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above and is condensed into ketones.

The liver has the capacity to produce from 115 to 180 grams of ketones per day once
ketogenesis has been initiated (4,15-17). Additionally, the liver is producing ketones at a maximal
rate by the third day of carbohydrate restriction (16). It appears that once the liver has become
ketogenic, the rate of ketone body formation is determined solely by the rate of incoming FFA
(12). This will have implications for the effects of exercise on levels of ketosis (see chapter 21 for
more details). Figure 1 graphically illustrates the 2 site model of ketogenesis.

Figure 1: The two site model of ketogenesis

Liver Blood Fat cell

FFA

FFA Triglyceride

Ketones

Insulin

Glucagon

Summary

The production of ketone bodies in the liver requires a depletion of liver glycogen and a
subsequent fall in malonyl-CoA concentrations allowing the enzyme carnitine palmityl tranferase
I (CPT-1) to become active. CPT-1 is responsible for carrying free fatty acids into the
mitochondria to be burned. At the same time CPT-1 is becoming active, a drop in blood glucose
causes a decrease in the insulin/glucagon ratio allowing free fatty acids to be mobilized from fat
cells to provide the liver with substrate for ketone body formation.

Technical note: Malonyl-CoA and Carnitine Palmityl Transferase-1 (CPT-1)

Rather than liver glycogen per se, the primary regulator of ketogenesis in the liver is a

substance called malonyl-CoA (8,13). Malonyl-CoA is an intermediate in fat synthesis which

is present in high amounts when liver glycogen is high. When the liver is full of glycogen, fat

synthesis (lipogenesis) is high and fat breakdown (lipolysis) is low (8).

Malonyl-CoA levels ultimately determine whether the liver begins producing ketone

bodies or not. This occurs because malonyl-CoA inhibits the action of an enzyme called

carnitine palmityl tranferase 1 (CPT-1) both in the liver and other tissues such as muscle

(8,13).

CPT-1 is responsible for transporting FFA into the mitochondria to be burned. As FFA

are burned, a substance called acetyl-CoA is produced. When carbohydrate is available,

acetyl-CoA is used to produce more energy in the Krebs cycle. When carbohydrate is not

available, acetyl-CoA cannot enter the Krebs cycle and will accumulate in the liver (figure 2).

As Malonyl-CoA levels drop and CPT-1 becomes active, FFA oxidation occurs rapidly

causing an increase in the level of acetyl-CoA. As discussed in the next section, when acetyl-