Physiological Ketosis

Physiological hyperketonemia is found in the suckling neonate (high-fat diet of the milk; Figure 1), postexercise (depletion of hepatic glycogen reserves), and after prolonged fasting (more than 24 h; Figure 7). All these situations have in common a low hepatic carbohydrate status (depletion of glycogen and/or activation of gluconeogenesis) and therefore from a physiological standpoint one would expect an increased rate of ketogenesis. Comparison of the factors which can influence ketogenesis in suckling and fasting (Table 2) shows the expected broad agreement.

Table 1 Range of blood ketone body concentrations in humans

Situation

Ketone body concentration (mmol l-1)

Fed normal diet

about 0.1

Fed high-fat diet

up to 3

Fasted: 12-24 h

up to 0.3

Fasted: 48-72 h

2.0-3.0

Postexercise

up to 2

Late pregnancy

up to 1

Late pregnancy: fasted 48 h

4.0-6.0

Neonate: 0-1 days

0.2-0.5

Neonate: 5-10 days

0.7-1.0

Hypoglycemia

1.0-5.0

Untreated diabetes mellitus

Adipose tissue

Brain

Adipose tissue

Nonesterified fatty acids

Figure 7 Intertissue fluxes of substrates in the starved state. Thickness of line denotes rate of flux.

Nonesterified fatty acids

Figure 7 Intertissue fluxes of substrates in the starved state. Thickness of line denotes rate of flux.

More detailed information on the hierarchy of the regulatory factors during onset and reversal of keto-genesis has been obtained for the fasting state by measurements at short time intervals. The first event after withdrawal of food is a lowering of plasma insulin accompanied by an increase in plasma fatty acids (stimulation of lipolysis). However, for an appreciable period (8-10 h) there is no increase in blood ketone bodies or in the in vitro rates of hepatic ketogenesis (measured with saturating fatty acid concentrations). The major increment in ketogenic rate occurs at the nadir of the hepatic malonyl-CoA concentrations and when the sensitivity of CAT I to malonyl-CoA is starting to increase rapidly. This long time lag before a change in sensitivity of the protein to malonyl-CoA inhibition is thought to be due to the time required to bring about alterations to the lipid environment of the outer mitochondrial membrane.

Confirmation of this view is that on refeeding, when insulin rapidly increases and plasma fatty acids decrease with a parallel decrease in blood ketone bodies, there is again a time lag before malonyl-CoA concentrations rise and a longer one before sensitivity returns. In physiological and

Table 2 Comparison of factors influencing ketogenesis in suckling and fasted states

Factor

Suckling

Fasted

Plasma nonesterified fatty acids

Increased

Increased

Plasma insulin

Decreased

Decreased

Plasma glucagon

Increased

Increased

Hepatic carnitine

Increased

Increased

Hepatic lipogenesis

Decreased

Decreased

Hepatic malonyl-CoA

Decreased

Decreased

Hepatic CAT I activity

Increased

Increased

Sensitivity to malonyl-CoA

Decreased

Decreased

nutritional terms this delay of return to the normal fed settings of intrahepatic regulation makes excellent sense. It is only when the refeeding consists primarily of large amounts of carbohydrate that the starved liver needs to inhibit the activity of CAT I to prevent the oxidation of newly synthesized fatty acids. If the meal consists mainly of lipid with little carbohydrate the activity of CAT I needs to remain high to allow oxidation of the excess fatty acids. Thus the liver must sense a prolonged increase in plasma insulin before the high activity of CAT I is suppressed.

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