LIPOGENESIS

Lipogenesis, the synthesis of fatty acids and their esterification to glycerol to form triacylglycerols,
which occurs mainly in the liver in humans, with dietary carbohydrate as the major source of
carbon.
While the de novo synthesis of fatty acids from acetyl-CoA occurs in the cytosol on the fatty acid
synthase complex.
Fatty acid synthesis is the creation of fatty acids from acetyl-CoA and NADPH through the action
of enzymes called fatty acid synthases.

Lipogenesis is a term used to describe a process of fatty acid and triglyceride synthesis from
glucose or other substrates. This specific biosynthesis takes place predominantly in the liver, while
its occurrence in the adipose tissue is of minor significance – even under conditions of substantial
carbohydrate overfeeding.

Although our understanding of biochemistry and hormonal regulation of lipogenesis stems from
in vitro research on rodents, the biological importance, activity and tissue distribution of the
lipogenic pathways show considerable variation among different species. In humans, lipogenesis
plays an important role in physiologic and pathophysiologic conditions.

Steps in lipogenesis

Different human cells show the ability to convert carbohydrates (but also amino acid carbons) into
fatty acids via a biochemical pathway known as de novo lipogenesis. The initial step for such fatty
acid synthesis is acetyl-CoA carboxylation to malonyl-CoA with the help of the enzyme acetyl-
CoA carboxylase, which is mostly taking place in liver cells, but also in skeletal muscle and
adipose tissue.

Further events include an iterative integration of malonyl-CoA carbons into a fatty acid chain
which results with the synthesis of a palmitic acid, representing an energy-consuming process.
Additional action of elongase and desaturase enzymes can lead to the synthesis of stearic acid.

De novo lipogenesis from carbohydrate is associated with significant amounts of energy lost as
heat, irrespective of whether synthesized fat is oxidized or stored in form of a triglyceride. The
process is activated by insulin and inhibited by hyperglucogonemia (excess glucagon secretion)
and by cellular energy deprivation through 5’ AMP-activated protein kinase by glucagon.

Carbohydrates in the form of glucose, glycogen and lactate are considered to be the major
precursors for de novo lipogenesis in the fetus and neonate. De novo synthesis of fatty acids in
fetal lung has been studied extensively as the synthesis of surfactant is pivotal for normal
pulmonary function at birth.

Measurement of lipogenesis

Until the 1990s, lipogenesis in humans has largely been assessed via indirect calorimetry. This
measurement is based on the fact that synthesis of fatty acids from acetyl-CoA can be linked to a
sizable carbon dioxide production, which in turn upsurges the respiratory exchange ratio. Still,
with this method it was difficult to demonstrate net de novo lipid synthesis.

In the 1990s, new isotopic methods have been developed for the evaluation of hepatic lipogenesis
which incorporate tracers to the fatty acids secreted in very low density lipoproteins. Using this
method, de novo lipogenesis in the liver could be observed in individuals on high-carbohydrate
diets – even without net fat synthesis.

Deuterium is also used to quantitate the relative proportions of dietary and newly synthesized
triglyceride fatty acids. Measuring de novo lipogenesis by deuterium incorporation is considered
to be a safe, precise and highly sensitive method which can be used with short measurement
periods (i.e. less than 24 hours).

Lipogenesis Control and Regulation

Lipogenesis is the process involving the synthesis of fatty acids or triglycerides, which is
controlled and regulated by a number of factors in the body. The process is stimulated by a diet
high in carbohydrates and several hormones in the body, such as insulin, mediate the process.
Role of Insulin

Insulin is a peptide hormone that has a large impact on the body’s metabolic processes. It is
released from the pancreas in response to high blood glucose levels and has many effects on the
regulation of the concentration of glucose in the body. In particular, it promotes the storage of
glucose in the body and stimulates lipogenesis to reduce the glucose levels. It does this through the
activation of two enzymatic pathways:

 pyruvate dehydrogenase (PDH) dephosphorylation

 Acetyl-CoA carboxylase (ACC) conversion.

Pyruvate Dehydrogenase (PDH)

Dephosphorylation

When insulin is released it stimulates the activity of the PDH phosphatase enzyme, which plays
an important role in the removal of the phosphate from the pyruvate dehydrogenase, through a
process known as dephosphorylation. The end product of this reaction from PDH is acetyl-CoA.
When the levels of acetyl-CoA are increased, the lipogenesis pathway is stimulated and more lipid
molecules are synthesized.

Acetyl-CoA Carboxylase (ACC) Enzyme

In addition to its effect on PDH, insulin also stimulates the activity of the acetyl-CoA carboxylase
(ACC) enzyme. This enzyme is responsible for the conversion reaction from acetyl-CoA to
malonyl-CoA. The end product allows for additional carbon atoms that are used in the formation
of larger fatty acids through a process of biosynthesis

Role of Glucagon

Glucagon can be viewed as an antagonist of insulin as it has the opposite effect and decreases the
production of fatty acids through lipogenesis. It does this by increasing the process of
phosphorylation, which inhibits ACC and slows the synthesis of lipids. Therefore, glucagon also
plays an important role in the physiological regulation of lipogenesis by inhibiting the process
from occurring when it energy stores are immediately required.
Allosteric Regulation

When there is a high concentration of long chain fatty acids, they can inhibit the activity of ACC.
They act as negative allosteric regulators and stop the synthesis of fatty acids, or process of
lipogenesis

Energy Sources

ATP is a primary source of energy for the needs of human body cells, and when the ATP stores
are depleted, the levels of AMP rise. As a result, AMP-activated protein kinase initiated the
phosphorylation reaction of ACC and inhibits the lipogenesis process. This pathway is beneficial
due to its ability to prevent the diversion of glucose into fat storage pathways when there is a
requirement for energy sources in the body.

Control and Regulation

As a result of these various physiological mechanisms, the process of lipogenesis can be carried
out in a controlled manner. There are a number of hormones involved in this regulatory process,
in addition to allosteric regulators and energy sources that play a role.
 De novo pathway

Compiled by SKMwihia PhD Med.Biotech