Intricate Regulation of Phosphoenolpyruvate Carboxykinase (PEPCK) Isoforms in Normal Physiology and Disease.

BACKGROUND The phosphoenolpyruvate carboxykinase (PEPCK) isoforms are considered as rate limiting enzymes for gluconeogenesis and glyceroneogenesis pathways. PEPCK exhibits several interesting features such as a) organelle-specific isoforms (cytosolic and a mitochondrial) in vertebrate clade, b) tissue-specific expression of isoforms and c) organism-specific requirement of ATP or GTP as a cofactor. In higher organisms, PEPCK isoforms are intricately regulated and activated through several physiological and pathological stimuli such as corticoids, hormones, nutrient starvation and hypoxia. Isoform specific transcriptional/translational regulation and their interplay in maintaining glucose homeostasis remains to be fully understood. Mounting evidence indicates the significant involvement of PEPCK isoforms in physiological processes (development and longevity) and in the progression of a variety of diseases (metabolic disorders, cancer, Smith-Magenis syndrome). OBJECTIVE The present systematic review aimed to assimilate existing knowledge of transcriptional and translational regulation of PEPCK isoforms derived from cell, animal and clinical models.. CONCLUSION Based on current knowledge and extensive bioinformatics analysis, in this review we have provided a comparative (epi)genetic understanding of PCK1 and PCK2 genes encompassing regulatory elements, disease associated polymorphisms, copy number variations, regulatory miRNAs and CpG densities. We have also discussed various exogenous and endogenous modulators of PEPCK isoforms and their signaling mechanisms. Comprehensive review of existing knowledge of PEPCK regulation and function may enable identification of the underlying gaps to design new pharmacological strategies and interventions for the diseases associated with gluconeogenesis.

[1]  M. Magnuson,et al.  Cytosolic phosphoenolpyruvate carboxykinase as a cataplerotic pathway in the small intestine. , 2018, American journal of physiology. Gastrointestinal and liver physiology.

[2]  H. Friess,et al.  SIRT2 Promotes the Migration and Invasion of Gastric Cancer through RAS/ERK/JNK/MMP-9 Pathway by Increasing PEPCK1-Related Metabolism12 , 2018, Neoplasia.

[3]  A. Harris,et al.  The glycerol backbone of phospholipids derives from noncarbohydrate precursors in starved lung cancer cells , 2018, Proceedings of the National Academy of Sciences.

[4]  Q. Y. Li,et al.  Intermittent Hypoxia Disrupts Glucose Homeostasis in Liver Cells in an Insulin-Dependent and Independent Manner , 2018, Cellular Physiology and Biochemistry.

[5]  Shuqun Cheng,et al.  Overexpression of PCK1 Gene Antagonizes Hepatocellular Carcinoma Through the Activation of Gluconeogenesis and Suppression of Glycolysis Pathways , 2018, Cellular Physiology and Biochemistry.

[6]  D. Mota-Rojas,et al.  Foetal and neonatal energy metabolism in pigs and humans: a review. , 2018 .

[7]  K. Satyamoorthy,et al.  Genistein represses PEPCK‐C expression in an insulin‐independent manner in HepG2 cells and in alloxan‐induced diabetic mice , 2018, Journal of cellular biochemistry.

[8]  Y. Xiong,et al.  Metabolic reprogramming by PCK1 promotes TCA cataplerosis, oxidative stress and apoptosis in liver cancer cells and suppresses hepatocellular carcinoma , 2017, Oncogene.

[9]  Wan Lee,et al.  Data on the expression of PEPCK in HepG2 hepatocytes transfected with miR-195 , 2017, Data in brief.

[10]  W. Hung,et al.  Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) regulates the cell metabolism of pancreatic neuroendocrine tumors (pNET) and de-sensitizes pNET to mTOR inhibitors , 2017, Oncotarget.

[11]  Jichao Liang,et al.  MicroRNA-21 regulates hepatic glucose metabolism by targeting FOXO1. , 2017, Gene.

[12]  Tao Wang,et al.  Effect of L-arginine supplementation on the hepatic phosphatidylinositol 3-kinase signaling pathway and gluconeogenic enzymes in early intrauterine growth-restricted rats. , 2017, Experimental and therapeutic medicine.

[13]  R. Rodenburg,et al.  Novel homozygous PCK1 mutation causing cytosolic phosphoenolpyruvate carboxykinase deficiency presenting as childhood hypoglycemia, an abnormal pattern of urine metabolites and liver dysfunction. , 2017, Molecular genetics and metabolism.

[14]  K. Satyamoorthy,et al.  Context Dependent Regulation of Human Phosphoenolpyruvate Carboxykinase Isoforms by DNA Promoter Methylation and RNA Stability , 2016, Journal of cellular biochemistry.

[15]  C. Ross,et al.  Cytosolic phosphoenolpyruvate carboxykinase deficiency presenting with acute liver failure following gastroenteritis. , 2016, Molecular genetics and metabolism.

[16]  W. Thomas,et al.  Polybrominated Diphenyl Ether (PBDE)-Induced Suppression of Phosphoenolpyruvate Carboxykinase (PEPCK) Decreases Hepatic Glyceroneogenesis and Disrupts Hepatic Lipid Homeostasis , 2015, Journal of toxicology and environmental health. Part A.

[17]  G. Dubyak,et al.  Reciprocal Changes in Phosphoenolpyruvate Carboxykinase and Pyruvate Kinase with Age Are a Determinant of Aging in Caenorhabditis elegans* , 2015, The Journal of Biological Chemistry.

[18]  R. Deberardinis,et al.  PEPCK Coordinates the Regulation of Central Carbon Metabolism to Promote Cancer Cell Growth. , 2015, Molecular cell.

[19]  A. Kakinuma,et al.  Phenobarbital reduces blood glucose and gluconeogenesis through down-regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression in rats. , 2015, Biochemical and biophysical research communications.

[20]  Alexey Sergushichev,et al.  Mitochondrial Phosphoenolpyruvate Carboxykinase Regulates Metabolic Adaptation and Enables Glucose-Independent Tumor Growth. , 2015, Molecular cell.

[21]  H. Matsuoka,et al.  Phosphoenolpyruvate Carboxykinase, a Key Enzyme That Controls Blood Glucose, Is a Target of Retinoic Acid Receptor-Related Orphan Receptor α , 2015, PloS one.

[22]  J. Locasale,et al.  Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses , 2015, Cell.

[23]  I. Qadri,et al.  Upregulated hepatic expression of mitochondrial PEPCK triggers initial gluconeogenic reactions in the HCV-3 patients. , 2015, Asian Pacific journal of tropical medicine.

[24]  Huan Wang,et al.  Early-life exposure to high-fat diet may predispose rats to gender-specific hepatic fat accumulation by programming Pepck expression. , 2015, The Journal of nutritional biochemistry.

[25]  Janos X. Binder,et al.  DISEASES: Text mining and data integration of disease–gene associations , 2014, bioRxiv.

[26]  M. Sadasivam,et al.  The role of phosphoenolpyruvate carboxykinase in neuronal steroidogenesis under acute inflammation. , 2014, Gene.

[27]  K. F. Fajardo,et al.  Three rare diseases in one Sib pair: RAI1, PCK1, GRIN2B mutations associated with Smith-Magenis Syndrome, cytosolic PEPCK deficiency and NMDA receptor glutamate insensitivity. , 2014, Molecular genetics and metabolism.

[28]  C. Deng,et al.  Tumor suppressor p53 cooperates with SIRT6 to regulate gluconeogenesis by promoting FoxO1 nuclear exclusion , 2014, Proceedings of the National Academy of Sciences.

[29]  F. Viñals,et al.  Mitochondrial Phosphoenolpyruvate Carboxykinase (PEPCK-M) Is a Pro-survival, Endoplasmic Reticulum (ER) Stress Response Gene Involved in Tumor Cell Adaptation to Nutrient Availability* , 2014, The Journal of Biological Chemistry.

[30]  M. Yoder.  Inducing definitive hematopoiesis in a dish , 2014, Nature Biotechnology.

[31]  R. Kibbey,et al.  The mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK-M) and glucose homeostasis: has it been overlooked? , 2014, Biochimica et biophysica acta.

[32]  A. Harris,et al.  PCK2 activation mediates an adaptive response to glucose depletion in lung cancer , 2014, Oncogene.

[33]  G. Shulman,et al.  A Role for Mitochondrial Phosphoenolpyruvate Carboxykinase (PEPCK-M) in the Regulation of Hepatic Gluconeogenesis* , 2014, The Journal of Biological Chemistry.

[34]  E. Chini,et al.  Deleted in Breast Cancer 1 (DBC1) Protein Regulates Hepatic Gluconeogenesis* , 2014, The Journal of Biological Chemistry.

[35]  Masaud Shah,et al.  Screening and design of anti-diabetic compounds sourced from the leaves of neem (Azadirachta indica) , 2013, Bioinformation.

[36]  S. Park,et al.  HNF4α contributes to glucose formation in aged rat hepatocytes , 2013, Experimental Gerontology.

[37]  D. Iliopoulos,et al.  miRNAs link metabolic reprogramming to oncogenesis , 2013, Trends in Endocrinology & Metabolism.

[38]  J. C. Perales,et al.  PEPCK-M expression in mouse liver potentiates, not replaces, PEPCK-C mediated gluconeogenesis. , 2013, Journal of hepatology.

[39]  Irene Cantone,et al.  Epigenetic programming and reprogramming during development , 2013, Nature Structural &Molecular Biology.

[40]  G. Holloway,et al.  FAT/CD36 regulates PEPCK expression in adipose tissue. , 2013, American journal of physiology. Cell physiology.

[41]  V. Rotter,et al.  p53 promotes the expression of gluconeogenesis-related genes and enhances hepatic glucose production , 2013, Cancer & metabolism.

[42]  R. Hudson,et al.  A genetic polymorphism evolving in parallel in two cell compartments and in two clades , 2013, BMC Evolutionary Biology.

[43]  G. Carey,et al.  Polybrominated Diphenyl Ethers Alter Hepatic Phosphoenolpyruvate Carboxykinase Enzyme Kinetics in Male Wistar Rats: Implications for Lipid and Glucose Metabolism , 2013, Journal of toxicology and environmental health. Part A.

[44]  Joshua M. Finkelstein,et al.  Metabolism and disease , 2012, Nature.

[45]  S. Rahman,et al.  Increased Phosphoenolpyruvate Carboxykinase Gene Expression and Steatosis during Hepatitis C Virus Subgenome Replication , 2012, The Journal of Biological Chemistry.

[46]  L. Velloso,et al.  Fructose-induced hypothalamic AMPK activation stimulates hepatic PEPCK and gluconeogenesis due to increased corticosterone levels. , 2012, Endocrinology.

[47]  B. Vojtesek,et al.  The role of the 3' untranslated region in post-transcriptional regulation of protein expression in mammalian cells. , 2012, RNA biology.

[48]  K. Feingold,et al.  Inflammation inhibits the expression of phosphoenolpyruvate carboxykinase in liver and adipose tissue , 2012, Innate immunity.

[49]  K. Meyer,et al.  Hepatitis C Virus Activates the mTOR/S6K1 Signaling Pathway in Inhibiting IRS-1 Function for Insulin Resistance , 2012, Journal of Virology.

[50]  A. Sandelin,et al.  Metazoan promoters: emerging characteristics and insights into transcriptional regulation , 2012, Nature Reviews Genetics.

[51]  P. Li,et al.  Effect of insulin-like growth factor-1 (IGF-1) on the gluconeogenesis in calf hepatocytes cultured in vitro , 2012, Molecular and Cellular Biochemistry.

[52]  J. Lupski,et al.  Human genome sequencing in health and disease. , 2012, Annual review of medicine.

[53]  A. Speciale,et al.  Nutritional antioxidants and adaptive cell responses: an update. , 2011, Current molecular medicine.

[54]  S. Burgess,et al.  Flux through hepatic pyruvate carboxylase and phosphoenolpyruvate carboxykinase detected by hyperpolarized 13C magnetic resonance , 2011, Proceedings of the National Academy of Sciences.

[55]  Y. Xiong,et al.  Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase. , 2011, Molecular cell.

[56]  M. Hanson,et al.  Dietary Protein Restriction during F0 Pregnancy in Rats Induces Transgenerational Changes in the Hepatic Transcriptome in Female Offspring , 2011, PloS one.

[57]  Sarah Crunkhorn.  Metabolic disease: New role for HDACs in glucose homeostasis , 2011, Nature Reviews Drug Discovery.

[58]  Hai-Dan Yuan,et al.  An Active Part of Artemisia sacrorum Ledeb. Suppresses Gluconeogenesis through AMPK Mediated GSK3β and CREB Phosphorylation in Human HepG2 Cells , 2011, Bioscience, biotechnology, and biochemistry.

[59]  S. Kliewer,et al.  FGF15/19 regulates hepatic glucose metabolism by inhibiting the CREB-PGC-1α pathway. , 2011, Cell metabolism.

[60]  Dan Zhou,et al.  Gestational high fat diet programs hepatic phosphoenolpyruvate carboxykinase gene expression and histone modification in neonatal offspring rats , 2011, The Journal of physiology.

[61]  R. Evans,et al.  Class IIa Histone Deacetylases Are Hormone-Activated Regulators of FOXO and Mammalian Glucose Homeostasis , 2011, Cell.

[62]  John B. Thomas,et al.  A Hormone-Dependent Module Regulating Energy Balance , 2011, Cell.

[63]  Jianping Ye,et al.  Inhibition of glyceroneogenesis by histone deacetylase 3 contributes to lipodystrophy in mice with adipose tissue inflammation. , 2011, Endocrinology.

[64]  A. Pandey,et al.  miR-29a levels are elevated in the db/db mice liver and its overexpression leads to attenuation of insulin action on PEPCK gene expression in HepG2 cells , 2011, Molecular and Cellular Endocrinology.

[65]  J. Shulman,et al.  A Putative Alzheimer's Disease Risk Allele in PCK1 Influences Brain Atrophy in Multiple Sclerosis , 2010, PloS one.

[66]  Yaohui Nie,et al.  MAPK phosphatase-3 promotes hepatic gluconeogenesis through dephosphorylation of forkhead box O1 in mice. , 2010, The Journal of clinical investigation.

[67]  W. Wong,et al.  Hypoxia-inducible factors and the response to hypoxic stress. , 2010, Molecular cell.

[68]  R. Watanabe,et al.  Pharmacogenetics of Anti-Diabetes Drugs , 2010, Pharmaceuticals.

[69]  N. Trakooljul,et al.  Identification of target genes and pathways associated with chicken microRNA miR-143. , 2010, Animal genetics.

[70]  John Wei,et al.  Towards a comprehensive structural variation map of an individual human genome , 2010, Genome Biology.

[71]  Sabine Ehrt,et al.  Gluconeogenic carbon flow of tricarboxylic acid cycle intermediates is critical for Mycobacterium tuberculosis to establish and maintain infection , 2010, Proceedings of the National Academy of Sciences.

[72]  M. Nijland,et al.  Epigenetic modification of fetal baboon hepatic phosphoenolpyruvate carboxykinase following exposure to moderately reduced nutrient availability , 2010, The Journal of physiology.

[73]  K. Poutanen,et al.  Impact of Dietary Polyphenols on Carbohydrate Metabolism , 2010, International journal of molecular sciences.

[74]  D. Sabatini,et al.  mTORC1 activates SREBP-1c and uncouples lipogenesis from gluconeogenesis , 2010, Proceedings of the National Academy of Sciences.

[75]  F. Lemaigre,et al.  Organogenesis and development of the liver. , 2010, Developmental cell.

[76]  Oren Froy,et al.  Metabolism and circadian rhythms--implications for obesity. , 2010, Endocrine reviews.

[77]  Shijie Li,et al.  Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis , 2010, Proceedings of the National Academy of Sciences.

[78]  Zhang-Guo Gao,et al.  Exchange of a nuclear corepressor between NF-kappaB and CREB mediates inhibition of phosphoenolpyruvate carboxykinase transcription by NF-kappaB. , 2010, Chinese medical journal.

[79]  J. Alwine,et al.  Glutamine Metabolism Is Essential for Human Cytomegalovirus Infection , 2009, Journal of Virology.

[80]  M. A. Kelly,et al.  The promoter polymorphism -232C/G of the PCK1 gene is associated with type 2 diabetes in a UK-resident South Asian population , 2009, BMC Medical Genetics.

[81]  Steven J. M. Jones,et al.  Circos: an information aesthetic for comparative genomics. , 2009, Genome research.

[82]  M. Hurles,et al.  Copy number variation in human health, disease, and evolution. , 2009, Annual review of genomics and human genetics.

[83]  Thomas D. Wu,et al.  A highly annotated whole-genome sequence of a Korean individual , 2009, Nature.

[84]  Shwu‐Yuan Wu,et al.  Activation of SIRT1 by Resveratrol Represses Transcription of the Gene for the Cytosolic Form of Phosphoenolpyruvate Carboxykinase (GTP) by Deacetylating Hepatic Nuclear Factor 4α* , 2009, The Journal of Biological Chemistry.

[85]  R. Hanson.  Thematic Minireview Series: A Perspective on the Biology of Phosphoenolpyruvate Carboxykinase 55 Years After Its Discovery* , 2009, The Journal of Biological Chemistry.

[86]  M. Yadav,et al.  Epigenomic derangement of hepatic glucose metabolism by feeding of high fructose diet and its prevention by Rosiglitazone in rats. , 2009, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver.

[87]  V. Bhardwaj,et al.  Tumour necrosis factor‐α attenuates insulin action on phosphoenolpyruvate carboxykinase gene expression and gluconeogenesis by altering the cellular localization of Foxa2 in HepG2 cells , 2009, The FEBS journal.

[88]  Roger Corder,et al.  Endotoxin induced hyperlactatemia and hypoglycemia is linked to decreased mitochondrial phosphoenolpyruvate carboxykinase. , 2009, Life sciences.

[89]  M. Celeste Simon,et al.  The impact of O2 availability on human cancer , 2008, Nature Reviews Cancer.

[90]  C. Gottfried,et al.  Ketogenic diet-fed rats have increased fat mass and phosphoenolpyruvate carboxykinase activity. , 2008, Molecular nutrition & food research.

[91]  N. Denko,et al.  Hypoxia, HIF1 and glucose metabolism in the solid tumour , 2008, Nature Reviews Cancer.

[92]  R. Bartrons,et al.  Pck1 Gene Silencing in the Liver Improves Glycemia Control, Insulin Sensitivity, and Dyslipidemia in db/db Mice , 2008, Diabetes.

[93]  R. Hanson,et al.  Born to run; the story of the PEPCK-Cmus mouse. , 2008, Biochimie.

[94]  J. Scoazec,et al.  Vascular Development and Differentiation During Human Liver Organogenesis , 2008, Anatomical record.

[95]  D. Kelley,et al.  Estimates of hepatic glyceroneogenesis in type 2 diabetes mellitus in humans. , 2008, Metabolism: clinical and experimental.

[96]  Myung‐Sook Choi,et al.  Genistein and daidzein prevent diabetes onset by elevating insulin level and altering hepatic gluconeogenic and lipogenic enzyme activities in non‐obese diabetic (NOD) mice , 2008, Diabetes/metabolism research and reviews.

[97]  C. Anuradha,et al.  Effect of Genistein, a Soy Isof lavone, on Whole Body Insulin Sensitivity and Renal Damage Induced by a High-Fructose Diet , 2008, Renal failure.

[98]  David L Wilson,et al.  Overexpression of the Cytosolic Form of Phosphoenolpyruvate Carboxykinase (GTP) in Skeletal Muscle Repatterns Energy Metabolism in the Mouse*♦ , 2007, Journal of Biological Chemistry.

[99]  Guoxun Chen.  Liver lipid molecules induce PEPCK-C gene transcription and attenuate insulin action. , 2007, Biochemical and biophysical research communications.

[100]  B. Das,et al.  In vitro testing of anthelmintic efficacy of Flemingia vestita (Fabaceae) on carbohydrate metabolism in Rallietina echinobothrida. , 2007, Methods.

[101]  Jianping Ye,et al.  Nuclear corepressor is required for inhibition of phosphoenolpyruvate carboxykinase expression by tumor necrosis factor-alpha. , 2007, Molecular Endocrinology.

[102]  E. Eichler,et al.  Mutational and selective effects on copy-number variants in the human genome , 2007, Nature Genetics.

[103]  M. Owen,et al.  Candidate gene association study of insulin signaling genes and Alzheimer's disease: Evidence for SOS2, PCK1, and PPARγ as susceptibility loci , 2007, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[104]  E. Beale,et al.  PCK1 and PCK2 as candidate diabetes and obesity genes , 2007, Cell Biochemistry and Biophysics.

[105]  M. Magnuson,et al.  Cytosolic phosphoenolpyruvate carboxykinase does not solely control the rate of hepatic gluconeogenesis in the intact mouse liver. , 2007, Cell metabolism.

[106]  Julie C Kiefer,et al.  Epigenetics in development , 2007, Developmental dynamics : an official publication of the American Association of Anatomists.

[107]  J. Gray,et al.  Phosphoenolpyruvate carboxykinase in Arabidopsis: changes in gene expression, protein and activity during vegetative and reproductive development. , 2007, Plant & cell physiology.

[108]  Emma Saavedra,et al.  Energy metabolism in tumor cells , 2007, The FEBS journal.

[109]  D. Granner,et al.  Insulin represses phosphoenolpyruvate carboxykinase gene transcription by causing the rapid disruption of an active transcription complex: a potential epigenetic effect. , 2007, Molecular endocrinology.

[110]  B. Zinman,et al.  Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. , 2006, The New England journal of medicine.

[111]  J. Ioannidis,et al.  Concordance of functional in vitro data and epidemiological associations in complex disease genetics , 2006, Genetics in Medicine.

[112]  Jung-Sook Seo,et al.  Genistein and daidzein modulate hepatic glucose and lipid regulating enzyme activities in C57BL/KsJ-db/db mice. , 2006, Life sciences.

[113]  Robin Holliday,et al.  Epigenetics: A Historical Overview , 2006, Epigenetics.

[114]  M. McGrane,et al.  Vitamin A status in mice affects the histone code of the phosphoenolpyruvate carboxykinase gene in liver. , 2005, The Journal of nutrition.

[115]  D. Yeagley,et al.  Insulin regulation of PEPCK gene expression: a model for rapid and reversible modulation. , 2005, Current drug targets. Immune, endocrine and metabolic disorders.

[116]  S. Tilghman,et al.  Phosphoenolpyruvate carboxykinase and the critical role of cataplerosis in the control of hepatic metabolism , 2005, Nutrition & metabolism.

[117]  Qing Yang,et al.  Dual Specificity MAPK Phosphatase 3 Activates PEPCK Gene Transcription and Increases Gluconeogenesis in Rat Hepatoma Cells* , 2005, Journal of Biological Chemistry.

[118]  J. H. Kim,et al.  Association of a polymorphism in the gene encoding phosphoenolpyruvate carboxykinase 1 with high-density lipoprotein and triglyceride levels , 2005, Diabetologia.

[119]  Sachin S Hajarnis,et al.  3′-Untranslated Region of Phosphoenolpyruvate Carboxykinase mRNA Contains Multiple Instability Elements That Bind AUF1* , 2005, Journal of Biological Chemistry.

[120]  L. N. Valenti,et al.  Nuclear Trapping of the Forkhead Transcription Factor FoxO1 via Sirt-dependent Deacetylation Promotes Expression of Glucogenetic Genes* , 2005, Journal of Biological Chemistry.

[121]  Min Jung Park,et al.  Molecular mechanism of hypoxia‐mediated hepatic gluconeogenesis by transcriptional regulation , 2005, FEBS letters.

[122]  J. Friedman,et al.  Chronic hyperglycemia enhances PEPCK gene expression and hepatocellular glucose production via elevated liver activating protein/liver inhibitory protein ratio. , 2005, Diabetes.

[123]  Kazuya Yamada,et al.  SHARP‐2/Stra13/DEC1 as a potential repressor of phosphoenolpyruvate carboxykinase gene expression , 2005, FEBS letters.

[124]  Richard W. Hanson,et al.  Factors That Control the Tissue-Specific Transcription of the Gene for Phosphoenolpyruvate Carboxykinase-C , 2005, Critical reviews in biochemistry and molecular biology.

[125]  J. Prandota.  Possible pathomechanisms of sudden infant death syndrome: key role of chronic hypoxia, infection/inflammation states, cytokine irregularities, and metabolic trauma in genetically predisposed infants. , 2004, American journal of therapeutics.

[126]  B. Das,et al.  Effects of phytochemicals of Flemingia vestita (Fabaceae) on glucose 6-phosphate dehydrogenase and enzymes of gluconeogenesis in a cestode (Raillietina echinobothrida). , 2004, Comparative biochemistry and physiology. Toxicology & pharmacology : CBP.

[127]  Timothy R. Rebbeck,et al.  Assessing the function of genetic variants in candidate gene association studies , 2004, Nature Reviews Genetics.

[128]  T. Fukui,et al.  First Characterization of an Archaeal GTP-Dependent Phosphoenolpyruvate Carboxykinase from the Hyperthermophilic Archaeon Thermococcus kodakaraensis KOD1 , 2004, Journal of bacteriology.

[129]  F. Wondisford,et al.  Insulin regulation of hepatic gluconeogenesis through phosphorylation of CREB-binding protein , 2004, Nature Medicine.

[130]  Shwu‐Yuan Wu,et al.  SREBP-1c and Sp1 Interact to Regulate Transcription of the Gene for Phosphoenolpyruvate Carboxykinase (GTP) in the Liver* , 2004, Journal of Biological Chemistry.

[131]  Delin Chen,et al.  Mammalian SIRT1 Represses Forkhead Transcription Factors , 2004, Cell.

[132]  B. Zinman,et al.  Promoter polymorphism in PCK1 (phosphoenolpyruvate carboxykinase gene) associated with type 2 diabetes mellitus. , 2004, The Journal of clinical endocrinology and metabolism.

[133]  G. Velho,et al.  Expression of phosphoenolpyruvate carboxykinase gene in human adipose tissue: induction by rosiglitazone and genetic analyses of the adipocyte-specific region of the promoter in type 2 diabetes. , 2003, Biochimie.

[134]  H. Hammon,et al.  Dexamethasone and colostrum feeding affect hepatic gluconeogenic enzymes differently in neonatal calves. , 2003, Journal of animal science.

[135]  P. Flakoll,et al.  Mechanisms by which liver-specific PEPCK knockout mice preserve euglycemia during starvation. , 2003, Diabetes.

[136]  Bruce M. Spiegelman,et al.  Insulin-regulated hepatic gluconeogenesis through FOXO1–PGC-1α interaction , 2003, Nature.

[137]  Y. Matsuzawa,et al.  Identification of a Novel Variant in the Phosphoenolpyruvate Carboxykinase Gene Promoter in Japanese Patients with Type 2 Diabetes , 2003, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[138]  Ratna Prasad,et al.  Elements of the Glucocorticoid and Retinoic Acid Response Units Are Involved in cAMP-mediated Expression of the PEPCK Gene* , 2003, The Journal of Biological Chemistry.

[139]  J. Friedman,et al.  Phosphoenolpyruvate Carboxykinase Overexpression Selectively Attenuates Insulin Signaling and Hepatic Insulin Sensitivity in Transgenic Mice* , 2002, The Journal of Biological Chemistry.

[140]  Tsonwin Hai,et al.  The Roles of ATF3 in Liver Dysfunction and the Regulation of Phosphoenolpyruvate Carboxykinase Gene Expression* , 2002, The Journal of Biological Chemistry.

[141]  S. Trapani,et al.  Crystal structure of the dimeric phosphoenolpyruvate carboxykinase (PEPCK) from Trypanosoma cruzi at 2 A resolution. , 2001, Journal of molecular biology.

[142]  E. Ferrannini,et al.  Effect of physiological hyperinsulinemia on gluconeogenesis in nondiabetic subjects and in type 2 diabetic patients. , 2001, Diabetes.

[143]  R A Roth,et al.  Differential regulation of endogenous glucose-6-phosphatase and phosphoenolpyruvate carboxykinase gene expression by the forkhead transcription factor FKHR in H4IIE-hepatoma cells. , 2001, Biochemical and biophysical research communications.

[144]  S. Kalhan,et al.  Glyceroneogenesis and the Source of Glycerol for Hepatic Triacylglycerol Synthesis in Humans* , 2001, The Journal of Biological Chemistry.

[145]  M. Foretz,et al.  Insulin effects on sterol regulatory-element-binding protein-1c (SREBP-1c) transcriptional activity in rat hepatocytes. , 2000, The Biochemical journal.

[146]  R. Chalkley,et al.  Phosphoenolpyruvate Carboxykinase Is Necessary for the Integration of Hepatic Energy Metabolism , 2000, Molecular and Cellular Biology.

[147]  C. Kahn,et al.  Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. , 2000, Molecular cell.

[148]  D. Scott,et al.  The Molecular Physiology of Hepatic Nuclear Factor 3 in the Regulation of Gluconeogenesis* , 2000, The Journal of Biological Chemistry.

[149]  T. Yoshikawa,et al.  Tumor-associated metabolic alterations in patients with gastric and esophageal cancer. , 1999, Hepato-gastroenterology.

[150]  J. Wang,et al.  The phosphoenolpyruvate carboxykinase gene glucocorticoid response unit: identification of the functional domains of accessory factors HNF3 beta (hepatic nuclear factor-3 beta) and HNF4 and the necessity of proper alignment of their cognate binding sites. , 1999, Molecular endocrinology.

[151]  G. Slama,et al.  Biochemical and Molecular Roles of Nutrients A High Glycemic Index Starch Diet Affects Lipid Storage–Related Enzymes in Normal and to a Lesser Extent in Diabetic Rats , 1998 .

[152]  J. Coligan,et al.  Activating Transcription Factor-2 Regulates Phosphoenolpyruvate Carboxykinase Transcription through a Stress-inducible Mitogen-activated Protein Kinase Pathway* , 1998, The Journal of Biological Chemistry.

[153]  K. Jungermann,et al.  Human mitochondrial phosphoenolpyruvate carboxykinase 2 gene. Structure, chromosomal localization and tissue-specific expression. , 1998, The Biochemical journal.

[154]  A. Giaccia,et al.  The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. , 1998, Cancer research.

[155]  M. McGrane,et al.  Vitamin A regulates genes involved in hepatic gluconeogenesis in mice: phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. , 1997, The Journal of nutrition.

[156]  A. Gurney,et al.  The promoter regulatory regions of the genes for the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) from the chicken and the rat have different species-specific roles in gluconeogenesis. , 1997, The Journal of nutrition.

[157]  K. Jungermann,et al.  Molecular cloning, sequencing and expression of the cDNA of the mitochondrial form of phosphoenolpyruvate carboxykinase from human liver. , 1996, The Biochemical journal.

[158]  J. Flier,et al.  Insulin Regulation of Phosphoenolpyruvate Carboxykinase Gene Expression Does Not Require Activation of the Ras/Mitogen-activated Protein Kinase Signaling Pathway (*) , 1996, The Journal of Biological Chemistry.

[159]  A. Tao,et al.  Effects of vitamin A deficiency and retinoic acid treatment on expression of a phosphoenolpyruvate carboxykinase-bovine growth hormone gene in transgenic mice. , 1995, Biochemical and biophysical research communications.

[160]  I. Kettelhut,et al.  Increased Adipose Tissue Glyceroneogenesis in Rats Adapted to a High Protein, Carbohydrate-Free Diet , 1995, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[161]  R. O’Brien,et al.  Phosphatidylinositol 3-Kinase, but Not p70/p85 Ribosomal S6 Protein Kinase, Is Required for the Regulation of Phosphoenolpyruvate Carboxykinase (PEPCK) Gene Expression by Insulin , 1995, The Journal of Biological Chemistry.

[162]  X. Leverve,et al.  Mechanism of gluconeogenesis inhibition in rat hepatocytes isolated after in vivo hypoxia. , 1995, The American journal of physiology.

[163]  F. Sladek,et al.  The orphan receptors COUP-TF and HNF-4 serve as accessory factors required for induction of phosphoenolpyruvate carboxykinase gene transcription by glucocorticoids. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[164]  R. O’Brien,et al.  Comparison of the effects of insulin and okadaic acid on phosphoenolpyruvate carboxykinase gene expression. , 1994, The Biochemical journal.

[165]  F. Bosch,et al.  Transgenic mice overexpressing phosphoenolpyruvate carboxykinase develop non-insulin-dependent diabetes mellitus. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[166]  G L Johnson,et al.  Nuclear protein phosphatase 2A dephosphorylates protein kinase A-phosphorylated CREB and regulates CREB transcriptional stimulation , 1993, Molecular and cellular biology.

[167]  M. Hill,et al.  Identification of tumor necrosis factor as a transcriptional regulator of the phosphoenolpyruvate carboxykinase gene following endotoxin treatment of mice , 1992, Infection and immunity.

[168]  J. Liu,et al.  Opposing actions of Fos and Jun on transcription of the phosphoenolpyruvate carboxykinase (GTP) gene. Dominant negative regulation by Fos. , 1992, The Journal of biological chemistry.

[169]  M. Titheradge,et al.  Physiological concentrations of 2-oxoglutarate regulate the activity of phosphoenolpyruvate carboxykinase in liver. , 1992, The Biochemical journal.

[170]  J. Liu,et al.  Cyclic AMP induction of phosphoenolpyruvate carboxykinase (GTP) gene transcription is mediated by multiple promoter elements. , 1991, The Journal of biological chemistry.

[171]  H. Samuels,et al.  Specificity of a retinoic acid response element in the phosphoenolpyruvate carboxykinase gene promoter: consequences of both retinoic acid and thyroid hormone receptor binding. , 1991, Molecular and cellular biology.

[172]  J. Gustafsson,et al.  Characterization of a complex glucocorticoid response unit in the phosphoenolpyruvate carboxykinase gene , 1990, Molecular and cellular biology.

[173]  R. O’Brien,et al.  Identification of a sequence in the PEPCK gene that mediates a negative effect of insulin on transcription. , 1990, Science.

[174]  W. Roesler,et al.  Identification of multiple protein binding domains in the promoter-regulatory region of the phosphoenolpyruvate carboxykinase (GTP) gene. , 1989, Journal of Biological Chemistry.

[175]  Y. Hod,et al.  Cyclic AMP stabilizes the mRNA for phosphoenolpyruvate carboxykinase (GTP) against degradation. , 1988, The Journal of biological chemistry.

[176]  R Holliday,et al.  The inheritance of epigenetic defects. , 1987, Science.

[177]  G. Shaw,et al.  A conserved AU sequence from the 3′ untranslated region of GM-CSF mRNA mediates selective mRNA degradation , 1986, Cell.

[178]  J. Leonard,et al.  Mitochondrial phosphoenolpyruvate carboxykinase deficiency , 1986, European Journal of Pediatrics.

[179]  D. Granner,et al.  Inhibition of transcription of the phosphoenolpyruvate carboxykinase gene by insulin , 1983, Nature.

[180]  Y. Hod,et al.  The unique role of the kidney in gluconeogenesis in the chicken. The significance of a cytosolic form of phosphoenolpyruvate carboxykinase. , 1981, The Journal of biological chemistry.

[181]  D. Shouval,et al.  Premature appearance of hepatic phosphoenolpyruvate carboxykinase in fetal rats, not mediated by adenosine 3':5'-monophosphate. , 1979, European journal of biochemistry.

[182]  R. Hanson,et al.  Changes in hepatic messenger RNA for phosphoenolpyruvate carboxykinase (GTP) during development. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[183]  G. Leveille,et al.  Influence of diet on glucose tolerance, on the rate of glucose utilization and on gluconeogenic enzyme activities in the dog. , 1976, The Journal of nutrition.

[184]  J. Vidnes,et al.  GLUCONEOGENESIS IN INFANCY AND CHILDHOOD III. Deficiency of the Extramitochondrial Form of Hepatic Phosphoenolpyruvate Carboxykinase in a Case of Persistent Neonatal Hypoglycaemia , 1976, Acta paediatrica Scandinavica.

[185]  H. Bremer,et al.  TWO CASES OF PHOSPHOENOLPYRUVATE CARBOXYKINASE DEFICIENCY , 1976, Acta paediatrica Scandinavica.

[186]  H. Söling,et al.  Relationship between intracellular distribution of phosphoenolpyruvate carboxykinase, regulation of gluconeogenesis, and energy cost of glucose formation. , 1973, European journal of biochemistry.

[187]  G. Wolf,et al.  Subcellular Distribution of Pyruvate Carboxylase and Phosphoenolpyruvate Carboxykinase in Dog Liver and Kidney , 1972, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[188]  A. Garber,et al.  Phosphoenolpyruvate carboxykinase. I. Its role in gluconeogenesis. , 1972, The American journal of clinical nutrition.

[189]  H. J. Sallach,et al.  Human liver phosphoenolpyruvate carboxykinase: Evidence for a separate mitochondrial and cytosol enzyme , 1971 .

[190]  F. Ballard.  Kinetic studies with cytosol and mitochondrial phosphoenolpyruvate carboxykinases. , 1970, The Biochemical journal.

[191]  W. Brech,et al.  Studies on pyruvate carboxylase in rat and human liver. , 1970, Biochimica et biophysica acta.

[192]  R. Hanson,et al.  Metabolic Changes in Liver Associated with Spontaneous Ketosis and Starvation in Cows , 1968 .

[193]  R. Hanson,et al.  Phosphoenolpyruvate carboxykinase and pyruvate carboxylase in developing rat liver. , 1967, The Biochemical journal.

[194]  H. Krebs.  The Croonian Lecture, 1963 Gluconeogenesis , 1964, Proceedings of the Royal Society of London. Series B. Biological Sciences.

[195]  H. Lardy,et al.  Mammalian Liver Phosphoenolpyruvate Carboxykinase Activities , 1963 .

[196]  M. Utter,et al.  Mechanism of action of oxalacetic carboxylase. , 1954, The Journal of biological chemistry.

[197]  S. Donkin,et al.  Short communication: Regulation of hepatic gluconeogenic enzymes by dietary glycerol in transition dairy cows. , 2016, Journal of dairy science.

[198]  P. Sassone-Corsi,et al.  Metabolism and the circadian clock converge. , 2013, Physiological reviews.

[199]  Y. Xiong,et al.  Regulation of glycolysis and gluconeogenesis by acetylation of PKM and PEPCK. , 2011, Cold Spring Harbor symposia on quantitative biology.

[200]  Iuliana Ionita-Laza,et al.  Genetic association analysis of copy-number variation (CNV) in human disease pathogenesis. , 2009, Genomics.

[201]  J. Ye.  Emerging role of adipose tissue hypoxia in obesity and insulin resistance , 2009, International Journal of Obesity.

[202]  A. Shyu,et al.  Messenger RNA half-life measurements in mammalian cells. , 2008, Methods in enzymology.

[203]  J. Hamilton,et al.  Developmentally specific effects of the DNA cross‐linking agent mitomycin C on phosphoenolpyruvate carboxykinase gene expression in vivo: Correlation with changes in chromatin structure within the promoter region of the gene , 1998, Journal of biochemical and molecular toxicology.

[204]  R. Hanson,et al.  Regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression. , 1997, Annual review of biochemistry.

[205]  Y. Patel,et al.  Phosphoenolpyruvate carboxykinase (GTP): the gene and the enzyme. , 1994, Advances in enzymology and related areas of molecular biology.

[206]  M. Stoffel,et al.  cDNA sequence and localization of polymorphic human cytosolic phosphoenolpyruvate carboxykinase gene (PCK1) to chromosome 20, band q13.31: PCK1 is not tightly linked to maturity-onset diabetes of the young. , 1993, Human molecular genetics.

[207]  J. Trent,et al.  Human PCK1 encoding phosphoenolpyruvate carboxykinase is located on chromosome 20q13.2. , 1993, Genomics.

[208]  N. Benvenisty,et al.  Sequential changes in DNA methylation patterns of the rat phosphoenolpyruvate carboxykinase gene during development. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[209]  K. Pfüller,et al.  [Postnatal development of gluconeogenic key enzymes, phosphoenolpyruvate carboxykinase and pyruvate carboxylase, in pig liver]. , 1982, Acta biologica et medica Germanica.

[210]  F. Ballard.  Regulation of gluconeogenesis during exposure of young rats to hypoxic conditions. , 1971, The Biochemical journal.