Gluconeogenesis compartmentation

FIGURE 23.5 Pyruvate carboxyl compartmentalized reaction. Pyruva verted to oxaloacetate in the mitoci Because oxaloacetate cannot be trai across the mitochondrial membrant reduced to malate, transported to tl and then oxidized back to oxaloace gluconeogenesis can continue. 

This compartmentation of processes in the liver cells occurs with other pathways glycolysis occurs mainly in the perivenous cells whereas gluconeogenesis occurs mainly in the periportal cells (Chapter 6). 

Figure 16.28. Compartmental Cooperation. Oxaloacetate utilized in the cytosol for gluconeogenesis is formed in the mitochondrial matrix by carboxylation of pyruvate. Oxaloacetate leaves the mitochondrion by a specific transport system (not shovm) in the form of malate, -which is reoxidized to oxaloacetate in the cytosol.

A number of recent studies have focused on the compartmentation of key enzymes of gluconeogenesis and lipogenesis and on the differences which occur among mammalian species (for a general review of this work see Hanson, 1974). Some of the specific aspects of the consequences of compartmentation in various species will be discussed later in this chapter. At this point, it is important to draw several general principles which have emerged from studies with animals other than the rat. 

In the following sections we will deal with three specific metabolic processes—gluconeogenesis, fatty acid oxidation, and lipogenesis— which are regulated in part by the compartmentation of key enzyme systems. 

Unlike glycolysis, which occurs strictly in the cell cytosol, gluconeogen-esis involves a complex interaction between the mitochondrion and the cytosol. This interaction is necessitated by the irreversibility of the pyruvate kinase reaction, by the relative impermeability of the inner mitochondrial membrane to oxaloacetate, and by the specific mitochondrial location of pyruvate carboxylase. Compartmentation within the cell has led to the distribution of a number of enzymes (aspartate and alanine aminotransferases, and NAD -malate dehydrogenase) in both the mitochondria and the cytosol. In the classical situation represented by the rat, mouse, or hamster hepatocyte, the indirect "translocation" of oxaloacetate—the product of the pyruvate carboxylase reaction—into the cytosol is effected by the concerted action of these enzymes. Within the mitochondria oxaloacetate is converted either to malate or aspartate, or both. Following the exit of these metabolites from the mitochondria, oxaloacetate is regenerated by essentially similar reactions in the cytosol and is subsequently decarboxylated to P-enolpyruvate by P-enol-pyruvate carboxykinase. Thus the presence of a membrane barrier to oxaloacetate leads to the functioning of the malate-aspartate shuttle as an important element in gluconeogenesis. 

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