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The basic strategy of metabolism is simple: form ATP, reducing power, and building blocks for biosyntheses. This complex network of reactions is controlled by allosteric interactions and reversible covalent modifications of enzymes and changes in their amounts, by compartmentation, and by interactions between metabolically distinct organs. The enzyme catalyzing the committed step in a pathway is usually the most important control site. Opposing pathways such as gluconeogenesis and glycolysis are reciprocally regulated so that one pathway is usually quiescent when the other is highly active.
The metabolic patterns of the brain, muscle, adipose tissue, kidney, and liver are very different. Glucose is essentially the sole fuel for the brain in a well-fed person. During starvation, ketone bodies (acetoacetate and 3-hydroxybutyrate) become the predominant fuel of the brain. Adipose tissue is specialized for the synthesis, storage, and mobilization of triacylglycerols. The kidney produces urine and reabsorbs glucose. The diverse metabolic activities of the liver support the other organs. The liver can rapidly mobilize glycogen and carry out gluconeogenesis to meet the glucose needs of other organs. It plays a central role in the regulation of lipid metabolism. When fuels are abundant, fatty acids are synthesized, esterified, and sent from the liver to adipose tissue. In the fasting state, however, fatty acids are converted into ketone bodies by the liver.
Insulin signals the fed state: it stimulates the formation of glycogen and triacylglycerols and the synthesis of proteins. In contrast, glucagon signals a low blood-glucose level: it stimulates glycogen breakdown and gluconeogenesis by the liver and triacylglycerol hydrolysis by adipose tissue. After a meal, the rise in the blood-glucose level leads to increased secretion of insulin and decreased secretion of glucagon. Consequently, glycogen is synthesized in muscle and the liver. When the blood-glucose level drops several hours later, glucose is then formed by the degradation of glycogen and by the gluconeogenic pathway, and fatty acids are released by the hydrolysis of triacylglycerols. The liver and muscle then use fatty acids instead of glucose to meet their own energy needs so that glucose is conserved for use by the brain.
The metabolic adaptations in starvation serve to minimize protein degradation. Large amounts of ketone bodies are formed by the liver from fatty acids and released into the blood within a few days after the onset of starvation. After several weeks of starvation, ketone bodies become the major fuel of the brain. The diminished need for glucose decreases the rate of muscle breakdown, and so the likelihood of survival is enhanced.
Diabetes mellitus, the most common serious metabolic disease, is due to metabolic derangements resulting in an insufficiency of insulin and an excess of glucagon relative to the needs of the individual. The result is an elevated blood-glucose level, the mobilization of triacylglycerols, and excessive ketone-body formation. Accelerated ketone-body formation can lead to acidosis, coma, and death in untreated insulin-dependent diabetics.
Sprinting and marathon running are powered by different fuels to maximize power output. The 100-meter sprint is powered by stored ATP, creatine phosphate, and anaerobic glycolysis. In contrast, the oxidation of both muscle glycogen and fatty acids derived from adipose tissue is essential in the running of a marathon, a highly aerobic process.
The oxidation of ethanol results in an unregulated overproduction of NADH, which has several consequences. A rise in the blood levels of lactic acid and ketone bodies causes a fall in blood pH, or acidosis. The liver is damaged because the excess NADH causes excessive fat formation as well as the generation of acetaldehyde, a reactive molecule. Severe liver damage can result.
allosteric interaction
covalent modification
glycolysis
phosphofructokinase
citric acid cycle
oxidative phosphorylation
pentose phosphate pathway
gluconeogenesis
glycogen synthesis
glycogen degradation
glucose 6-phosphate
pyruvate
acetyl CoA
ketone body
starved-fed cycle
glucose homeostasis
insulin
glucagon
caloric homeostasis
leptin
creatine phosphate