Transcriptional regulation of PEPCK

The enzymatic activity phosphoenolpyruvate carboxykinase (PEPCK) is not regulated by phosphorylation of the protein, or changes in cytoplasmic factors, like many metabolic enzymes are.  But given its key role in such processes as gluconeogenesis, glyceroneogenesis and cataplerosis, PEPCK needs to be highly regulated under a number of various physiological conditions.  In reaction to various stimuli, the amount of PEPCK protein present in the cytoplasm increases or decreases dramatically.  This can be on the order of 6 to 10 fold over the course of a couple hours.  (It should be noted that there are two forms of PEPCK, one located in the mitochondria, and one in the cytoplasm.  It is expression of the cytoplasmic form that varies so widely).  More precisely, the expression of PEPCK is regulated at the step where the gene for PEPCK is transcribed from DNA to RNA, thus PEPCK is said to be transcriptionally regulated.  Transcription of the PEPCK gene is upregulated by a number of physiological signals, including hormones intracellular pH, oxygen tension, and possibly even glucose or one of its metabolites.  In general, these increases in PEPCK transcription are blocked by insulin.  PEPCK transcription has been intensely studied in many tissues such as the liver, kidney and adipose tissue.  A more recently there has been interest in its expression in lung and intestine.  However, almost nothing is known about transcriptional regulation in the brain.  This page will give an overview of the what is know about the transcription of PEPCK in tissues where it has been studies with the hope that more work will be done in neurons.

Hormones that control the transcription of PEPCK include glucagon, glucocorticoids (both naturally occurring steroids like cortisol and the artificial steroid dexamethasone), thyroid hormone and retinoic acid.  Glucagon increases intracellular cyclic AMP levels, which increases PEPCK transcription acting through a cAMP response element (CRE).  A ‘response element’ refers to a section of DNA before the coding region for the PEPCK protein, that increases transcription when the appropriate combination of cAMP and its binding proteins are present in the nucleus.  Similarly, steroid hormones act through a glucocorticoid response element (GRE).  Both glucagon and dexamethasone are currently approved for use in humans, and there is some evidence that dexamethasone can reduce seizure activity.  However dexamethasone has many actions unrelated to PEPCK, so whether it’s anti-epileptic effect is via PEPCK needs to be investigated.

In addition to glucagon, and steroids, there are two other sets of drugs currently approved for use in humans that have been shown to increase PEPCK levels, at least in adipose tissue.   The first group it the Thiazolidinediones, rosiglitazone and pioglitazone.  These drugs are used as insulin sensitizeres and are discussed in the glyceroneogenesis section.  The second class of drugs that increase PEPCK transcription are the fibrates fenofibrate (Tricor, Triglide) and gemfibrozil (Lopid).  These drugs are used to lower blood triglyceride levels.  Fibrates and Thiazolidinediones act by binding to intracellular receptors called a peroxisome proliferator-activated receptors, or PPARs.  After a ligand binds to the PPAR, it will form a heterodimer with a retinoic acid receptor.  And this whole complex then binds DNA at the peroxisome proliferator-activated receptor response element (PPRE) to increase PEPCK transcription.  The clinical effectiveness of the thiazolidinediones appears to be related directly to its role in up-regulating PEPCK.  The mechanism of action of fibrates may be unrelated to their effect on PEPCK.  And similarly to the brain, not much is know about the effect of either class of drugs on PEPCK expression in the brain or isolated neurons.  One question I am very interested in is whether PEPCK can be up-regulated in the brain.  And if so, can that be put to clinical use to improve the effectiveness or tolerability of the ketogenic diet as treatment for epilepsy.

Epilepsy may also be modulated by increasing PEPCK  expression in response to changes in cellular of metabolic state.  NAD+ interacts with CtBP and up regulates genes controlled by PGC-1alpha such as PEPCK.  Thus changes in the NAD/NADH ratio may have the same effect on epilepsy as hormones that increase gluconeogenesis.

Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1

Read about insulin and its role in down regluating PEPCK transcription here

What is a cAMP response unit? Roesler WJ. Mol Cell Endocrinol. 2000 Apr 25;162(1-2):1-7.

Mechanism of increased renal gene expression during metabolic acidosis.  Curthoys NP, Gstraunthaler G.  Am J Physiol Renal Physiol. 2001 Sep;281(3):F381-90. [PDF]

Regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression. Hanson RW, Reshef L. Annu Rev Biochem. 1997;66:581-611. [PDF]

Identification of multiple protein binding domains in the promoter-regulatory region of the phosphoenolpyruvate carboxykinase (GTP) gene. Roesler WJ, Vandenbark GR, Hanson RW.  J Biol Chem. 1989 Jun 5;264(16):9657-64.

The repression of hormone-activated PEPCK gene expression by glucose is insulin-independent but requires glucose metabolism.  Scott DK, O'Doherty RM, Stafford JM, Newgard CB, Granner DK.  J Biol Chem. 1998 Sep 11;273(37):24145-51. [PDF]

Further characterization of the glucocorticoid response unit in the phosphoenolpyruvate carboxykinase gene. The role of the glucocorticoid receptor-binding sites. Scott DK, Stromstedt PE, Wang JC, Granner DK. Mol Endocrinol. 1998 Apr;12(4):482-91. [PDF]

Characterization of a complex glucocorticoid response unit in the phosphoenolpyruvate carboxykinase gene. Imai E, Stromstedt PE, Quinn PG, Carlstedt-Duke J, Gustafsson JA, Granner DK. Mol Cell Biol. 1990 Sep;10(9):4712-9. [PDF]

Copyright 2011 Steve Kriegler