Gluconeogenesis Hepatocytes

Pittner, R.A., Fears, R. and Brindley, D.N. (1985). Effects of glucocorticoids and insulin on activities of phosphatidate phosphohydrolase, tyrosine aminotransferase and glycerol kinase in isolated rat hepatocytes in relation to the control of triacyglycerol synthesis and gluconeogenesis. Biochem. J. 225 455—462. 

T. Kashiwagura, C.J. Deutsch, J. Taylor, M. Erecinska, D.F. Wilson, Dependence of gluconeogenesis, urea synthesis, and energy metabolism of hepatocytes on intracellular pH, J. Biol. Chem. 259 (1984) 237-243. 

Depletion of ATP is caused by many toxic compounds, and this will result in a variety of biochemical changes. Although there are many ways for toxic compounds to cause a depletion of ATP in the cell, interference with mitochondrial oxidative phosphorylation is perhaps the most common. Thus, compounds, such as 2,4-dinitrophenol, which uncouple the production of ATP from the electron transport chain, will cause such an effect, but will also cause inhibition of electron transport or depletion of NADH. Excessive use of ATP or sequestration are other mechanisms, the latter being more fully described in relation to ethionine toxicity in chapter 7. Also, DNA damage, which causes the activation of poly(ADP-ribose) polymerase (PARP), may lead to ATP depletion (see below). A lack of ATP in the cell means that active transport into, out of, and within the cell is compromised or halted, with the result that the concentration of ions such as Na+, K+, and Ca2+ in particular compartments will change. Also, various synthetic biochemical processes such as protein synthesis, gluconeogenesis, and lipid synthesis will tend to be decreased. At the tissue level, this may mean that hepatocytes do not produce bile efficiently and proximal tubules do not actively reabsorb essential amino acids and glucose. 

This Mg2+-activated enzyme is found on the lumenal side of the endoplasmic reticulum of hepatocytes and renal cells (see Fig. 15-6). Muscle and brain tissue do not contain this enzyme and so cannot carry out gluconeogenesis. Glucose produced by gluconeogenesis in the liver or kidney or ingested in the diet is delivered to brain and muscle through the bloodstream. 

To meet these changing circumstances, the liver has remarkable metabolic flexibility. For example, when the diet is rich in protein, hepatocytes supply themselves with high levels of enzymes for amino acid catabolism and gluconeogenesis. Within hours after a shift to a high-carbohydrate diet, the levels of these enzymes begin to drop and the hepatocytes increase their synthesis of enzymes essential to carbohydrate metabolism and fat synthesis. Liver enzymes turn over (are synthesized and degraded) at live to ten times the rate of enzyme turnover in other tissues, such as muscle. Extrahepatic... 

Answer In the liver, lactate is converted to pyruvate and then to glucose by gluconeogenesis (see Figs 14-15, 14-16). This pathway includes the glycolytic bypass step catalyzed by fructose 1,6-bisphosphatase (FBPase-1). A defect in this enzyme would prevent the entry of lactate into the gluconeogenic pathway in hepatocytes, causing lactate to accumulate in the blood. 

The distribution of metabolic functions within acinar zones is determined principally by the microenvironment of the hepatocytes. Cells in zone 1 are the first to respond to changes in the portal blood, such as glucose and insulin levels, and therefore play important roles in glycolysis and gluconeogenesis. Protein synthesis, P-oxidation of fatty acids, cholesterol synthesis and bile acid secretion also predominate in zone 1. Ordinarily zone 3 hepatocytes are the principal site of cytochrome P450 oxidation/reduction activity as well as NADPH and NADH reductase metabolism, making this region more susceptible... 

MTP-1403 (91) and MTP-1307 (92) are able to improve glucose tolerance in normal rats and in insulin-resistant mice and lower fasting plasma glucose in rats but not in insulin-deficient diabetic animals. In rats, the hypogly-caemic effect is accompanied by an increase in insulin levels, more pronounced with MTP-1307 than with MTP-1403. The mechanism of action is unknown. In vitro MTP-1307 inhibits gluconeogenesis in hepatocytes and glucose oxidation in adipose tissue, at 0.1 to 3 mM [397]. 

Monge, L., Ortega, J. L., Cabello, M. A. and Felin, J. E. (1985). Additive effect of chlorpropamide and insulin on gluconeogenesis and on fructose 2,6-biphosphate levels in isolated rat hepatocytes. Abstract International Diabetes Federation, Spain. 

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