The formation of ketone bodies, called ketogenesis, is at the heart of the ketogenic diet and the processes involved need to be understood. The primary regulators of ketone body formation are the hormones insulin and glucagon. The shift that occurs in these two hormones, a decrease in insulin and an increase in glucagon is one of the major regulating steps regulating ketogenesis.
A great amount of research has been performed to determine exactly what is involved in ketogenesis. All the research has led to a model involving two sites: the fat cell and the liver. In addition, the enzyme mitochondrial HMG CoA reductase (MHS) has been suggested as a third site of regulation. For our purposes, MHS and its effects are unimportant so we will focus only on the first two sites of regulation: the fat cell and the liver.
The fat cell
The breakdown of fat in fat cells, is determined primarily by the hormones insulin and the catecholamines. When insulin is high, free fatty acid mobilization is inhibited and fat storage is stimulated through the enzyme lipoprotein lipase (LPL). When insulin decreases, free fatty acids (FFA) are mobilized both due to the absence of insulin as well as the presence of lipolytic (fat mobilizing) hormones such as the catecholamines. Glucagon, cortisol and growth hormone play additional but minor roles.
Insulin has a much stronger anti-lipolytic effect than the catecholamines have a lipolytic effect. If insulin is high, even though catecholamines are high as well, lipolysis is blocked. It is generally rare to have high levels of both insulin and catecholamines in the body. This is because the stimuli to raise catecholamine levels, such as exercise, tend to lower insulin and vice versa.
Breakdown and transport of Triglyceride.
When the proper signal reaches the fat cell, stored triglyceride (TG) is broken down into glycerol and three free fatty acid (FFA) chains. FFA travels through the bloodstream, bound to a protein called albumin. Once in the bloodstream, FFA can be used for energy production by most tissues of the body, with the exception of the brain and a few others.
FFA’s not used for energy by other tissues will reach the liver and be oxidized (burned) there. If there is sufficient FFA and the liver is prepared to produce ketone bodies, ketones are produced and released into the bloodstream.
The fat cell should be considered one regulatory site for ketone body formation in that a lack of adequate FFA will prevent ketones from being made in the liver. That is, even if the liver is in a mode to synthesize ketone bodies, a lack of FFA will prevent the development of ketosis.
The liver is always producing ketones to some small degree and they are always present in the bloodstream. Under normal dietary conditions, ketone concentrations are simply too low to be of any physiological consequence. A ketogenic diet increases the amount of ketones which are produced and the blood concentrations seen. Thus ketones should not be considered a toxic substance or a byproduct of abnormal human metabolism. Rather, ketones are a normal physiological substance that plays many important roles in the human body.
The liver is the second site involved in ketogenesis and arguably the more important of the two. Even in the presence of high FFA levels, if the liver is not in a ketogenic mode, ketones will not be produced.
The major determinant of whether the liver will produce ketone bodies is the amount of liver glycogen present. The primary role of liver glycogen is to maintain normal blood glucose levels. When dietary carbohydrates are removed from the diet and blood glucose falls, glucagon signals the liver to break down its glycogen stores to glucose which is released into the bloodstream. After approximately 12-16 hours, depending on activity, liver glycogen is almost completely depleted. At this time, ketogenesis increases rapidly. In fact, after liver glycogen is depleted, the availability of FFA will determine the rate of ketone production. The
With the two regulating sites of ketogenesis discussed, we can return to the discussion of insulin and glucagon and their role in establishing ketosis. When carbohydrates are consumed, insulin levels are high and glucagon levels are low. Glycogen storage is stimulated and fat synthesis in the liver will occur. Fat breakdown is inhibited both in the fat cell as well as in the liver.
When carbohydrates are removed from the diet, liver glycogen will eventually be emptied as the body tries to maintain blood glucose levels. Blood glucose will drop as liver glycogen is depleted. As blood glucose decreases, insulin will decrease and glucagon will increase. Thus there is an overall decrease in the insulin/glucagon ratio (I/G ratio).
As insulin drops, FFA are mobilized from the fat cell, providing adequate substrate for the liver to make ketones. Since liver glycogen is depleted, CPT-1 becomes active, burning the incoming FFA, which produces acetyl-CoA. Acetyl-CoA accumulates as discussed in the section 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. Additionally, the liver is producing ketones at a maximal rate by the third day of carbohydrate restriction. It appears that once the liver has become ketogenic, the rate of ketone body formation is determined solely by the rate of incoming FFA. This will have implications for the effects of exercise on levels of ketosis.
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.
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.
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.
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-31
CoA levels increase to high levels, they are condensed into acetoacetic acid which can further be converted to beta-hydroxybutyrate and acetone, the three major ketone bodies.
Lyle McDonald, The Ketogenic Diet: A Complete Diet for the Dieter and the Practitioner, published in 1998 by Lyle McDonald