KETOGENESIS: BODY TYPES, SYNTHESIS AND DEGRADATION - BIOLOGY - 2024

The ketogenesis is the process by which the acetoacetate, β-hydroxybutyrate and acetone is obtained, which together are called ketone bodies. This complex and finely regulated mechanism takes place in the mitochondria, from the catabolism of fatty acids.

Obtaining ketone bodies takes place when the body is subjected to exhaustive periods of fasting. Although these metabolites are mostly synthesized in liver cells, they are found as an important source of energy in various tissues, such as skeletal muscle and in cardiac and brain tissues.

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Β-Hydroxybutyrate and acetoacetate are metabolites used as substrates in the heart muscle and the cortex of the kidney. In the brain, ketone bodies become important sources of energy when the body has depleted its glucose store.

General characteristics

Ketogenesis is considered a very important physiological function or metabolic pathway. Generally, this mechanism takes place in the liver, although it has been shown that it can be carried out in other tissues capable of metabolizing fatty acids.

The formation of ketone bodies is the main metabolic derivation of acetyl-CoA. This metabolite is obtained from the metabolic pathway known as β-oxidation, which is the degradation of fatty acids.

The availability of glucose in the tissues where β-oxidation occurs determines the metabolic fate of acetyl-CoA. In particular situations, the oxidized fatty acids are directed almost entirely to the synthesis of ketone bodies.

Types and properties of ketone bodies

The main ketone body is acetoacetate or acetoacetic acid, which is mostly synthesized in liver cells. The other molecules that make up ketone bodies are derived from acetoacetate.

The reduction of acetoacetic acid gives rise to D-β-hydroxybutyrate, the second ketone body. Acetone is a compound that is difficult to degrade and is produced by a spontaneous decarboxylation reaction of acetoacetate (so it does not require the intervention of any enzyme), when it is present in high concentrations in the blood.

The designation of ketone bodies has been provided by convention, since strictly speaking β-hydroxybutyrate does not have a ketone function. These three molecules are soluble in water, which facilitates their transport in the blood. Its main function is to provide energy to certain tissues such as skeletal and cardiac muscle.

The enzymes involved in the formation of ketone bodies are mainly in liver and kidney cells, which explains why these two locations are the main producers of these metabolites. Its synthesis occurs solely and exclusively in the mitochondrial matrix of cells.

Once these molecules are synthesized, they pass into the bloodstream, going to the tissues that require them, where they are degraded to acetyl-CoA.

Synthesis of ketone bodies

Conditions for ketogenesis

The metabolic fate of acetyl-CoA from β-oxidation depends on the metabolic requirements of the body. This is oxidized to CO ₂ and H ₂ O via the citric acid cycle or the synthesis of fatty acids, if the metabolism of lipids and carbohydrates is stable in the body.

When the body needs the formation of carbohydrates, oxaloacetate is used for the manufacture of glucose (gluconeogenesis) instead of starting the citric acid cycle. This occurs, as mentioned, when the body has some inability to obtain glucose, in cases such as prolonged fasting or the presence of diabetes.

Due to this, the acetyl-CoA resulting from the oxidation of fatty acids is used for the production of ketone bodies.

Mechanism

The ketogenesis process begins from the products of β-oxidation: acetacetyl-CoA or acetyl-CoA. When the substrate is acetyl-CoA, the first step consists of the condensation of two molecules, a reaction catalyzed by acetyl-CoA transferase, to produce acetacetyl-CoA.

Acetacetyl-CoA is condensed with a third acetyl-CoA through the action of HMG-CoA synthase, to produce HMG-CoA (β-hydroxy-β-methylglutaryl-CoA). HMG-CoA is degraded to acetoacetate and acetyl-CoA by the action of HMG-CoA lyase. In this way the first ketone body is obtained.

Acetoacetate is reduced to β-hydroxybutyrate by the intervention of β-hydroxybutyrate dehydrogenase. This reaction is dependent on NADH.

The major acetoacetate ketone body is a β-keto acid, which undergoes non-enzymatic decarboxylation. This process is simple and produces acetone and CO _2.

This series of reactions thus gives rise to ketone bodies. These, being soluble in water, can be easily transported through the bloodstream, without the need to anchor themselves to an albumin structure, as is the case of fatty acids that are insoluble in aqueous medium.

Β-oxidation and ketogenesis are related

Fatty acid metabolism produces the substrates for ketogenesis, so these two pathways are functionally related.

Acetoacetyl-CoA is an inhibitor of fatty acid metabolism, since it stops the activity of acyl-CoA dehydrogenase, which is the first enzyme of β-oxidation. Furthermore, it also exerts inhibition on acetyl-CoA transferase and HMG-CoA synthase.

The enzyme HMG-CoA synthase, subordinated by CPT-I (an enzyme involved in the production of acyl carnitine in β-oxidation), plays an important regulatory role in the formation of fatty acids.

Regulation of β-oxidation and its effect on ketogenesis

The feeding of organisms regulates a complex set of hormonal signals. The carbohydrates, amino acids and lipids consumed in the diet are deposited in the form of triacylglycerols in adipose tissue. Insulin, an anabolic hormone, is involved in the synthesis of lipids and the formation of triacylglycerols.

At the mitochondrial level, β-oxidation is controlled by the entry and participation of some substrates in the mitochondria. The CPT I enzyme synthesizes Acyl Carnitine from cytosolic Acyl CoA.

When the body is fed, Acetyl-CoA carboxylase is activated and citrate increases CPT I levels, while its phosphorylation (reaction dependent on cyclic AMP) decreases.

This causes an accumulation of malonyl CoA, which stimulates the synthesis of fatty acids and blocks their oxidation, preventing a futile cycle from being generated.

In the case of fasting, the activity of the carboxylase is very low since the levels of the CPT I enzyme have been reduced and it has also been phosphorylated, activating and promoting the oxidation of lipids, which will subsequently allow the formation of ketone bodies through acetyl-CoA.

Degradation

Ketone bodies diffuse out of the cells where they were synthesized and are transported to peripheral tissues by the bloodstream. In these tissues they can be oxidized through the tricarboxylic acid cycle.

In peripheral tissues, β-hydroxybutyrate is oxidized to acetoacetate. Subsequently, the acetoacetate present is activated by the action of the enzyme 3-ketoacyl-CoA transferase.

Succinyl-CoA acts as a CoA donor by converting itself to succinate. Activation of acetoacetate occurs to prevent succinyl-CoA from being converted to succinate in the citric acid cycle, with coupled synthesis of GTP by the action of succinyl-CoA synthase.

The resulting acetoacetyl-CoA undergoes a thiolytic breakdown, producing two acetyl-CoA molecules that are incorporated into the tricarboxylic acid cycle, better known as the Krebs cycle.

Liver cells lack 3-ketoacyl-CoA transferase, preventing this metabolite from being activated in these cells. In this way it is guaranteed that the ketone bodies do not oxidize in the cells where they were produced, but that they can be transferred to the tissues where their activity is required.

Medical relevance of ketone bodies

In the human body, high concentrations of ketone bodies in the blood can cause special conditions called acidosis and ketonemia.

The manufacture of these metabolites corresponds to the catabolism of fatty acids and carbohydrates. One of the most common causes of a pathological ketogenic condition is the high concentration of acetic dicarbonate fragments that are not degraded by the tricarboxylic acid oxidation pathway.

As a consequence, there is an increase in the levels of ketone bodies in the blood above 2 to 4 mg / 100 N and their presence in the urine. This results in the disturbance of the intermediate metabolism of these metabolites.

Certain defects in the pituitary neuroglandular factors that regulate the degradation and synthesis of ketone bodies, together with disorders in the metabolism of hydrocarbons, are responsible for the condition of hyperketonemia.

Diabetes mellitus and accumulation of ketone bodies

Diabetes mellitus (type 1) is an endocrine disease that causes increased production of ketone bodies. Inadequate insulin production disables the transport of glucose to muscles, liver and adipose tissue, thus accumulating in the blood.

Cells in the absence of glucose begin the process of gluconeogenesis and the breakdown of fat and protein to restore their metabolism. As a consequence, oxaloacetate concentrations decrease and lipid oxidation increases.

An accumulation of acetyl-CoA then occurs, which in the absence of oxaloacetate cannot follow the citric acid pathway, thus causing the high production of ketone bodies, characteristic of this disease.

The accumulation of acetone is detected by its presence in the urine and breath of people who have this condition, and is in fact one of the symptoms that indicate the manifestation of this disease.

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