Ketogenesis

• Ketogenesis is the process where excess acetyl CoA is converted into ketone bodies.
• The process occurs in the liver.

Biological Importance

• The primary purpose of ketone body formation in the liver involves distributing excess fuel (acetyl-CoA) to other tissues.
• Even-numbered fatty acids are more ketogenic than odd-numbered fatty acids.
• Ketone bodies do not need to bind lipoproteins or albumin for transport, as they are polar molecules.
• Most tissues utilize ketone bodies, with the exception of the liver.

Triggers

• During fasting, the liver receives a flood of fatty acids mobilized from adipose tissue.
• Elevated hepatic acetyl CoA inhibits pyruvate dehydrogenase, while it activates pyruvate carboxylase to form OAA.
• OAA is used by the liver for gluconeogenesis, instead of the TCA cycle.
• Most of the acetyl CoA is directed towards ketone body synthesis.
• Fatty acid oxidation reduces the NAD+ to NADH ratio, which then causes a shift of OAA to malate.

Ketogenesis Defined

• High rates of fatty acid oxidation produce considerable quantities of acetoacetate and 3-hydroxybutyrate (β-hydroxybutyrate).
• Acetoacetate undergoes spontaneous decarboxylation which yields acetone.
• The ketone bodies include acetoacetate, acetone, and 3-hydroxybutyrate.
• Acetoacetate and 3-hydroxybutyrate can be interconverted by 3-hydroxybutyrate dehydrogenase.

Ketogenesis Process

• Two acetyl CoA molecules condense to form acetoacetyl-CoA through reversal of thiolase reaction.
• Acetoacetyl-CoA is the starting point for ketogenesis.
• Acetoacetyl-CoA also comes from the terminal carbons of a fatty acid during B-oxidation.
• 3-hydroxy-3-methylglutaryl-CoA synthase causes condensation of acetoacetyl-CoA with another molecule of acetyl-CoA which forms HMG-CoA.
• Subsequently, 3-hydroxy-3-methylglutaryl-CoA lyase causes acetyl-CoA to split off from HMG-CoA, resulting in free acetoacetate.
• The liver is where those reactions occur.
• 3-hydroxybutyrate is the main ketone body.
• HMG CoA synthase is mainly found in the liver.

Regulation of Ketogenesis

• Ketogenesis occurs at three levels: control of FFA mobilization, activity of CPT-1, and partition of acetyl CoA
• Ketosis requires an increase in circulating free fatty acids from lipolysis of triacylglycerol in adipose tissue.
• Free fatty acids are ketone body precursors in the liver.
• The liver extracts about 30% of free fatty acids that pass through it.
• Factors that regulate free fatty acid mobilization from adipose tissue control ketogenesis.
• Liver carnitine-acyl transferase-I activity determines the rate of ketone body formation.
• In fed states, CAT activity is inhibited by malonyl-CoA, which results in less acetyl-CoA and decreased ketogenesis.
• In starvation, CAT-I activity is high because of low malonyl-CoA, causing more acetyl-CoA and increased ketogenesis.
• Acetyl-CoA from B-oxidation can be oxidized in the citric acid cycle or enter ketogenesis to form ketone bodies.
• ATP levels in the cell regulate ketogenesis.
• High ATP levels favor ketogenesis, while low ATP levels prevent ketogenesis.

Diseases

• Impairment of fatty acid oxidation can lead to hypoglycemia, fatty infiltration of organs, and hypoketonemia.

Ketosis

• Abnormally high levels of ketone bodies in the blood or urine is ketonemia/hyperketonemia or ketonuria, respectively, and the overall condition is called ketosis.
• As ketone bodies are strong acids, they are buffered when blood or tissue are present.
• Continued excretion depletes the alkali reserve which causes ketoacidosis.
• Excessive ketone body formation can cause Diabetic ketoacidosis (DKA), causing acidosis that impairs hemoglobin's ability to bind oxygen.

Ketolysis

• Ketolysis is the degradation of ketone bodies.
• Ketone bodies are produced in the liver, then they reach peripheral tissues through circulation.
• The heart, kidney cortex, brain, and skeletal muscle use ketone bodies for energy.

Acetoacetate

• In extrahepatic tissues, acetoacetate is activated to acetoacetyl-CoA by succinyl-CoA-acetoacetate CoA transferase.
• CoA is transferred from succinyl-CoA to form acetoacetyl-CoA, which is then split by thiolase to form acetyl CoA which enters the TCA cycle.
• In the liver, it is activated to acetoacetyl CoA which is used as a precursor for cholesterol synthesis.

Acetoacetate Utilization

• Acetoacetate is activated by acetoacetyl-CoA synthetase with ATP, Mg 2+, and CoA to form acetoacetyl-CoA, and this reaction is similar to fatty acid activation, which produces AMP and PPi.
• Acetoacetate activation can also occur via CoA-SH transfer from succinyl-CoA by succinyl-CoA: acetoacetate CoA transferase or thiophorase, to form aceto acetyl-CoA.
• Thiolase cleaves aceto acetyl-CoA into two molecules of acetyl-CoA.
• Then the acetyl-CoAs are oxidized by the citric acid cycle.

β-Hydroxybutyrate utilization

• The major pathway is the conversion of β-Hydroxybutyrate to acetoacetate by dehydrogenase.
• NAD + serves as the hydrogen acceptor.
• Acetoacetate formed from NAD+ is utilized for energy production.
• The minor route is the direct activation of β-hydroxy butyrate by synthetase to β-hydroxy butyryl-CoA, then dehydrogenation to acetoacetyl-CoA, catalyzed by Dehydrogenase.

Acetone Utilization

• Extrahepatic tissue utilizes acetone slowly
• Acetone is removed by excretion in the urine and also through the lungs as CO2.