Fuel metabolism

Caprio S et al Oxidative fuel metabolism during mild hypoglycemia critical role of free fatty acids. Am J Physiol... 

The classical endocrine system is composed of a series of glands that secrete hormones directly into the blood where they are carried to act on cells in the body often quite distant from the place of secretion. Insulin, for example, secreted from (3 pancreatic islet cells has actions on fuel metabolism in most tissues of the body. Compare this with a radio or television broadcast originating in one place but arriving at multiple sites. 

Where two enzymes compete for the same substrate, we expect to see some form of metabolic control and in this case the concentrations of NADH and acetyl-CoA are the key controlling factors (Figure 6.44). When glucose is not available as a fuel, metabolism switches to 3- oxidation of fatty acids, which generates more than sufficient quantities of both NADH and acetyl-CoA to drive the TCA cycle and to maintain oxidative phosphorylation. Pyruvate dehydrogenase activity is suppressed and pyruvate carboxylase is stimulated by ATP, NADH and acetyl-CoA (strictly speaking by low mitochondrial ratios of ADP/ATP, NAD+/NADH and coenzyme A/acetyl-CoA), so... 

In addition to its effects on the activity of existing enzymes, insulin also regulates the expression of as many as 150 genes, including some related to fuel metabolism... 

As complex as the regulation of carbohydrate metabolism is, it is far from the whole story of fuel metabolism. The metabolism of fats and fatty acids is very closely tied to that of carbohydrates. Hormonal signals such as insulin and changes in diet or exercise are equally important in regulating fat metabolism and integrating it with that of carbohydrates. We shall return to this overall metabolic integration in mammals in Chapter 23,... 

FIGURE 23-28 Fuel metabolism in the liver during prolonged fasting or in uncontrolled diabetes mellitus. After depletion of stored carbohydrates, to proteins become an important source of glucose, produced from glucogenic amino acids by gluconeogenesis. ... 

Figure 7-1. Pathways of fuel metabolism and oxidative phosphorylation. Pyruvate may be reduced to lactate in the cytoplasm or may be transported into the mitochondria for anabolic reactions, such as gluconeogenesis, or for oxidation to acetyl-CoA by the pyruvate dehydrogenase complex (PDC). Long-chain fatty acids are transported into mitochondria, where they undergo [ -oxidation to ketone bodies (liver) or to acetyl-CoA (liver and other tissues). Reducing equivalents (NADH, FADII2) are generated by reactions catalyzed by the PDC and the tricarboxylic acid (TCA) cycle and donate electrons (e ) that enter the respiratory chain at NADH ubiquinone oxidoreductase (Complex 0 or at succinate ubiquinone oxidoreductase (Complex ID- Cytochrome c oxidase (Complex IV) catalyzes the reduction of molecular oxygen to water, and ATP synthase (Complex V) generates ATP fromADP Reprinted with permission from Stacpoole et al. (1997).

The PDC is the subject of intense scrutiny because of its pivotal role in fuel metabolism and its association with numerous acquired and congenital disorders. Descriptions of proven or putative acquired deficiencies of the compfex may be found elsewhere this chapter focuses on the genetics, biochemistry, clinical presentation, and course of congenital defects in the PDC. Over 200 cases of PDC deficiency have been reported, and many other cases have been diagnosed but remain unpublished. The diagnosis in most patients has been based on demonstrating reduced total catalytic activity of the complex or in one of its component enzymes. 

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