from the plasma non-esterified fatty acid pool but also from fatty acids newly synthesized through hepatic de novo lipogenesis. Recently, the transcription factor ChREBP (carbohydrate responsive element binding protein) has emerged as a central determinant of lipid synthesis in liver through its transcriptional control of key genes of the lipogenic pathway, including fatty acid synthase and acetyl CoA carboxylase. In this mini-review, we will focus on the importance of ChREBP in the physiopathology of hepatic steatosis and insulin resistance by discussing the physiological and metabolic consequences of ChREBP knockdown in liver of ob/ob mice.
- Published
- 2008
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37. Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2.
- Author
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Dentin R, Liu Y, Koo SH, Hedrick S, Vargas T, Heredia J, Yates J 3rd, and Montminy M
- Subjects
- Animals, Cell Line, Eating physiology, Fasting physiology, Gene Expression Regulation drug effects, Gluconeogenesis drug effects, Glucose metabolism, Homeostasis drug effects, Humans, Insulin pharmacology, Male, Mice, Nuclear Proteins metabolism, Phosphorylation, Protein Processing, Post-Translational drug effects, Protein Serine-Threonine Kinases metabolism, Transcription Factors, Ubiquitin metabolism, Ubiquitin-Protein Ligases metabolism, Diabetes Mellitus genetics, Diabetes Mellitus metabolism, Gluconeogenesis genetics, Insulin metabolism, Trans-Activators metabolism
- Abstract
During feeding, increases in circulating pancreatic insulin inhibit hepatic glucose output through the activation of the Ser/Thr kinase AKT and subsequent phosphorylation of the forkhead transcription factor FOXO1 (refs 1-3). Under fasting conditions, FOXO1 increases gluconeogenic gene expression in concert with the cAMP responsive coactivator TORC2 (refs 4-8). In response to pancreatic glucagon, TORC2 is de-phosphorylated at Ser 171 and transported to the nucleus, in which it stimulates the gluconeogenic programme by binding to CREB. Here we show in mice that insulin inhibits gluconeogenic gene expression during re-feeding by promoting the phosphorylation and ubiquitin-dependent degradation of TORC2. Insulin disrupts TORC2 activity by induction of the Ser/Thr kinase SIK2, which we show here undergoes AKT2-mediated phosphorylation at Ser 358. Activated SIK2 in turn stimulated the Ser 171 phosphorylation and cytoplasmic translocation of TORC2. Phosphorylated TORC2 was degraded by the 26S proteasome during re-feeding through an association with COP1, a substrate receptor for an E3 ligase complex that promoted TORC2 ubiquitination at Lys 628. Because TORC2 protein levels and activity were increased in diabetes owing to a block in TORC2 phosphorylation, our results point to an important role for this pathway in the maintenance of glucose homeostasis.
- Published
- 2007
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38. ChREBP, a transcriptional regulator of glucose and lipid metabolism.
- Author
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Postic C, Dentin R, Denechaud PD, and Girard J
- Subjects
- Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Humans, Liver metabolism, Mice, Mice, Obese, Nuclear Proteins, Obesity metabolism, Signal Transduction, Transcription Factors, Glucose metabolism, Insulin Resistance, Lipid Metabolism physiology, Liver physiology, Obesity complications
- Abstract
Dysregulations in hepatic lipid synthesis are often associated with obesity and type 2 diabetes, and therefore a perfect understanding of the regulation of this metabolic pathway appears essential to identify potential therapeutic targets. Recently, the transcription factor ChREBP (carbohydrate-responsive element-binding protein) has emerged as a major mediator of glucose action on lipogenic gene expression and as a key determinant of lipid synthesis in vivo. Indeed, liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in obese ob/ob mice. Since ChREBP cellular localization is a determinant of its functional activity, a better knowledge of the mechanisms involved in regulating its nucleo-cytoplasmic shuttling and/or its post-translational activation is crucial in both physiology and physiopathology. Here, we review some of the studies that have begun to elucidate the regulation and function of this key transcription factor in liver.
- Published
- 2007
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39. [The regulation of gene expression by glucose].
- Author
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Girard J, Dentin R, Benhamed F, Denechaud PD, and Postic C
- Subjects
- Glycolysis genetics, Humans, Lipids genetics, Lipids physiology, Signal Transduction, Transcription Factors physiology, Transcription, Genetic, Triglycerides physiology, Gene Expression Regulation physiology, Glucose physiology
- Abstract
Glucose should not be considered uniquely as a cellular fuel but also as a signaling molecule involved in the regulation of genes encoding glycolytic and lipogenic enzymes and, as such, in storage of triglycerides. Transcriptional effects of glucose on glycolytic and lipogenic enzymes involve a specific transcription factor, ChREBP, whose characteristics and mechanism of activation are described. Finally, the possible implication of ChREBP in the physiopathology of obesity and type 2 diabetes are discussed.
- Published
- 2007
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40. Liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in ob/ob mice.
- Author
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Dentin R, Benhamed F, Hainault I, Fauveau V, Foufelle F, Dyck JR, Girard J, and Postic C
- Subjects
- Adipose Tissue metabolism, Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Blood Glucose analysis, Dietary Carbohydrates administration & dosage, Down-Regulation genetics, Fatty Acids, Nonesterified blood, Fatty Liver genetics, Fatty Liver prevention & control, Glucose metabolism, Glucose Tolerance Test, Glycogen analysis, Insulin physiology, Leptin deficiency, Lipids analysis, Lipids biosynthesis, Liver metabolism, Male, Mice, Mice, Obese, Muscle, Skeletal chemistry, Nuclear Proteins analysis, Nuclear Proteins genetics, Obesity genetics, RNA, Messenger analysis, RNA, Small Interfering genetics, Signal Transduction, Transcription Factors genetics, Transfection, Triglycerides blood, Fatty Liver etiology, Insulin Resistance physiology, Liver chemistry, Nuclear Proteins antagonists & inhibitors, Obesity complications, Transcription Factors antagonists & inhibitors
- Abstract
Obesity is a metabolic disorder often associated with type 2 diabetes, insulin resistance, and hepatic steatosis. Leptin-deficient (ob/ob) mice are a well-characterized mouse model of obesity in which increased hepatic lipogenesis is thought to be responsible for the phenotype of insulin resistance. We have recently demonstrated that carbohydrate responsive element-binding protein (ChREBP) plays a key role in the control of lipogenesis through the transcriptional regulation of lipogenic genes, including acetyl-CoA carboxylase and fatty acid synthase. The present study reveals that ChREBP gene expression and ChREBP nuclear protein content are significantly increased in liver of ob/ob mice. To explore the involvement of ChREBP in the physiopathology of hepatic steatosis and insulin resistance, we have developed an adenovirus-mediated RNA interference technique in which short hairpin RNAs (shRNAs) were used to inhibit ChREBP expression in vivo. Liver-specific inhibition of ChREBP in ob/ob mice markedly improved hepatic steatosis by specifically decreasing lipogenic rates. Correction of hepatic steatosis also led to decreased levels of plasma triglycerides and nonesterified fatty acids. As a consequence, insulin signaling was improved in liver, skeletal muscles, and white adipose tissue, and overall glucose tolerance and insulin sensitivity were restored in ob/ob mice after a 7-day treatment with the recombinant adenovirus expressing shRNA against ChREBP. Taken together, our results demonstrate that ChREBP is central for the regulation of lipogenesis in vivo and plays a determinant role in the development of the hepatic steatosis and of insulin resistance in ob/ob mice.
- Published
- 2006
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41. Activation of AMP-activated protein kinase in the liver: a new strategy for the management of metabolic hepatic disorders.
- Author
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Viollet B, Foretz M, Guigas B, Horman S, Dentin R, Bertrand L, Hue L, and Andreelli F
- Subjects
- AMP-Activated Protein Kinases, Animals, Diabetes Mellitus, Type 2 drug therapy, Enzyme Activation drug effects, Humans, Liver drug effects, Liver Diseases drug therapy, Multienzyme Complexes drug effects, Obesity drug therapy, Protein Serine-Threonine Kinases drug effects, Diabetes Mellitus, Type 2 enzymology, Glucose metabolism, Glycogen metabolism, Liver enzymology, Liver Diseases enzymology, Multienzyme Complexes metabolism, Obesity enzymology, Protein Serine-Threonine Kinases metabolism
- Abstract
It is now becoming evident that the liver has an important role in the control of whole body metabolism of energy nutrients. In this review, we focus on recent findings showing that AMP-activated protein kinase (AMPK) plays a major role in the control of hepatic metabolism. AMPK integrates nutritional and hormonal signals to promote energy balance by switching on catabolic pathways and switching off ATP-consuming pathways, both by short-term effects on phosphorylation of regulatory proteins and by long-term effects on gene expression. Activation of AMPK in the liver leads to the stimulation of fatty acid oxidation and inhibition of lipogenesis, glucose production and protein synthesis. Medical interest in the AMPK system has recently increased with the demonstration that AMPK could mediate some of the effects of the fat cell-derived adiponectin and the antidiabetic drugs metformin and thiazolidinediones. These findings reinforce the idea that pharmacological activation of AMPK may provide, through signalling and metabolic and gene expression effects, a new strategy for the management of metabolic hepatic disorders linked to type 2 diabetes and obesity.
- Published
- 2006
- Full Text
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42. Hepatic gene regulation by glucose and polyunsaturated fatty acids: a role for ChREBP.
- Author
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Dentin R, Denechaud PD, Benhamed F, Girard J, and Postic C
- Subjects
- Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Glycolysis, Humans, Mice, Nuclear Proteins deficiency, Nuclear Proteins genetics, Nuclear Proteins physiology, Transcription Factors deficiency, Transcription Factors genetics, Transcription Factors physiology, Fatty Acids, Unsaturated physiology, Gene Expression Regulation, Glucose physiology, Liver physiology, Transcription Factors metabolism
- Abstract
The liver is a major site for carbohydrate metabolism (glycolysis and glycogen synthesis) and triglyceride synthesis (lipogenesis). In the last decade, increasing evidence has emerged to show that nutrients, in particular, glucose and fatty acids, are able to regulate hepatic gene expression in a transcriptional manner. Indeed, although insulin was long thought to be the major regulator of hepatic gene expression, it is now clear that glucose metabolism rather that glucose itself also contributes substantially to the coordinated regulation of carbohydrate and lipid homeostasis in liver. In fact, the recent discovery of the glucose-signaling transcription factor carbohydrate responsive element binding protein (ChREBP) shed some light on the molecular mechanisms by which glycolytic and lipogenic genes are reciprocally regulated by glucose and fatty acids in liver. Here, we will review some of the recent studies that have begun to elucidate the regulation and function of this key transcription factor in liver. Indeed, a better understanding of the mechanisms by which glucose and fatty acids control hepatic gene expression may provide novel insight into the development of new therapeutic strategies for a better management of diseases involving blood glucose and/or disorders of lipid metabolism.
- Published
- 2006
- Full Text
- View/download PDF
43. Carbohydrate responsive element binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c): two key regulators of glucose metabolism and lipid synthesis in liver.
- Author
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Dentin R, Girard J, and Postic C
- Subjects
- Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Gene Expression Regulation, Enzymologic, Glucokinase biosynthesis, Humans, Rats, Sterol Regulatory Element Binding Protein 1, CCAAT-Enhancer-Binding Proteins physiology, DNA-Binding Proteins physiology, Glucose metabolism, Lipids biosynthesis, Liver metabolism, Transcription Factors physiology
- Abstract
In mammals, the regulation of hepatic metabolism plays a key role in whole body energy balance, since the liver is the major site of carbohydrate metabolism (glycolysis and glycogen synthesis) and triglyceride synthesis (lipogenesis). Lipogenesis is regulated through the acute control of key enzyme activities by means of allosteric and covalent modifications. Moreover, the synthesis of most glycolytic and lipogenic enzymes is regulated in response to dietary status, in which glucose, in particular, is a crucial energy nutrient. This latter response occurs in large part through transcriptional regulation of genes encoding glycolytic and lipogenic enzymes. In the past few years, recent advances have been made in understanding the transcriptional regulation of hepatic glycolytic and lipogenic genes by insulin and glucose. Although insulin is a major regulator of hepatic lipogenesis, there is increasing evidence that glucose also contributes to the coordinated regulation of carbohydrate and lipid metabolism in liver. Here, we review the respective roles of the transcription factor sterol regulatory element binding protein-1c (SREBP-1c) in mediating the effect of insulin on hepatic gene expression, and the role of carbohydrate responsive element binding protein (ChREBP) in regulating gene transcription by glucose.
- Published
- 2005
- Full Text
- View/download PDF
44. Hepatic glucokinase is required for the synergistic action of ChREBP and SREBP-1c on glycolytic and lipogenic gene expression.
- Author
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Dentin R, Pégorier JP, Benhamed F, Foufelle F, Ferré P, Fauveau V, Magnuson MA, Girard J, and Postic C
- Subjects
- Acetyl-CoA Carboxylase metabolism, Adenoviridae genetics, Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Blotting, Northern, CCAAT-Enhancer-Binding Proteins metabolism, Carbohydrate Metabolism, Cell Nucleus metabolism, Cells, Cultured, Fatty Acid Synthases metabolism, Glucose metabolism, Glucose-6-Phosphate metabolism, Glycogen metabolism, Hepatocytes metabolism, Immunoblotting, Kinetics, Lipid Metabolism, Liver metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Microscopy, Fluorescence, Nuclear Proteins, Pentosephosphates metabolism, Proteins metabolism, Pyruvate Kinase metabolism, RNA metabolism, RNA, Messenger metabolism, RNA, Small Interfering metabolism, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Sterol Regulatory Element Binding Protein 1, Time Factors, Transcription, Genetic, CCAAT-Enhancer-Binding Proteins physiology, DNA-Binding Proteins metabolism, DNA-Binding Proteins physiology, Gene Expression Regulation, Glucokinase physiology, Liver enzymology, Transcription Factors metabolism
- Abstract
Hepatic glucokinase (GK) catalyzes the phosphorylation of glucose to glucose 6-phosphate (G6P), a step which is essential for glucose metabolism in liver as well as for the induction of glycolytic and lipogenic genes. The sterol regulatory element-binding protein-1c (SREBP-1c) has emerged as a major mediator of insulin action on hepatic gene expression, but the extent to which its transcriptional effect is caused by an increased glucose metabolism remains unclear. Through the use of hepatic GK knockout mice (hGK-KO) we have shown that the acute stimulation by glucose of l-pyruvate kinase (l-PK), fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and Spot 14 genes requires GK expression. To determine whether the effect of SREBP-1c requires GK expression and subsequent glucose metabolism, a transcriptionally active form of SREBP-1c was overexpressed both in vivo and in primary cultures of control and hGK-KO hepatocytes. Our results demonstrate that the synergistic action of SREBP-1c and glucose metabolism via GK is necessary for the maximal induction of l-PK, ACC, FAS, and Spot 14 gene expression. Indeed, in hGK-KO hepatocytes overexpressing SREBP-1c, the effect of glucose on glycolytic and lipogenic genes is lost because of the impaired ability of these hepatocytes to efficiently metabolize glucose, despite a marked increase in low K(m) hexokinase activity. Our studies also reveal that the loss of glucose effect observed in hGK-KO hepatocytes is associated with a decreased in the carbohydrate responsive element-binding protein (ChREBP) gene expression, a transcription factor suggested to mediate glucose signaling in liver. Decreased ChREBP gene expression, achieved using small interfering RNA, results in a loss of glucose effect on endogenous glycolytic (l-PK) and lipogenic (FAS, ACC) gene expression, thereby demonstrating the direct implication of ChREBP in glucose action. Together these results support a model whereby both SREBP-1c and glucose metabolism, acting via ChREBP, are necessary for the dietary induction of glycolytic and lipogenic gene expression in liver.
- Published
- 2004
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