Transcription gluconeogenesis

Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes a critical reaction in gluconeogenesis, which under many conditions is the rate-limiting step in the pathway. A cAlVfP response element (CRE) and a glucocorticoid response element (GRE) are each located upstream from the transcription start site. 

Phosphoenolpyruvate carboxykinase (PEP-CK), a key enzyme in gluconeogenesis, is regulated by several hormones, all of which affect the transcription of the PEP-CK gene. Cortisol, glucagon, and thyroxin induce PEP-CK, while insulin inhibits its induction (see p. 158). 

Figure 17-20 The interlocking pathways of glycolysis, gluconeogenesis, and fatty acid oxidation and synthesis with indications of some aspects of control in hepatic tissues. (— ) Reactions of glycolysis, fatty acid degradation, and oxidation by the citric acid cycle. ) Biosynthetic pathways. Some effects of insulin via indirect action on enzymes , 0, or on transcription 0/ 0. Effects of glucagon , .

Yoon JC, Puigserver P, Chen GX, Donovan J, Wu ZD, et al. 2001 Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413 131-38... 

Bind to nuclear peroxisome proliferator-activating receptors (PPARs) involved in transcription of insulin-responsive genes —> sensitization of tissues to insulin, plus 4- hepatic gluconeogenesis and triglycerides and t insulin receptor numbers (Figure VII-2-2). 

PCK1 Phosphoenolpyruvate carboxykinase, key enzyme in gluconeogenesis, catalyzes early reaction in carbohydrate biosynthesis, glucose represses transcription and accelerates mRNA degradation, regulated by Mcmlp and Cat8p, located in the cytosol... 

Insulin inhibits transcription of the enzyme phosphoenolpyruvate carboxykinase (PEPCK). PEPCK is a key enzyme in gluconeogenesis and transcription is the primary means of regulating it. By inhibiting PEPCK transcription, insulin can depress glucose production tremendously. (Conversely, the hormone glucagon, which increases blood glucose levels, stimulates PEPCK transcription.)... 

For PEPCK to function in gluconeogenesis, oxaloacetate produced in the pyruvate carboxylase reaction in the mitochondria, must be transported to the cytoplasm. PEPCK is not under any known allosteric control. Activity of the enzyme is regulated by hormonal control of its transcription. Glucagon stimulates transcription of the structural gene for PEPCK. Insulin inhibits transcription of the enzyme. By inhibiting PEPCK gene transcription, insulin tends to depress gluconeogenesis rates. 

The conversion of oxaloacetate to PEP by PEP-carboxykinase (PEPCK, Eq. 14-43 Fig. 17-20) is another control point in gluconeogenesis. Insulin inhibits gluconeogenesis by decreasing transcription of the mRNA for this enzyme. Glucagon and cAMP stimulate its transcription. The activity of PEP carboxykinase " is also enhanced by Mn + and by very low concentrations of Fe +. However, the enzyme is readily inactivated by Fe " and oxygen. Any regulatory significance is uncertain. 

REGULATION OF GENE TRANSCRIPTION A major action of insulin is the regulation of transcription of more than 100 specific genes. InsuMn inhibits the transcription of phosphoenolpyruvate carboxykinase, contributing to insulin s inhibition of gluconeogenesis this effect of insulin may explain why the liver overproduces glucose in the insuhn-resistant state that is characteristic of type 2 DM. 

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