KETOGENESIS

DEFINITION OF KETOGENESIS
Ketogenesis refers to the metabolic process through which ketone bodies are produced in the
liver from fatty acids when carbohydrate availability is limited or in a state of prolonged fasting.
This process involves the conversion of fatty acids into acetyl-CoA (acetyl coenzyme A), which
then leads to the synthesis of ketone bodies such as acetoacetate, β-hydroxybutyrate, and
acetone. These ketone bodies serve as an alternative energy source for tissues, especially the
brain, heart, and skeletal muscles, during times of low glucose availability.

BIOCHEMICAL BASIS OF KETOGENESIS

The biochemical basis of ketogenesis involves a series of steps primarily occurring in the liver:

1. Activation of Fatty Acids

Before entering the process of ketogenesis, fatty acids must be activated. This step
involves the attachment of Coenzyme A (CoA) to fatty acids, forming fatty acyl-CoA
molecules. This process occurs in the cytoplasm of the liver cells.
2. Beta – Oxidation
Fatty acyl-CoA molecules are transported into the mitochondria, where beta-oxidation
occurs. During beta-oxidation, fatty acids undergo a series of reactions that repeatedly
cleave two-carbon units from the fatty acyl-CoA chain, producing acetyl-CoA molecules.
This process generates NADH and FADH2, which enter the electron transport chain to
produce ATP.
3. Formation of Acetyl – CoA
 The acetyl-CoA generated from beta-oxidation cannot enter the citric acid cycle (Krebs
cycle) in excessive amounts due to the limited availability of oxaloacetate, a precursor in
the cycle. Instead, excess acetyl-CoA leads to the initiation of ketogenesis.
4. Ketone Body Synthesis
Acetyl-CoA molecules produced in excess during beta-oxidation are used as substrates
for ketone body synthesis. Acetyl-CoA undergoes condensation reactions to form ketone
bodies such as acetoacetate, β-hydroxybutyrate, and acetone. Acetoacetate is the
primary ketone body formed, and some of it is converted to β-hydroxybutyrate or
spontaneously decarboxylates to form acetone.
5. Release of Ketone Bodies
Ketone bodies, mainly β-hydroxybutyrate and acetoacetate, are released into the
bloodstream and transported to various tissues, especially the brain, heart, and skeletal
muscles. These tissues can convert ketone bodies back into acetyl-CoA, which is
utilized as an alternative energy source through a reversal process known as ketolysis.

This process of ketogenesis serves as a vital mechanism to generate alternative fuel sources,
specifically ketone bodies, to provide energy for tissues, especially the brain, in situations where
glucose availability is limited.

KETONE BODIES
Ketone bodies are produced by the liver and used peripherally as an energy source when
glucose is not readily available. The two main ketone bodies are acetoacetate (AcAc) and beta-
hydroxybutyrate (HB), while acetone is the third, and least abundant, ketone body.

ACETOACETATE

Acetoacetate is a ketone body produced in the liver during periods of

low glucose availability, such as fasting or low-carbohydrate diets. It is
synthesized through ketogenesis from acetyl-CoA and serves as a
vital energy source, especially for tissues like the brain, heart, and
muscles when glucose levels are low. Acetoacetate can be converted
into beta-hydroxybutyrate or spontaneously decarboxylated to form
acetone. These ketone bodies serve as an alternative fuel source to glucose when the body's
carbohydrate stores are depleted.
BETA – HYDROXYBUTYRATE
Beta-hydroxybutyrate (BHB) is one of the three ketone bodies
produced in the liver during periods of low carbohydrate intake or
fasting. It is synthesized from acetoacetate, primarily in the
mitochondria of liver cells, and is transported through the
bloodstream to provide energy to tissues such as the brain, heart,
and muscles. BHB is the most abundant ketone body circulating in
the blood during ketosis and serves as an essential energy source when glucose availability is
limited. It can be converted back to acetoacetate in certain tissues and is often measured in
blood tests as an indicator of ketosis in ketogenic diets or fasting states.
ACETONE
Acetone is the simplest and most volatile of the three ketone bodies
produced during ketosis. It's formed spontaneously from the breakdown of
acetoacetate, another ketone body. In the liver, a small portion of
acetoacetate is converted into acetone through a non-enzymatic process.
Acetone is less utilized as an energy source compared to beta-
hydroxybutyrate and acetoacetate. It's released from the body primarily
through exhalation and urine. The presence of acetone is often detectable in the breath, giving a
characteristic fruity odor, particularly noticeable during states of increased ketone production,
such as fasting or adhering to a ketogenic diet.

REGULATION OF KETOGENESIS
Ketogenesis can be upregulated by hormones such as glucagon, cortisol, thyroid hormones,
and catecholamines by causing a more significant breakdown of free fatty acids, thus increasing
the amount available to be used in the ketogenic pathway. However, insulin is the primary
hormonal regulator of this process.
Insulin regulates many key enzymes in the ketogenic pathway, and a state of low insulin triggers
the process. A low insulin state leads to:
 Increased free fatty acids (FFAs)
o Due to decreased inhibition of hormone-sensitive lipase
 Increased uptake of FFAs into the mitochondria
o Due to decreased activation of acetyl-CoA carboxylase, decreasing malonyl CoA,
which disinhibits Carnitine Palmitoyl transferase 1 (CPT1)
 Increased production of ketone bodies
o Due to increased HMG-CoA activity