Ketone bodies starvation state

Increased fatty acid oxidation is a characteristic of starvation and of diabetes meUims, leading to ketone body production by the Ever (ketosis). Ketone bodies are acidic and when produced in excess over long periods, as in diabetes, cause ketoacidosis, which is ultimately fatal. Because gluconeogenesis is dependent upon fatty acid oxidation, any impairment in fatty acid oxidation leads to hypoglycemia. This occurs in various states of carnitine deficiency or deficiency of essential enzymes in fatty acid oxidation, eg, carnitine palmitoyltransferase, or inhibition of fatty acid oxidation by poisons, eg, hypoglycin. 

Many tissues (muscle, liver, renal cortex) prefer fat for an energy supply, at least in the resting state. The exception is red blood cells and brain. These tissues depend heavily on glycolysis for energy. Red cells cannot survive without glucose (no mitochondria), but during prolonged starvation, brain can adapt to utilize fat metabolites produced by the liver (ketone bodies). 

In the fed state, the only fuel used by the brain is glucose, derived from the blood. In prolonged starvation or chronic hypoglycaemia, ketone bodies are nsed which rednce the rate of utilisation of glucose by the brain bnt, even so, glucose still provides about 50% of the energy. Consequently, under all conditions, maintenance of the blood glucose concentration is essential for the function of the brain the mechanisms that are responsible for this are discnssed in Chapters 6, 12 and 16. 

Most often the metabolic state of an organism is reflected by the small molecules present in plasma. Figure 24.4 illustrates the plasma levels of glucose, ketone bodies, and fatty acids as a function of the number of days of starvation. As you can see, the glucose level drops about 30% as the period of starvation becomes prolonged the fatty acid level rises about twofold, while the level of ketone bodies rises severalfold. 

The first stage in the synthesis of cholesterol is the formation of isopentenyl pyrophosphate Fig. 1). Acetyl CoA and acetoacetyl CoA combine to form 3-hydroxy-3-methylglutaryl CoA (HMG CoA). This process takes place in the liver, where the HMG CoA in the mitochondria is used to form ketone bodies during starvation (see Topic K2), whereas that in the cytosol is used to synthesize cholesterol in the fed state (under the influence of cholesterol). HMG CoA is then reduced to mevalonate by HMG CoA reductase Fig. 1). This is the committed step in cholesterol biosynthesis and is a key control point. Mevalonate is converted into 3-isopentenyl pyrophosphate by three consecutive reactions each involving ATP, with C02 being released in the last reaction Fig. 1). 

In starvation, glucose making, stimulating PEP CK Uses oxaloacetic, also lost another way Ketone bodies, what is odd is that the oxidation state Also favours the reduction of OA to give malate. 

The pathogenesis of ketoacidosis is discussed in detail in Chapter 25. Ketoacids such as P-hydroxybutyrate and 2-oxoglutarate accumulate and represent the unmeasured anions. Accumulation of these ketone bodies causes a decrease in HCOJ, a normal or low serum chloride, and a liigh anion gap. Ketoacids also accumulate in states of starvation and alcoholic malnutrition. 

Fig. 13-18 Major metabolic interorgan fuel flow during established steady-state starvation. Amino acids are indicated by aa, fatty acids by FA, and ketone bodies by KB.

It would be incorrect to assume that the changes described above follow a reproducible chronological pattern. While the production of ketone bodies is associated with starvation, it is possible that ketone body formation occurs much earlier. Similarly, processes such as gluconeogenesis occur even in the fed state, but the net contribution of these pathways becomes more important as starvation progresses. 

Ketones commonly are elevated in the blood in states of starvation, as the body calls upon its fatty acids (stored as triglycerides) to break down and provide fuel. Ketones may also be elevated in diabetes mellicus, where glucose does not enter the cell and carmot be efficiently utilized. Triglycerides then break down to provide the fetty acids and acetyl CoA useful as fuel, sometimes with formation of ketones as well. In severe diabetic ketosis, one may actually detect the smell of acetone coming from the patient. 

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