Ketogenesis Is Regulated At Three Crucial Steps

(1) Ketosis does not occur in vivo unless there is an increase in the level of circulating free fatty acids that arise from lipolysis of triacylglycerol in adipose tissue. Free fatty acids are the precursors of ketone bodies in the liver. The liver, both in fed and in fasting conditions, extracts about 30% of the free fatty acids passing through it, so that at high concentrations the flux passing into the liver is substantial. Therefore, the factors regulating mobilization of free fatty acids from adipose tissue are important in controlling ketogenesis (Figures 22-9 and 25-8).

(2) After uptake by the liver, free fatty acids are either P-oxidized to CO2 or ketone bodies or esterified to triacylglycerol and phospholipid. There is regulation of entry of fatty acids into the oxidative pathway by car-nitine palmitoyltransferase-I (CPT-I), and the remainder of the fatty acid uptake is esterified. CPT-I activity is

Ketogenesis Pathway
Figure 22-8. Transport of ketone bodies from the liver and pathways of utilization and oxidation in extrahe-patic tissues.

ADIPOSE TISSUE

Triacylglycerol

Lipolysis

BLOOD

LIVER

CPT-I gateway

Acyl-CoA

fi-Oxidation

Acylglycerols

Ketogenesis

Acetyl-CoA

Acylglycerols

Citric acid cycle

Ketone bodies

Figure 22-9. Regulation of ketogenesis. ©-©show three crucial steps in the pathway of metabolism of free fatty acids (FFA) that determine the magnitude of ketogenesis. (CPT-I, carnitine palmitoyltransferase-I.)

low in the fed state, leading to depression of fatty acid oxidation, and high in starvation, allowing fatty acid oxidation to increase. Malonyl-CoA, the initial intermediate in fatty acid biosynthesis (Figure 21-1), formed by acetyl-CoA carboxylase in the fed state, is a potent inhibitor of CPT-I (Figure 22-10). Under these conditions, free fatty acids enter the liver cell in low concentrations and are nearly all esterified to acylglycerols and transported out of the liver in very low density lipopro-teins (VLDL). However, as the concentration of free fatty acids increases with the onset of starvation, acetyl-CoA carboxylase is inhibited directly by acyl-CoA, and [malonyl-CoA] decreases, releasing the inhibition of CPT-I and allowing more acyl-CoA to be fi-oxidized. These events are reinforced in starvation by decrease in the [insulin]/[glucagon] ratio. Thus, fi-oxidation from free fatty acids is controlled by the CPT-I gateway into the mitochondria, and the balance of the free fatty acid uptake not oxidized is esterified.

(3) In turn, the acetyl-CoA formed in P-oxidation is oxidized in the citric acid cycle, or it enters the pathway of ketogenesis to form ketone bodies. As the level of serum free fatty acids is raised, proportionately more free fatty acid is converted to ketone bodies and less is oxidized via the citric acid cycle to CO2. The partition of acetyl-CoA between the ketogenic pathway and the pathway of oxidation to CO2 is so regulated that the total free energy captured in ATP which results from the oxidation of free fatty acids remains constant. This may be appreciated when it is realized that complete oxidation of 1 mol of palmitate involves a net production of 129 mol of ATP via P-oxidation and CO2 production in the citric acid cycle (see above), whereas only 33 mol of ATP are produced when acetoacetate is the end product and only 21 mol when 3-hydroxybutyrate is the end product. Thus, ketogenesis may be regarded as a mechanism that allows the liver to oxidize increasing quantities of fatty acids within the constraints of a tightly coupled system of oxidative phosphorylation— without increasing its total energy expenditure.

Theoretically, a fall in concentration of oxaloacetate, particularly within the mitochondria, could impair the ability of the citric acid cycle to metabolize acetyl-CoA and divert fatty acid oxidation toward ketogenesis. Such a fall may occur because of an increase in the [NADH]/[NAD+] ratio caused by increased P-oxida-tion affecting the equilibrium between oxaloacetate and malate and decreasing the concentration of oxaloac-etate. However, pyruvate carboxylase, which catalyzes the conversion of pyruvate to oxaloacetate, is activated by acetyl-CoA. Consequently, when there are significant amounts of acetyl-CoA, there should be sufficient oxaloacetate to initiate the condensing reaction of the citric acid cycle.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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