Gluconeogenesis

Abstract

Gluconeogenesis is a pivotal biochemical pathway in which glucose is synthesised from non‐carbohydrate precursors, that is, lactate, alanine, glutamine and glycerol, during prolonged starvation. This pathway utilises most glycolytic enzymes in the reverse direction, except the three irreversible steps, which are bypassed by four additional enzymes, pyruvate carboxylase (PC), phosphoeonolpyruvate carboxykinase (PEPCK), fructose‐1,6‐bisphosphatase (FBPase) and glucose‐6‐phosphatase (G6Pase), known as the ‘gluconeogenic enzymes’. Elevated levels of glucagon and glucocorticoids during prolonged fasting stimulate gluconeogenesis in the short and long term. A short‐term response to these hormones involves reversible phosphorylation and allosteric modifications, which can alter the activities of the gluconeogenic enzymes. In contrast, a long‐term response involves the modulation of transcriptional activity of their (nuclear) encoded genes. CREB (cAMP‐responsive element binding protein), FoxO1 (forkhead box O1), PPARα (peroxisome proliferator activated receptor alpha) and PGC1α (peroxisome proliferator activated‐receptor gamma coactivator‐1α) are the key transcription factors that control most gluconeogenic enzymes. Deregulation of glucogeneogic enzymes perturbs systemic glucose homeostasis, causing diabetes.

Key Concepts

  • Mammals are well adapted to nutrient deprivation in order to survive during food restriction.
  • Glucose is the sole energy source for brain and red blood cells.
  • Alteration of glucoregulatory hormones during starvation influences glucose production from liver and kidney by programming relevant biochemical pathways.
  • Binding of glucoregulatory hormones to their receptors transmits the biochemical signals or molecules that affect the activity of key gluconeogenic enzymes or transcription of gluconeogenic genes.
  • Loss‐of‐function mutations of gluconeogenic enzyme genes or deregulation of gluconeogenic pathway results in the failure of the body to maintain glucose homeostasis

Keywords: gluconeogeneis; pyruvate carboxylase; phosphoenolpyruvate carboxykinase; fructose‐1,6‐bisphosphatase; glucose‐6‐phosphotase; fasting; liver; kidney; transcription; glucoregulator hormone

Figure 1. Schematic diagram showing gluconeogenic and glycolytic pathways. The former is regulated by four gluconeogenic enzymes: pyruvate carboxylase (PC), cytoplasmic or mitochondrial phosphoenolpyruvate carboxykinase (PEPCK‐C or PEPCK‐M, respectively), fructose‐1,6‐bisphosphatase (FBPase) and glucose‐6‐phosphatase (G6Pase), which are shown by red arrows, while the irreversible reactions catalysed by pyruvate kinase (PK), phosphofructokinase1 (PFK1) and glucokinase (GK) are shown by blue arrows. The gluconeogenic substrates lactate (Cori cycle), alanine (glucose–alanine cycle), glutamine and glycerol via lipolysis are shown by green arrows.
Figure 2. Role of glutamine in renal gluconeogenesis. Increased catabolism of amino acids in muscle increases the levels of plasma glutamine. Metabolic acidosis, a physiological condition characterised by increased acidity in plasma, enhances the rate of glutamine uptake in renal proximal tubules where glutamine is deaminated to glutamate by glutaminase (GLS) and further to α‐ketoglutarate by glutamate dehydrogenase (GDH). α‐Ketoglutarate then enters the rest of the gluconeogenic pathway except PC, as shown in the diagram. The renal ammonium ions (NH4+; blue arrows) formed during deamination reaction are excreted into the urine to neutralise the acidity of the luminal fluid, while the increased bicarbonate ions (HCO3; red arrows) generated during gluconeogenesis are transported into the blood to neutralise the acidity in plasma.
Figure 3. Hormonal regulation of gluconeogenic enzymes at transcriptional and post‐translational levels. During starvation, glucagon and glucocorticoids stimulate the transcription of PC, PEPCK and G6Pase genes through post‐translational modifications of the relevant transcription factors and co‐activators, which in turn affect their bindings to their cognate sequences. Glucagon signalling via PKA activation also results in depleted levels of F26P, which in turn stimulates FBPase I activity while stimulating PC activity via acetyl‐CoA, which is produced during excessive β oxidation. PKA signalling also stimulates the phosphorylation of CREB and interaction with its coactivators CRTC2/CBP/p300 to bind to the CRE of gluconeogenic gene promoters. During this period, FoxO1 also sustains transcription of gluconeogenic genes. Conversely, insulin suppresses transcription of PC, PEPCK and G6Pase genes via phosphorylation of FoxO1, resulting in its cytosolic retention and thus inhibiting transcription of gluconeogenic enzyme genes. Insulin signalling also attenuates PKA signalling, resulting in the disassembly of CREB/CRTC2/CBP/p300 complex, and thus suppressing gluconeogenesis. Insulin signalling via Akt2 activation also causes phosphorylation of PFK2/FBP2 bifunctional enzyme, resulting in the accumulation of F26P, which in turn allosterically inhibits FBPase I activity. A high level of L‐aspartate synthesis, as a consequence of a high rate of oxaloacetate transamination, inhibits PC activity as a feedback regulation loop.
close

References

Altarejos JY and Montminy M (2011) CREB and the CRTC coactivators: sensor for hormonal and metabolic signals. Nature Reviews Molecular Cell Biology 12: 141–155.

Brooks GA (2009) Cell‐cell and intracellular lactate shuttles. The Journal of Physiology 587 (Pt 23): 5591–5600.

Burgess SC, He T, Yan Z, et al. (2007) Cytosolic phosphoenolpyruvate carboxykinase does not solely control the rate of hepatic gluconeogenesis in the intact mouse liver. Cell Metabolism 5: 312–320.

Cassuto H, Olswang Y, Heinemann S, et al. (2003) The transcriptional regulation of phosphoenolpyru‐ vate carboxykinase gene in the kidney requires the HNF‐1 binding site of the gene. Gene 318: 177–184.

Cassuto H, Kochan K, Chakravarty K, et al. (2005) Glucocorticoids regulate transcription of the gene for phosphoenolpyruvate carboxykinase in the liver via an extended glucocorticoid regulatory unit. Journal of Biological Chemistry 280: 33873–33884.

Chou JY, Jun HS and Mansfield BC (2010) Glycogen storage disease type I and G6Pase –b deficiency: etiology and therapy. Nature Reviews Endocrinology 6: 676–688.

Dentin R, Hendrick S, Xie J, Yate J and Montminy M (2008) Hepatic glucose sensing via the CREB coactivator CRTC2. Science 319: 1402–1405.

El‐Maghrabi MR, Lange AJ, Kiimmel L and Pilkis SJ (1991) The Rat Fructose‐1,6‐bisphosphatase Gene. The Journal of Biological Chemistry 266: 2115–2120.

Fang Y, Guo Y, Hamblin M, et al. (2011) Inhibition of gluconeogenic genes by calcium‐regulated heat‐stable protein 1 via repression of peroxisome proliferator‐activated receptor α. The Journal of Biological Chemistry 286: 40584–40594.

Gerich JE, Meyer C, Woerle HJ and Stumvoll M (2001) Renal gluconeogenesis: its importance in human glucose homeostasis. Diabetes Care 24: 382–391.

Hanson RW and Reshef L (1997) Regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression. Annual Review of Biochemistry 66: 581–611.

Hajarnis S, Schroeder JM and Curthoys NP (2005) 3′‐Untranslated region of phosphoenolpyruvate carboxykinase mRNA contains multiple instability elements that bind AUF1. The Journal of Biological Chemistry 280: 28272–28280.

He L, Naik K, Meng S, et al. (2012) Transcriptional co‐activator p300 maintains basal hepatic gluconeogenesis. The Journal of Biological Chemistry 287: 32069–32077.

Hutton JC and O'Brien RM (2009) Glucose‐6‐phosphatase catalytic subunit gene family. The Journal of Biological Chemistry 284: 29241–29245.

Im SS, Kim MY, Kwon SK, et al. (2011) Peroxisome proliferator activated receptor is responsible for the up‐regulation of hepatic glucose‐6‐phosphatase gene expression in fasting and db/db mice. The Journal of Biological Chemistry 286: 1157–1164.

Jitrapakdee S, Maurice MST, Rayment I, et al. (2008) Structure, mechanism and regulation of pyruvate carboxylase. Biochemical Journal 413: 369–387.

Katz J and Tayek JA (1999) Recycling of glucose and determination of the Cori Cycle and gluconeogenesis. American Journal of Physiology 277: E401–E407.

Ke HM, Zhang YP and Lipscomb WN (1990) Crystal structure of fructose‐1,6‐bisphosphatase complexed with fructose‐6‐phosphate, AMP, and magnesium. Proceedings of the National Academy of Sciences of the United States of America 87: 5243–5247.

Kersten S, Seydoux J, Peters JM, et al. (1999) Peroxisome proliferator activated receptor alpha mediates the adaptive response to fasting. Journal of Clinical Investigation 103: 1489–1498.

Kumashiro N, Beddow SA, Vatner DF, et al. (2013) Targeting pyruvate carboxylase reduces gluconeogenesis and adiposity and improves insulin resistance. Diabetes 62: 2183–2194.

Lamont BJ, Visinoni S, Fam BC, et al. (2006) Expression of human fructose‐1,6‐bisphosphatase in the liver of transgenic mice results in increased glycerol gluconeogenesis. Endocrinology 147: 2764–2772.

Lange AJ, Argaud D, el‐Maghrabi MR, et al. (1994) Isolation of a cDNA for the catalytic subunit of rat liver glucose‐6‐phosphatase: regulation of gene expression in FAO hepatoma cells by insulin, dexamethasone and cAMP. Biochemical and Biophysical Research Communications 201: 302–309.

Maechler P and Wollheim CB (2001) Mitochondrial function in normal and diabetic beta‐cells. Nature 414: 807–812.

Matte A, Tari LW, Goldie H and Delbaere LTJ (1997) Structure and mechanism of phosphoenolpyruvate carboxykinase. The Journal of Biological Chemistry 272: 8105–8108.

Meyer C, Dostou JM, Welle SL and Gerich JE (2002) Role of human, liver, and skeletal muscle in postprandial glucose homeostasis. American Journal of Physiology, Endorinology and Metabolism 282: E419–E427.

Moon S, Kim JH, Han JH, et al. (2011) Novel compound heterozygous mutations in the fructose‐1,6‐bisphosphatase gene cause hypoglycemia and lactic acidosis. Metabolism 60: 107–113.

Mullur R, Liu YY and Brent GA (2014) Thyroid hormone regulation of metabolism. Physiological Reviews 94 (2): 355–382.

Nordlie RC, Foster JD and Lange AJ (1999) Regulation of glucose production by liver. Annual Review of Nutrition 19: 379–406.

O'Brien RM, Lucas PC, Forest CD, Magnunson MA and Granner DK (1990) Identification of a sequence in the P‐enolpyruvate carboxykinase gene that mediates the negative effect of insulin on transcription. Science 249: 533–537.

Park EA, Song S, Vinson C and Roesler WJ (1999) Role of CCAAT enhancer‐binding protein beta in the thyroid hormone and cAMP induction of phosphoenolpyruvate carboxykinase gene transcription. The Journal of Biological Chemistry 274: 211–217.

Petersen KF, Blair JB and Shulman GI (1995) Triiodothyronine treatment increases substrate cycling between pyruvate carboxylase and malic enzyme in perfused rat liver. Metabolism 44 (11): 1380–1383.

Previs SF, Brunengraber DZ and Brunengraber H (2009) Is there glucose production outside of the liver and kidney? Annual Review of Nutrition 29: 43–57.

Puigserver P, Rhee J, Donovan J, et al. (2003) Insulin‐regulated hepatic gluconeogenesis through FOXO1‐PGC‐1alpha interaction. Nature 433: 550–555.

Reddy JK and Hashimoto T (2001) Peroxisomal beta‐oxidation and peroxisome proliferator‐activated receptor‐activated receptor alpha: an adaptive metabolic system. Annual Review of Nutrition 21: 193–230.

Samuel VT, Beddow SA, Iwasaki T, et al. (2009) Fasting hyperglycemia is not associated with increased expession of PEPCK or G6Pc in patients with Type 2 Diabetes. Proceedings of the National Academy of Sciences of the United States of America 106: 12121–12126.

Singh BK, Sinha RA, Zhou J, et al. (2013) FoxO1 deacetylation regulates thyroid hormone‐induced transcription of key hepatic gluconeogenic genes. The Journal of Biological Chemistry 288: 30365–30372.

Stark R, Guebre‐Egziabher F, Zhao X, et al. (2014) A role for mitochondrial phosphoenolpyruvate carboxykinase (PEPCK‐M) in the regulation of hepatic gluconeogenesis. The Journal of Biological Chemistry 289: 7257–7263.

Stumvoll M, Meyer C, Perriello G, et al. (1998) Human kidney and liver gluconeogenesis: evidence for organ substrate selectivity. American Journal of Physiology 274: E817–E826.

Taylor L and Curthoys NP (2004) Glutamine metabolism: role in acid base balance. Biochemistry and Molecular Biology Education 32: 291–304.

Tayyem RF, Zalloum HM, Elmaghrabi MR, Yousef AM and Mubarak MS (2012) ligand‐based designing, in silico screening and biological evaluation of new potent fructose‐1,6‐bisphosphatase (FBPase) inhibitors. European Journal of Medicinal Chemistry 56: 70–95.

Thonpho A, Sereeruk C, Rojvirat P and Jitrapakdee S (2010) Identification of the cyclic AMP responsive element (CRE) that mediates transcriptional regulation of the pyruvate carboxylase gene in HepG2 cells. Biochemical and Biophysical Research Communications 393: 714–719.

Tillmann H, Bernhard D and Eschrich K (2002) Fructose‐1,6‐bisphosphatase genes in animals. Gene 291: 57–66.

Trinh KY, O'Doherty RM, Anderson P, Lange AJ and Newgard CB (1998) Perturbation of fuel homeostasis caused by overexpression of the glucose‐6‐phosphatase catalytic subunit in liver of normal rats. The Journal of Biological Chemistry 273: 31615–31620.

Troy S, Soty M, Ribeiro L, et al. (2008) Intestinal gluconeogenesis is a key factor for early metabolic changes after gastric bypass but not after gastric lap‐band in mice. Cell Metabolism 8: 201–211.

Valera A, Pujol A, Pelegrin M and Bosch F (1994) Transgenic mice overexpressing phosphoenolpyruvate carboxykinase develop non‐ insulin‐dependent diabetes mellitus. Proceedings of the National Academy of Sciences of the United States of America 91: 9151–9154.

Vander Kooi BT, Onuma H, Oeser JK, et al. (2005) The glucose‐6‐phosphatase catalytic subunit gene promoter contains both positive and negative glucocorticoids response elements. Molecular Endocrinology 19: 3001–3022.

Visinoni S, Fam BC, Blair A, et al. (2008) Increased glucose production in mice overexpressing human fructose‐1,6‐bisphosphatase in the liver. American Journal of Physiology, Endocrinology and Metabolism 295: E1132–E1141.

Voice MW, Borthwick EB, Coughtrie MW and Burchell A (1995) The in vivo regulation of hepatic and renal glucose‐6‐phosphatase by thyroxine. Biochimica et Biophysica Acta 1231 (2): 176–180.

Wu C, Khan SA, Peng LJ and Lange AJ (2006) Role for fructose‐2,6‐bisphosphate in the control of fuel metabolism: beyond its allosteric effects on glycolytic and gluconeogenic enzymes. Advances in Enzyme Regulation 46: 72–88.

Yoon JC, Puigserver P, Chen G, et al. (2001) Control of hepatic gluconeogenesis through the transcriptional coactivator PGC1α. Nature 413: 131–138.

Further Reading

Adeva M, González‐Lucán M, Seco M and Donapetry C (2013) Enzymes involved in l‐lactate metabolism in humans. Mitochondrion 13: 615–629.

Chakravarty K, Cassuto H, Reshef L and Hanson RW (2005) Factors that control the tissue‐specific transcription of the gene for phosphoenolpyruvate carboxykinase‐C. Critical Reviews in Biochemistry and Molecular Biology 40: 129–154.

Desvergne B, Michalik L and Wahli W (2006) Transcriptional regulation of metabolism. Physiological Reviews 86: 465–514.

Gerich JE (2010) Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications. Diabetic Medicine 27: 136–142.

Herzig S, Long F, Jhala US, et al. (2001) CREB regulates hepatic gluconeogenesis through the coactivator PGC‐1. Nature 413: 179–183.

Jitrapakdee S (2012) Transcription factors and coactivators controlling nutrient and hormonal regulation of hepatic gluconeogenesis. International Journal of Biochemistry and Cell Biology 44: 33–45.

Landau BR, Wahren J, Chandramouli V, et al. (1996) Contributions of gluconeogenesis to glucose production in the fasted state. The Journal of Clinical Investigation 98: 378–385.

Marcolongo P, Fulceri R, Gamberucci A, et al. (2013) Multiple roles of glucose‐6‐phosphatases in pathophysiology: state of the art and future trends. Biochimica et Biophysica Acta 1830: 2608–2618.

Saltiel AR and Kahn CR (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414: 799–806.

St Maurice M, Reinhardt L, Surinya KH, et al. (2007) Domain architecture of pyruvate carboxylase, a biotin‐dependent multifunctional enzyme. Science 317 (5841): 1076–1079.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Wattanavanitchakorn, Siriluck, and Jitrapakdee, Sarawut(Feb 2016) Gluconeogenesis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000627.pub3]