Transcriptional control of genes that regulate glycolysis and gluconeogenisis adult liver

Glycolysis is the metabolic pathway through which glucose is converted to pyruvate, with a net yield of two moles of ATP and NADH per mole of glucose used. In liver, the glycolytic flux is low except when glucose concentrations are high or during anoxia. The main function of glycolysis in liver is therefore to provide substrates for anabolic processes. Gluconeogenesis is the reverse of glycolysis, pyruvate being converted to glucose. While glycolysis occurs in every tissue, gluconeogenesis is specific for the liver, the kidney and the small intestine. Gluconeogenesis supplies glucose to the body and provides a way to dispose of amino acids and of lactate produced by erythrocytes and during muscular contraction. It is also a means of disposal for glycerol produced during lipolysis.
Glycolysis and gluconeogenesis share several enzymes. These enzymes catalyze reactions that are close to equilibrium (reversible) under physiological conditions. On the other hand, three substrate cycles – the glucose/glucose-6-phosphate, fructose-6-phosphate/fructose-1,6-biphosphate and the phosphoenopyruvate/pyruvate cycles – involve exergonic reactions and regulate the pace of glycolysis and gluconeogenesis. These exergonic reactions, which are maintained far from equilibrium, are catalyzed by different enzymes in the glycolytic and gluconeogenic pathways, and it is not a surprise that these key enzymes are the main targets for regulatory process. Three types of regulatory mechanisms have to be considered (Hers and Hue, 1983; Pilkis et al., 1988). The first one involves the supply of glycolytic or gluconeogenic substrates. The second mechanism exerts a fast (minutes) control on the catalytic properties of the enzymes through phosphorylation and allosteric changes. The third type of control implies slow adaptations (hours/days) following changes in gene expression and protein synthesis.
The first two types of mechanisms have been extensively reviewed (Hers and Hue, 1983; Pilkis et al., 1988). As to the slow control mechanisms, only the general principles of the hormonal and nutritional regulation have been reviewed (Granner and Pilkis, 1990; Pilkis and Granner, 1992). Moreover, during the past years, new data have accumulated that describe the molecular mechanisms of the long term regulation of glycolysis and gluconeogenesis. These mechanisms mainly act at the level of gene transcription and imply basal, tissue-specific, hormonal and nutritional regulatory processes. The present review is an update of these four processes.
The essential role of the liver in blood glucose homeostasis underscores the importance of the hepatic glycolytic and gluconeogenic pathways. This paper is therefore restricted to the transcriptional control in liver of the genes coding for glycolytic and gluconeogenic enzymes.
The principles of transcription regulation in higher encaryotes may be summarized as follows. The promoter of a gene coding for an mRNA is located immediately upstream of the transcription initiation site. This promoter is required for accurate, directional, and efficient initiation of transcription factors (trans-acting-factors). While some cic-acting sequences are common to many genes (e.g. TATA or CG boxes), others mediate specific responses, e.g. to extracellular signals or tissue-specific regulators. Enhancers and silencers are cic-acting sequences that stimulate or inhibit the activity of a promoter. Their functional organization is similar to that of promoters, but they act in a position- and orientation-independent way and they are unable to initiate transcription.
A wide variety of transcription factors have been described. These include the general or basal transcription factors and the upstream regulatory factors. Basal transcription factors (reviewed in Drapkin et al, 1993) form a transcription initiation complex that is anchored on the TATA box and attracts RNA polymerase II to the transcription initiation site. The upstream regulatory factors modulate the activity of the initiation complex by a mechanism that is not well understood.
The upstream factors displays a modular structure in that the DNA-binding and transcription regulatory domains can often be separated. The activity of the transcription factors may be modulated by several effector mechanisms, as e.g. phosphorylation, glycosylation or hormone binding. Also, in many cases transcription factors from homo- and heterodimers through specific dimerization domains. Dimerization may affect both DNA-binding and transcriptional activity, and is therefore a key regulatory mechanism for the control of gene expression. .
Liver gene expression is, at least in part, controlled by ubiquitous and liver-enriched factors. A classification of the latter is given in Table I. Table II shows the ubiquitous factors that regulate the genes coding for glycolytic and gluconeogenic enzymes. Some key properties of these proteins are mentioned in the Tables