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Gene Review

Pck1  -  phosphoenolpyruvate carboxykinase 1,...

Mus musculus

Synonyms: AI265463, PEPCK, PEPCK-C, Pck-1, Pepck
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Disease relevance of Pck1


Psychiatry related information on Pck1

  • Our findings strongly suggest that vitamin A is required during liver development for staged expression of the PEPCK gene and that HNF4alpha may be involved in mediating vitamin A regulation of the PEPCK gene at these critical periods [5].
  • In mice fed the control diet, food deprivation for 15 h resulted in PEPCK mRNA levels that were 3.5-fold higher, Fru-1,6-P2ase mRNA levels that were 2-fold higher, and 6-PF-2-K/Fru-2,6-P2ase mRNA levels that were 3.4-fold higher than in fed mice [6].

High impact information on Pck1


Chemical compound and disease context of Pck1

  • Furthermore, ectopic expression of MKP-3 in hepatoma cells by adenoviral infection increased the expression of PEPCK and G6Pase genes and led to elevated glucose production [1].
  • However, C/EBPbeta deletion affected streptozotocin-diabetic response by: (a) delaying hyperglycemia, (b) preventing the increase of plasma free fatty acids, (c) limiting the full induction of PEPCK and glucose 6-phosphatase genes, and (d) preventing the increase in gluconeogenesis rate [11].
  • Treatment of ob/ob mice with 30 mg/kg b.i.d. A-769662 decreased hepatic expression of PEPCK, G6Pase, and FAS, lowered plasma glucose by 40%, reduced body weight gain and significantly decreased both plasma and liver triglyceride levels [12].
  • In acidosis, the mRNA of kidney system N amino acid transporter SNAT3 (SLC38A3/SN1) showed a strong induction similar to that of PEPCK, whereas all other tested mRNAs encoding glutamine or glutamate transporters were unchanged or reduced in abundance [13].
  • Sterility of PEPCK/bGH females appeared to be due to luteal failure since treatment with progesterone led to pregnancy [14].

Biological context of Pck1


Anatomical context of Pck1

  • The mutation abolished expression of the gene in white adipose tissue and considerably reduced its expression in brown adipose tissue, whereas the level of PEPCK-C mRNA in liver and kidney remained normal [10].
  • The overexpression of the PEPCK gene led to an increase in glucose production from pyruvate in hepatocytes in primary culture [17].
  • We further demonstrate that the adipocyte-specific transcription factor PPAR gamma 2, previously identified as a regulator of the adipocyte P2 enhancer, binds in a heterodimeric complex with RXR alpha to the PEPCK 5'-flanking region at two sites, termed PCK1 (bp -451 to -439) and PCK2 (bp -999 to -987) [18].
  • Transient transfection assays of a chimeric PEPCK-chloramphenicol acetyltransferase construct showed a residual PEPCK promoter activity in the Hepa cell line, which was slightly stimulated by cotransfection with a single transcription factor from either the C/EBP family or HNF-1 alpha but not at all affected by cotransfection of HNF-4 [19].
  • PPARgamma/RXR occupies gAF1/PCK1 in adipocytes, and mutation of gAF1/PCK1 enhances PEPCK promoter transactivation by PPARgamma/RXR in fibroblasts, suggesting that this element is also a negative PPARgamma response element [20].

Associations of Pck1 with chemical compounds

  • The importance of glyceroneogenesis in adipose tissue was assessed in mice by specifically eliminating the expression of the cytosolic form of phosphoenolpyruvate carboxykinase (PEPCK-C), an enzyme that plays a pivotal role in the pathway [10].
  • It has been shown that the PEPCK gene is a retinoid-responsive gene, but whether it is regulated by vitamin A in the fetus has not been established [5].
  • SH exerted beneficial effects on the plasma glucose and lipid homeostasis possibly ascribed to its specific effects on lipogenesis related genes (SREBP1a, FAS, GAPT), and PEPCK, glucose 6-phosphatase gene expressions in liver [21].
  • Given that a ninefold elevation of the hepatic malate concentration occurs in the liver-specific PEPCK knockout mice, we suggest that one or more intermediary metabolites may directly regulate expression of the affected genes [22].
  • Here we show that, unlike the PPARgamma agonist rosiglitazone, LPA was unable to increase transcription of PPARgamma-sensitive genes (PEPCK and ALBP) in the mouse preadipose cell line 3T3F442A [23].

Physical interactions of Pck1

  • Previously, we reported that in LLC-PK1 and derived kidney cell lines, mutation of the hepatic nuclear factor 1 (HNF-1) binding site in PEPCK-C gene promoter markedly reduced both the basal activity of the gene promoter and its response to acidic pH [24].

Regulatory relationships of Pck1


Other interactions of Pck1

  • Electrophoretic mobility shift assays indicated that ATF3 bound to the ATF/cAMP-responsvie element site derived from the promoter of the gene encoding the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) [16].
  • Furthermore, in contrast to C57BL/6 mice, the expression of G6Pase, PEPCK and PGC-1alpha genes during feeding was not down-regulated in db/db mice [29].
  • This synergistic effect depended on the presence in the PEPCK promoter region of the HNF-1 recognition sequence and on the presence of two C/EBP recognition sequences [19].
  • These cells mimicked the fetal liver by appreciably expressing the alpha-fetoprotein and albumin genes but not the phosphoenolpyruvate carboxykinase (PEPCK) gene [19].
  • In agreement with in vivo studies, hepatocyte lines derived from mice homozygous for the deletion expressed reduced mRNA levels of a number of liver genes including TAT, PEPCK, X1, X2, and X7 in comparison with heterozygous and wild-type cell lines [30].

Analytical, diagnostic and therapeutic context of Pck1


  1. Dual specificity MAPK phosphatase 3 activates PEPCK gene transcription and increases gluconeogenesis in rat hepatoma cells. Xu, H., Yang, Q., Shen, M., Huang, X., Dembski, M., Gimeno, R., Tartaglia, L.A., Kapeller, R., Wu, Z. J. Biol. Chem. (2005) [Pubmed]
  2. Hypoglycemia and impaired hepatic glucose production in mice with a deletion of the C/EBPbeta gene. Liu, S., Croniger, C., Arizmendi, C., Harada-Shiba, M., Ren, J., Poli, V., Hanson, R.W., Friedman, J.E. J. Clin. Invest. (1999) [Pubmed]
  3. Mechanisms by which liver-specific PEPCK knockout mice preserve euglycemia during starvation. She, P., Burgess, S.C., Shiota, M., Flakoll, P., Donahue, E.P., Malloy, C.R., Sherry, A.D., Magnuson, M.A. Diabetes (2003) [Pubmed]
  4. Hormonal regulation of chimeric genes containing the phosphoenolpyruvate carboxykinase promoter regulatory region in hepatoma cells infected by murine retroviruses. Hatzoglou, M., Park, E., Wynshaw-Boris, A., Kaung, H.L., Hanson, R.W. J. Biol. Chem. (1988) [Pubmed]
  5. Vitamin A depletion is associated with low phosphoenolpyruvate carboxykinase mRNA levels during late fetal development and at birth in mice. Ghoshal, S., Pasham, S., Odom, D.P., Furr, H.C., McGrane, M.M. J. Nutr. (2003) [Pubmed]
  6. 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. Shin, D.J., McGrane, M.M. J. Nutr. (1997) [Pubmed]
  7. CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Herzig, S., Long, F., Jhala, U.S., Hedrick, S., Quinn, R., Bauer, A., Rudolph, D., Schutz, G., Yoon, C., Puigserver, P., Spiegelman, B., Montminy, M. Nature (2001) [Pubmed]
  8. Hepatic fibrosis, glomerulosclerosis, and a lipodystrophy-like syndrome in PEPCK-TGF-beta1 transgenic mice. Clouthier, D.E., Comerford, S.A., Hammer, R.E. J. Clin. Invest. (1997) [Pubmed]
  9. Overproduction of cholesterol and fatty acids causes massive liver enlargement in transgenic mice expressing truncated SREBP-1a. Shimano, H., Horton, J.D., Hammer, R.E., Shimomura, I., Brown, M.S., Goldstein, J.L. J. Clin. Invest. (1996) [Pubmed]
  10. A mutation in the peroxisome proliferator-activated receptor gamma-binding site in the gene for the cytosolic form of phosphoenolpyruvate carboxykinase reduces adipose tissue size and fat content in mice. Olswang, Y., Cohen, H., Papo, O., Cassuto, H., Croniger, C.M., Hakimi, P., Tilghman, S.M., Hanson, R.W., Reshef, L. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  11. The transcription factor CCAAT/enhancer-binding protein beta regulates gluconeogenesis and phosphoenolpyruvate carboxykinase (GTP) gene transcription during diabetes. Arizmendi, C., Liu, S., Croniger, C., Poli, V., Friedman, J.E. J. Biol. Chem. (1999) [Pubmed]
  12. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cool, B., Zinker, B., Chiou, W., Kifle, L., Cao, N., Perham, M., Dickinson, R., Adler, A., Gagne, G., Iyengar, R., Zhao, G., Marsh, K., Kym, P., Jung, P., Camp, H.S., Frevert, E. Cell metabolism. (2006) [Pubmed]
  13. Regulation of renal amino acid transporters during metabolic acidosis. Moret, C., Dave, M.H., Schulz, N., Jiang, J.X., Verrey, F., Wagner, C.A. Am. J. Physiol. Renal Physiol. (2007) [Pubmed]
  14. Fertility of transgenic female mice expressing bovine growth hormone or human growth hormone variant genes. Naar, E.M., Bartke, A., Majumdar, S.S., Buonomo, F.C., Yun, J.S., Wagner, T.E. Biol. Reprod. (1991) [Pubmed]
  15. Estrogen-related receptor alpha is a repressor of phosphoenolpyruvate carboxykinase gene transcription. Herzog, B., Cardenas, J., Hall, R.K., Villena, J.A., Budge, P.J., Giguère, V., Granner, D.K., Kralli, A. J. Biol. Chem. (2006) [Pubmed]
  16. The roles of ATF3 in liver dysfunction and the regulation of phosphoenolpyruvate carboxykinase gene expression. Allen-Jennings, A.E., Hartman, M.G., Kociba, G.J., Hai, T. J. Biol. Chem. (2002) [Pubmed]
  17. Transgenic mice overexpressing phosphoenolpyruvate carboxykinase develop non-insulin-dependent diabetes mellitus. Valera, A., Pujol, A., Pelegrin, M., Bosch, F. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  18. PPAR gamma 2 regulates adipose expression of the phosphoenolpyruvate carboxykinase gene. Tontonoz, P., Hu, E., Devine, J., Beale, E.G., Spiegelman, B.M. Mol. Cell. Biol. (1995) [Pubmed]
  19. Transcriptional regulation of the phosphoenolpyruvate carboxykinase gene by cooperation between hepatic nuclear factors. Yanuka-Kashles, O., Cohen, H., Trus, M., Aran, A., Benvenisty, N., Reshef, L. Mol. Cell. Biol. (1994) [Pubmed]
  20. Peroxisome proliferator-activated receptor gamma and chicken ovalbumin upstream promoter transcription factor II negatively regulate the phosphoenolpyruvate carboxykinase promoter via a common element. Eubank, D.W., Duplus, E., Williams, S.C., Forest, C., Beale, E.G. J. Biol. Chem. (2001) [Pubmed]
  21. Salicornia herbacea prevents high fat diet-induced hyperglycemia and hyperlipidemia in ICR mice. Park, S.H., Ko, S.K., Choi, J.G., Chung, S.H. Arch. Pharm. Res. (2006) [Pubmed]
  22. Phosphoenolpyruvate carboxykinase is necessary for the integration of hepatic energy metabolism. She, P., Shiota, M., Shelton, K.D., Chalkley, R., Postic, C., Magnuson, M.A. Mol. Cell. Biol. (2000) [Pubmed]
  23. Lysophosphatidic acid inhibits adipocyte differentiation via lysophosphatidic acid 1 receptor-dependent down-regulation of peroxisome proliferator-activated receptor gamma2. Simon, M.F., Daviaud, D., Pradère, J.P., Grès, S., Guigné, C., Wabitsch, M., Chun, J., Valet, P., Saulnier-Blache, J.S. J. Biol. Chem. (2005) [Pubmed]
  24. The transcriptional regulation of phosphoenolpyruvate carboxykinase gene in the kidney requires the HNF-1 binding site of the gene. Cassuto, H., Olswang, Y., Heinemann, S., Sabbagh, K., Hanson, R.W., Reshef, L. Gene (2003) [Pubmed]
  25. Repression and activation of transcription of phosphoenolpyruvate carboxykinase gene during liver development. Cassuto, H., Aran, A., Cohen, H., Eisenberger, C.L., Reshef, L. FEBS Lett. (1999) [Pubmed]
  26. Long-term treatment with novel glycogen synthase kinase-3 inhibitor improves glucose homeostasis in ob/ob mice: molecular characterization in liver and muscle. Kaidanovich-Beilin, O., Eldar-Finkelman, H. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  27. Retinoid regulation of the phosphoenolpyruvate carboxykinase gene in liver. Shin, D.J., Odom, D.P., Scribner, K.B., Ghoshal, S., McGrane, M.M. Mol. Cell. Endocrinol. (2002) [Pubmed]
  28. Evidence from transgenic mice that myc regulates hepatic glycolysis. Valera, A., Pujol, A., Gregori, X., Riu, E., Visa, J., Bosch, F. FASEB J. (1995) [Pubmed]
  29. Nutrient control of phosphorylation and translocation of Foxo1 in C57BL/6 and db/db mice. Aoyama, H., Daitoku, H., Fukamizu, A. Int. J. Mol. Med. (2006) [Pubmed]
  30. Isolation and characterization of mouse hepatocyte lines carrying a lethal albino deletion. Chou, J.Y., Ruppert, S., Shelly, L.L., Pan, C.J. J. Biol. Chem. (1991) [Pubmed]
  31. Assignment of the rat genes coding for alpha 1-antitrypsin (PI), phosphoenolpyruvate carboxykinase (PEPCK), alcohol dehydrogenase (ADH), and fructose-1,6-bisphosphatase (FDP). Fulchignoni-Lataud, M.C., Szpirer, J., Levan, G., Weiss, M.C. Mamm. Genome (1992) [Pubmed]
  32. Identification of a novel mouse hepatic 52 kDa protein that interacts with the cAMP response element of the rat angiotensinogen gene. Wu, J., Jiang, Q., Chen, X., Wu, X.H., Chan, J.S. Biochem. J. (1998) [Pubmed]
  33. RNA polymerase II association with the phosphoenolpyruvate carboxykinase (PEPCK) promoter is reduced in vitamin A-deficient mice. Scribner, K.B., McGrane, M.M. J. Nutr. (2003) [Pubmed]
  34. Lactotroph hyperplasia in the pituitaries of female mice expressing high levels of bovine growth hormone. Vidal, S., Stefaneanu, L., Thapar, K., Aminyar, R., Kovacs, K., Bartke, A. Transgenic Res. (1999) [Pubmed]
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