Formation of ketone bodies from acetyl-CoA, metabolic causes and importance

Mitochondria of hepatocytes can convert acetyl-CoA resulting from MK oxidation into ketone bodies which include acetoacetic acide (acetoacetate), β-hydroxybutyrate and acetone.

Acetoacetic acid and beta-hydroxybutyric acid are transported in the blood to peripheral tissues where they are converted again to acetyl-CoA, which can subsequently be used the Krebs cycle.

Importance

Keto bodies are an important source of nrg for peripheral tissues because:

1. they are soluble in aqueous solutions and therefore do not need to be incorporated into lipoproteins or transported using albumin like other lipids
2. they are produced in hepatocytes during periods when the amount of acetyl-CoA exceeds the oxidative capacity of the hepatocyte
3. they are used proportionally by extrahepatic tissues (e.g. skeletal muscle, myocardium or renal cortex) in relation to their concentration in the blood.  The brain can also use ketone bodies to meet its energy needs when their concentration in the blood rises significantly. In this way, ketone bodies save glucose.  It is especially important during long-term starvation

Acetyl-CoA

Fatty acid oxidation disorders are generally manifested by hypoketosis (due to a reduced amount of acetyl-CoA) and hypoglycemia (due to an increased consumption of glucose to generate energy). During starvation, the liver is "flooded" by fatty acids (FA) mobilized from adipose tissue. Increased concentration of hepatic acetyl-CoA mainly from FA degradation inhibits pyruvate dehydrogenase and activates pyruvate carboxylase

The resulting oxaloacetate is used in hepatocytes for gluconeogenesis rather than for Krebs cycle and so acetyl-CoA is involved in the synthesis of ketone bodies (ketogenesis).

Oxidation of FA reduces the ratio of NAD+ and NADH and increases the conversion of oxaloacetate to malate by NADH. This shifts acetyl-CoA away from gluconeogenesis towards ketogenesis.

Synthesis

ketone bodies synthesis

Although the liver continuously synthesizes small amounts of ketone bodies, their production becomes much higher during starvation, when ketone bodies are used as a source of energy for peripheral tissues.

The first step in the synthesis of ketone bodies, the formation of acetoacetyl-CoA, which takes place as a reverse thiolase reaction of FA oxidation.

Mitochondrial HMG-CoA synthase combines the third molecule of acetyl-CoA with acetoacetyl-CoA to form 3-hydroxy-3-methylglutarylCoA (HMG-CoA). HMG-CoA is also a cholesterol precursor

HMG-CoA synthase is a key enzyme in the synthesis of ketone bodies and is found in sufficient quantities only in the liver.HMG-CoA is cleaved to form acetoacetate and acetylCoA.

• Acetoacetate can be reduced to form 3-hydroxybutyrate with NADH as the H donor, it can also spontaneously decarboxylate in the blood to form acetone - a volatile, biologically non-metabolizable substance that can be released in the breath
• The balance between acetoacetate and 3-hydroxybutyrate is conditioned by the NAD+/NADH ratio. Since this ratio is low during fatty acid oxidation, the synthesis of 3-hydroxybutyrate is preferred. The production of free CoA during ketogenesis allows fatty acid oxidation to continue.

3-hydroxybutyrate is oxidized to acetoacetate by 3-hydroxybutyrate dehydrogenase, producing NADH.

A molecule of CoA obtained from succinyl-CoA is then attached to acetoacetate using succinyl-CoA-acetoacetate-CoA transferase. This reaction is reversible, but its product, acetoacetyl-CoA, is actively removed by converting it to two molecules of acetyl-CoA.

Extrahepatic tissues, which include the brain, but do not include cells without mitochondria (e.g. erythrocytes), effectively oxidize acetoacetate and 3-hydroxybutyrate in this way. On the contrary, even if the liver actively produces ketone bodies, it lacks thiophorase and thus cannot use ketone bodies as fuel.

Complications

If the rate of ketosynthesis is higher than the rate of their consumption, their concentration in the blood (ketonemia) and possibly also in the urine (ketonuria) begins to rise. This condition is most often observed in uncontrolled type 1 diabetes mellitus

In diabetic individuals with severe ketosis, excretion of ketone bodies in the urine can reach a concentration of up to 5,000 mg/24 hours, and their concentration in the blood up to 90 mg/dl (physiological value is less than 3 mg/dl).

A frequent symptom of DM ketoacidosis is the smell of acetone in the breath from increased synthesis.

An increased concentration of ketone bodies in the blood causes acidemia.  The carboxyl group of ketone bodies has a pKa of around 4. Therefore, each ketone body loses a proton during its circulation in the blood, thereby lowering the body's pH.  Also, the excretion of glucose and ketone bodies in the urine causes dehydration of the body.  Therefore, an increased H+ concentration in a reduced plasma volume can cause severe acidosis (ketoacidosis).  Ketoacidosis can also be observed during starvation.

Sources

MATOUŠ, Bohuslav, et al. Základy lékařské chemie a biochemie. 1. vydání. Praha : Galén, 2010. 540 s.