Lipid Metabolism

Fats and Oils

Fats and oils are the most common forms of lipids. Their main roles are to provide energy,
insulate the body and facilitate the transport of fat-soluble vitamins. Fat is a natural lipid
material that is normally solid at room temperature. Oils are similar to fats except that they
are generally liquid at room temperature.
These two materials are integral parts of the human diet. They are normally used as
a shortening agent in food processing. It normally provides lubrication in some food
products, and may also give structure to baked materials such as cakes and doughnuts. Oils
are also used for frying different food products. Because of the high heat transfer properties
of the oil, it is normally used to produce foods that are crisp and firm.
Aside from its function as a shortening agent, oil also contributes a great amount in terms of
the taste of the food. When food products are fried, certain oxidation reactions occur
producing a complex set of possible flavors. Olive oil, for example, is a good oil to use for
gourmet food products and in pasta and salad dressing. Coconut and palm oil, on the other
hand, are very good for frying.
The last main important purpose of fats and oil is that because of their dense nature, they
have easily stored sources of calories. Also, because of their non-polar nature, they can be
used to transport various fat-soluble vitamins such as vitamins A, D, and E. In the human
body, lipids also play a big role in the synthesis of lipid hormones. Different
polyunsaturated fatty acids are needed by the body to produce prostaglandins.
Structure of fats and oils
Fats and oils are generally called triglycerides or triacylglycerols. The general structure of a
triglyceride is composed of three fatty acids units joined to glycerol and trihydroxy alcohol.
Lipid Metabolism
Lipid metabolism can be divided into two major types. One of these is lipogenesis, which
involves the synthesis of lipids and fatty acid oxidation in which energy is produced when
fatty acids are metabolized. The metabolism of lipids is closely related to the metabolic
processes for carbohydrates. This is because there are times when carbohydrates are
metabolized, sometimes forming fats.
Triacylglycerols are transported in body fluids by molecules called lipoproteins. The
general configuration of a lipoprotein involves having the hydrophobic region inside the
core of the sphere, while the superficial layer is composed of the hydrophilic regions.

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At different parts of the digestive tract, metabolism of triacylglycerols may occur. The
mechanism of metabolism is facilitated by a group of enzymes called lipases. Lipases
catalyze the hydrolysis of the ester bond of the triacylglycerol.
Lipases are generally classified as intracellular or extracellular. Intracellular lipases
include hormone-sensitive lipase in adipocytes and lysosomal lipases. Extracellular lipases,
on the other hand, include pancreatic lipase and lipoprotein lipase.
Hormones control the activity of hormone-sensitive lipase. An example of this is the increase
in lipase activity when an individual suffers from stress. The stress triggers a release of the
hormones adrenaline/noradrenaline.
The hormone attaches itself to a receptor which eventually leads to the processing of inactive
lipases to convert them to active ones. Active lipases separate the triacylglycerol into
glycerol and free fatty acids. The fatty acids produced are taken up from the blood plasma
by tissues that require nutrients.
On the other hand, glycerol, since it cannot be utilized in adipocytes, serves as a substrate for
gluconeogenesis in the liver.
Glycerol is acted upon by glycerol kinase, consuming one ATP in the process, to produce L-
glycerol-3-phosphate (L-G3P). L-G3P will be converted to a dihydroxyacetone phosphate
using glycerol phosphate dehydrogenase. An NAD+ is also converted to NADH in the
process.
Finally, the dihydroxyacetone phosphate readily isomerizes to form the D-glyceraldehyde-3-
phosphate.
To be able to synthesize triacylglycerol back, a glycerol-3-phosphate can be processed by
first reacting it with a fatty acid in the presence of an acyltransferase and in the expense of a
FAD molecule. Addition of one fatty acid leads to the production of a lysophosphatidic
molecule. The process can be repeated to add another fatty acid to glycerol, forming a
phosphatidic acid.
The next step is to remove the phosphate group using phosphatase. The product for this
step is a diacylglycerol. Another fatty acid may then esterify with the last OH group of the
diacylglycerol to produce the triacylglycerol.
Fats (or triglycerides) within the body are ingested as food or synthesized by adipocytes or
hepatocytes from carbohydrate precursors. Lipid metabolism entails the oxidation of fatty
acids to either generate energy or synthesize new lipids from smaller constituent molecules.
Lipid metabolism is associated with carbohydrate metabolism, as products of glucose (such
as acetyl CoA) can be converted into lipids.

Figure 1. A triglyceride molecule (a) breaks down into a monoglyceride (b).

Lipid metabolism begins in the intestine where ingested triglycerides are broken down into
smaller chain fatty acids and subsequently into monoglyceride molecules by pancreatic
lipases, enzymes that break down fats after they are emulsified by bile salts. When food
reaches the small intestine in the form of chyme, a digestive hormone called cholecystokinin

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(CCK) is released by intestinal cells in the intestinal mucosa. CCK stimulates the release of
pancreatic lipase from the pancreas and stimulates the contraction of the gallbladder to
release stored bile salts into the intestine. CCK also travels to the brain, where it can act as a
hunger suppressant.

Figure 2. Chylomicrons contain triglycerides, cholesterol molecules, and other

apolipoproteins (protein molecules). They function to carry these water-insoluble molecules
from the intestine, through the lymphatic system, and into the bloodstream, which carries the
lipids to adipose tissue for storage.
Together, the pancreatic lipases and bile salts break down triglycerides into free fatty acids.
These fatty acids can be transported across the intestinal membrane. However, once they
cross the membrane, they are recombined to again form triglyceride molecules. Within the
intestinal cells, these triglycerides are packaged along with cholesterol molecules in
phospholipid vesicles called chylomicrons. The chylomicrons enable fats and cholesterol to
move within the aqueous environment of your lymphatic and circulatory systems.
Chylomicrons leave the enterocytes by exocytosis and enter the lymphatic system via lacteals
in the villi of the intestine. From the lymphatic system, the chylomicrons are transported to
the circulatory system. Once in the circulation, they can either go to the liver or be stored in
fat cells (adipocytes) that comprise adipose (fat) tissue found throughout the body.
Lipolysis
To obtain energy from fat, triglycerides must first be broken down by hydrolysis into their
two principal components, fatty acids and glycerol. This process, called lipolysis, takes place
in the cytoplasm. The resulting fatty acids are oxidized by β-oxidation into acetyl CoA,
which is used by the Krebs cycle. The glycerol that is released from triglycerides after
lipolysis directly enters the glycolysis pathway as DHAP. Because one triglyceride molecule
yields three fatty acid molecules with as much as 16 or more carbons in each one, fat
molecules yield more energy than carbohydrates and are an important source of energy for
the human body. Triglycerides yield more than twice the energy per unit mass when
compared to carbohydrates and proteins. Therefore, when glucose levels are low,
triglycerides can be converted into acetyl CoA molecules and used to generate ATP through
aerobic respiration.
The breakdown of fatty acids, called fatty acid oxidation or beta (β)-oxidation, begins in
the cytoplasm, where fatty acids are converted into fatty acyl CoA molecules. This fatty acyl
CoA combines with carnitine to create a fatty acyl carnitine molecule, which helps to

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transport the fatty acid across the mitochondrial membrane. Once inside the mitochondrial
matrix, the fatty acyl carnitine molecule is converted back into fatty acyl CoA and then into
acetyl CoA. The newly formed acetyl CoA enters the Krebs cycle and is used to produce
ATP in the same way as acetyl CoA derived from pyruvate.

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Figure 3. Click for a larger image. During fatty acid oxidation, triglycerides can be broken
down into acetyl CoA molecules and used for energy when glucose levels are low.

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Ketogenesis
If excessive acetyl CoA is created from the oxidation of fatty acids and the Krebs cycle is
overloaded and cannot handle it, the acetyl CoA is diverted to create ketone bodies. These
ketone bodies can serve as a fuel source if glucose levels are too low in the body. Ketones
serve as fuel in times of prolonged starvation or when patients suffer from uncontrolled
diabetes and cannot utilize most of the circulating glucose. In both cases, fat stores are
liberated to generate energy through the Krebs cycle and will generate ketone bodies when
too much acetyl CoA accumulates.
In this ketone synthesis reaction, excess acetyl CoA is converted into
hydroxymethylglutaryl CoA (HMG CoA). HMG CoA is a precursor of cholesterol and is
an intermediate that is subsequently converted into β-hydroxybutyrate, the primary ketone
body in the blood.

Figure 4. Excess acetyl CoA is diverted from the Krebs cycle to the ketogenesis pathway.
This reaction occurs in the mitochondria of liver cells. The result is the production of β-
hydroxybutyrate, the primary ketone body found in the blood.
Ketone Body Oxidation
Organs that have classically been thought to be dependent solely on glucose, such as the
brain, can actually use ketones as an alternative energy source. This keeps the brain
functioning when glucose is limited. When ketones are produced faster than they can be used,
they can be broken down into CO2 and acetone. The acetone is removed by exhalation. One
symptom of ketogenesis is that the patient’s breath smells sweet like alcohol. This effect
provides one way of telling if a diabetic is properly controlling the disease. The carbon
dioxide produced can acidify the blood, leading to diabetic ketoacidosis, a dangerous
condition in diabetics.
Ketones oxidize to produce energy for the brain. beta (β)-hydroxybutyrate is oxidized to
acetoacetate and NADH is released. An HS-CoA molecule is added to acetoacetate, forming
acetoacetyl CoA. The carbon within the acetoacetyl CoA that is not bonded to the CoA then
detaches, splitting the molecule in two. This carbon then attaches to another free HS-CoA,
resulting in two acetyl CoA molecules. These two acetyl CoA molecules are then processed
through the Krebs cycle to generate energy.

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Figure 5. When glucose is limited, ketone bodies can be oxidized to produce acetyl CoA to be
used in the Krebs cycle to generate energy.
Lipogenesis
When glucose levels are plentiful, the excess acetyl CoA generated by glycolysis can be
converted into fatty acids, triglycerides, cholesterol, steroids, and bile salts. This process,
called lipogenesis, creates lipids (fat) from the acetyl CoA and takes place in the cytoplasm
of adipocytes (fat cells) and hepatocytes (liver cells). When you eat more glucose or
carbohydrates than your body needs, your system uses acetyl CoA to turn the excess into fat.
Although there are several metabolic sources of acetyl CoA, it is most commonly derived
from glycolysis. Acetyl CoA availability is significant, because it initiates lipogenesis.
Lipogenesis begins with acetyl CoA and advances by the subsequent addition of two carbon
atoms from another acetyl CoA; this process is repeated until fatty acids are the appropriate
length. Because this is a bond-creating anabolic process, ATP is consumed. However, the
creation of triglycerides and lipids is an efficient way of storing the energy available in
carbohydrates. Triglycerides and lipids, high-energy molecules, are stored in adipose tissue
until they are needed.
Although lipogenesis occurs in the cytoplasm, the necessary acetyl CoA is created in the
mitochondria and cannot be transported across the mitochondrial membrane. To solve this
problem, pyruvate is converted into both oxaloacetate and acetyl CoA. Two different
enzymes are required for these conversions. Oxaloacetate forms via the action of pyruvate
carboxylase, whereas the action of pyruvate dehydrogenase creates acetyl CoA. Oxaloacetate
and acetyl CoA combine to form citrate, which can cross the mitochondrial membrane and
enter the cytoplasm. In the cytoplasm, citrate is converted back into oxaloacetate and acetyl
CoA. Oxaloacetate is converted into malate and then into pyruvate. Pyruvate crosses back
across the mitochondrial membrane to wait for the next cycle of lipogenesis. The acetyl CoA
is converted into malonyl CoA that is used to synthesize fatty acids. Figure 6 summarizes the
pathways of lipid metabolism.

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Figure 6. Lipids may follow one of several pathways during metabolism. Glycerol and fatty
acids follow different pathways.