Lipid Metabolism

LECTURE

Prof. Talal Abdulrazzaq Alkawry

 BIOMEDICAL IMPORTANCE
The lipids are a heterogeneous group of compounds most of
them found in the body fall into the categories of:,
▪ fatty acids
▪ triacylglycerols
▪ glycerophospholipids
▪ sphingolipids
▪ eicosanoids
▪ cholesterol
▪ bile salts
▪ steroid hormones
▪ fat-soluble vitamins
Prof. Talal Alkawry
 BIOMEDICAL IMPORTANCE

➢ These lipids have very diverse chemical structures

and functions.
➢ They are related by a common property: their relative
insolubility in water.
➢ They soluble in nonpolar solvents such as ether and
chloroform.
➢ Fatty acids, which are stored as triacylglycerols, serve
as fuels, providing the body with its major source of
energy
Prof. Talal Alkawry
 BIOMEDICAL IMPORTANCE

Prof. Talal Alkawry

Summary of fatty acid metabolism
 BIOMEDICAL IMPORTANCE

➢ They are important dietary constituents not only

because of the high energy value of fats but also
because essential fatty acids, fat-soluble vitamins, and
other lipophilic micronutrients are contained in the fat of
natural foods
➢ Dietary supplementation with long-chain ω3 fatty
acids is believed to have beneficial effects in a
number of chronic diseases, including
cardiovascular disease, rheumatoid arthritis, and
dementia.
Prof. Talal Alkawry
 BIOMEDICAL IMPORTANCE

➢ Fat is stored in adipose tissue, where it also serves

as a thermal insulator in the subcutaneous tissues
and around certain organs.

➢ Nonpolar lipids act as electrical insulators, allowing

rapid propagation of depolarization waves along
myelinated nerves.
➢ Lipids are transported in the blood combined with
proteins in lipoprotein particles.
Prof. Talal Alkawry
 BIOMEDICAL IMPORTANCE

➢ Lipids have essential roles in nutrition and health and

knowledge of lipid biochemistry is necessary for the
understanding of many important biomedical
conditions, including obesity, diabetes mellitus, and
atherosclerosis
➢ Fatty acids, which are stored as triacylglycerols, serve
as fuels, providing the body with its major source of
energy
➢ Glycerophospholipids and sphingolipids, which contain
esterified fatty acids, are found in membranes and in
Prof. Talal Alkawry
 BIOMEDICAL IMPORTANCE

blood lipoproteins at the interfaces between the lipid

components of these structures and the surrounding
water
➢ These membrane lipids form hydrophobic barriers
between subcellular compartments and between
cellular constituents and the extracellular milieu.
➢ Polyunsaturated fatty acids containing 20 carbons
form the eicosanoids, which regulate many cellular
processes
Prof. Talal Alkawry
BIOMEDICAL

Summary of eicosanoid synthesis

➢ Cholesterol adds stability to the phospholipid bilayer of

membranes.
➢ It serves as the precursor of the bile salts, detergent-like
compounds that function in the process of lipid digestion
and absorption
Prof. Talal Alkawry
 BIOMEDICAL

Summary of cholesterol metabolism

➢ Cholesterol also serves as the precursor of the steroid

hormones, which have many actions, including the
regulation of metabolism, growth, and reproduction.
Prof. Talal Alkawry
 Digestion and Transport
of Dietary Lipids
Prof. Talal Alkawry
➢ Triacylglycerols are the major fat in the human diet,
consisting of three fatty acids esterified to a glycerol backbone.
➢ Limited digestion of these lipids occurs in the mouth
(lingual lipase) and stomach (gastric lipase) because of
the low solubility of the substrate .
➢ In the intestine, however, the fats are emulsified by
bile salts that are released from the gallbladder.
➢ This increases the available surface area of the lipids for
pancreatic lipase and colipase to bind and to digest the
triglycerides.
Prof. Talal Alkawry
➢ Degradation products are free fatty acids and 2-
monoacylglycerol.
➢ When partially digested food enters the intestine, the
hormone cholecystokinin is secreted by the intestine,
which signals the gallbladder to contract and release bile
acids, and the pancreas to release digestive enzymes
➢ In addition to triacylglycerols, phospholipids, cholesterol,,
and cholesterol esters (cholesterol esterified to fatty
acids) are present in the foods we eat.
Prof. Talal Alkawry
➢ Phospholipids are hydrolyzed in the intestinal lumen by
phospholipase A2, and cholesterol esters are hydrolyzed
by cholesterol esterase.
➢ Both of these enzymes are secreted from the pancreas.
➢ The products of enzymatic digestion (free fatty acids,
glycerol, lysophospholipids, cholesterol) form micelles
with bile acids in the intestinal lumen.
➢ The micelles interact with the enterocyte membrane and
allow diffusion of the lipid soluble components across the
enterocyte membrane into the cell.
Prof. Talal Alkawry
➢ The bile acids, however, do not enter the enterocyte at
this time.
➢ They remain in the intestine, travel further down, and are
then reabsorbed and sent back to the liver by the
enterohepatic circulation.
➢ This allows the bile salts to be used multiple times in fat
digestion.
➢ The intestinal epithelial cells will resynthesize
triacylglycerol from free fatty acids and 2-monacylglycerol
and will package them with a protein, apolipoprotein B-48,
. Talal Alkawry
Prof.
Recycling of bile salts
phospholipids, and cholesterol esters into a soluble
lipoprotein particle known as a chylomicron.
➢ The chylomicrons are secreted into the lymph and
eventually end up in the circulation, where they can
distribute dietary lipids to all tissues of the body.
➢ Once in circulation, the newly released (“nascent”)
chylomicrons interact with another lipoprotein particle,
HDL (high-density lipoprotein) and acquire two
apoproteins from HDL, apoprotein CII and E.
Prof. Talal Alkawry
➢ This converts the nascent chylomicron to a “mature”
chylomicron. The apoCII on the mature chylomicron
activates the enzyme lipoprotein lipase (LPL), which is
located on the inner surface of the capillary endothelial
cells of muscle and adipose tissue.
➢ The LPL digests the triglyceride in the chylomicron,
producing free fatty acids and glycerol.
➢ The fatty acids enter the adjacent organs either for
energy production (muscle) or fat storage (adipocyte).
Prof. Talal Alkawry
➢ The glycerol that is released is metabolized in the liver.

➢ As the chylomicron loses triglyceride, its density

increases and it becomes a chylomicron remnant, which
is taken up by the liver by receptors that recognize
apolipoprotein E

➢ In the liver, the chylomicron remnant is degraded into its

component parts for further disposition by the liver.

Prof. Talal Alkawry

 I. Digestion of Triacylglycerols
➢ Triacylglycerols are the major fat in the human diet
because they are the major storage lipid in the plants and
animals that constitute our food supply.
➢ Triacylglycerols contain a glycerol backbone to which
three fatty acids are esterified

Prof. Talal Alkawry

 I. Digestion of Triacylglycerols

➢ The main route for digestion of triacylglycerols involves

hydrolysis to fatty acids and 2- monoacylglycerols in the
lumen of the intestine.
➢ However, the route depends to some extent on the chain
length of the fatty acids
➢ Lingual and gastric lipases are produced by cells at the
back of the tongue and in the stomach, respectively
➢ These lipases preferentially hydrolyze short- and
medium-chain fatty acids (containing 12 or fewer carbon
atoms) from dietary triacylglycerols.
Prof. Talal Alkawry
 I. Digestion of Triacylglycerols
➢ Therefore, they are most active in infants and young children, who
drink relatively large quantities of cow’s milk, which contains
triacylglycerols with a high percentage of short- and medium-
chain fatty acids.

❑ Action of Bile Salts

➢ Dietary fat leaves the stomach and
enters the small intestine, where
it is emulsified (suspended in small
particles in the aqueous environment)
by bile salts

Prof. Talal Alkawry Structure of a bile salt 587

 I. Digestion of Triacylglycerols

➢ The bile salts are amphipathic compounds synthesized in

the liver and secreted via the gallbladder into the
Intestinal lumen..
➢ The contraction of the gallbladder and secretion of
pancreatic enzymes are stimulated by the gut hormone
cholecystokinin, which is secreted by the intestinal cells
when stomach contents enter the intestine.
➢ Bile salts act as detergents, binding to the globules of
dietary fat as they are broken up by the peristaltic
action of the intestinal muscle
Prof. Talal Alkawry
 I. Digestion of Triacylglycerols

➢ This emulsified fat,

which has an
increased surface
area as compared
with unemulsified
fat, is attacked by
digestive enzymes
from the pancreas

Prof. Talal Alkawry

 I. Digestion of Triacylglycerols

❑ Action of Pancreatic Lipase

➢ The major enzyme that digests dietary triacylglycerols is
a lipase produced in the pancreas
➢ Pancreatic lipase is secreted along with another protein,
colipase, along with bicarbonate, which neutralizes the
acid that enters the intestine with partially digested food
from the stomach.
➢ Bicarbonate raises the pH of the contents of the intestinal
lumen into a range (pH ~ 6) that is optimal for the action of
all of the digestive enzymes of the intestine
Prof. Talal Alkawry
 I. Digestion of Triacylglycerols
➢ Bicarbonate secretion from the
pancreas is stimulated by the
hormone secretin, which is
released from the intestine
when acid enters the duodenum
➢ The pancreas also produces esterases that
remove fatty acids from compounds (such as
cholesterol esters) and phospholipase A2
that digests phospholipids to a free fatty acid
and a lysophospholipid
Prof. Talal Alkawry
Prof. Talal Alkawry
 Blood Lipoproteins
Chylomicrons
• produced in intestinal epithelial cells from dietary fat.
• carries triacylglycerol in blood.
VLDL (very low density lipoprotein)
• produced in liver mainly from dietary carbohydrate.
• carries triacylglycerol in blood.
IDL (intermediate density lipoprotein)
• produced in blood (remnant of VLDL after triacylglycerol
digestion).
• endocytosed by liver or converted to LDL.
Prof. Talal Alkawry
 Blood Lipoproteins

LDL (low density lipoprotein)

• produced in blood (remnant of IDL after triacylglycerol
digestion; end product of VLDL.
• contains high concentration of cholesterol and
cholesterol esters.
• endocytosed by liver and peripheral tissues.
HDL (high density lipoprotein)
• produced in liver and intestine.
• exchanges proteins and lipids with other lipoproteins
• functions in the return of cholesterol from peripheral
tissues to the liver.
Prof. Talal Alkawry
The Lymphatic System

▪ lymph
• Lymph is a clear-to-white fluid made of: White blood cells, especially lymphocytes, the cells
that attack bacteria in the blood and body tissues

▪ lymphatic vessels
• a network of thin tubes that carry lymph and white blood cells
• Lymphatic vessels branch, like blood vessels, into all the tissues of the body.

▪ lymph nodes
• Lymph nodes are small structures that work as filters for foreign substances.

▪ bone marrow
▪ spleen
▪ thymus
Prof. Talal Alkawry
 Triacylglycerols Metabolism
➢ Triacylglycerols, the major dietary lipids, are digested
in the lumen of the intestine.
➢ The initial digestive products, free fatty acids and 2-
monoacylglycerol, are reconverted to triacylglycerols in
intestinal epithelial cells, packaged in lipoproteins known
as chylomicrons (so they can safely enter the
circulation), and secreted into the lymph.
➢ Ultimately, chylomicrons enter the blood, serving as one of
the major blood lipoproteins.
Prof. Talal Alkawry
 Triacylglycerols Metabolism

➢ Very low density lipoprotein

(VLDL) is produced in the
liver, mainly from dietary
carbohydrate.

Overview of triacylglycerol
Prof. Talal Alkawry metabolism in the fed state
 Triacylglycerols Metabolism

➢ Lipogenesis is an insulin-stimulated process through

which glucose is converted to fatty acids, which are
subsequently esterified to glycerol to form the
triacylglycerols that are packaged in VLDL and secreted
from the liver.
➢ Thus, chylomicrons primarily transport dietary lipids, and
VLDL transports endogenously synthesized lipids.

Prof. Talal Alkawry

 Triacylglycerols Metabolism

➢ The triacylglycerols of chylomicrons and VLDL are

digested by lipoprotein lipase (LPL), an enzyme found
attached to capillary endothelial cells.

➢ The fatty acids that are released are taken up by

muscle and many other tissues and oxidized to CO2
and water to produce energy.

➢ After a meal, these fatty acids are taken up by

adipose tissue and stored as triacylglycerols.

Prof. Talal Alkawry

 Triacylglycerols Metabolism

➢ LPL converts chylomicrons to chylomicron remnants

and VLDL to intermediate density lipoprotein (IDL).

➢ These products, which have a relatively low

triacylglycerol content, are taken up by the liver by the
process of endocytosis and degraded by lysosomal
action.
➢ IDL may also be converted to low density lipoprotein (LDL)
by further digestion of triacylglycerol.

Prof. Talal Alkawry

 Triacylglycerols Metabolism

➢ Endocytosis of LDL occurs in peripheral tissues as well

as the liver, and is the major means of cholesterol
transport and delivery to peripheral tissues.

➢ The principal function of high density lipoprotein (HDL) is

to transport excess cholesterol obtained from peripheral
tissues to the liver and to exchange proteins and lipids
with chylomicrons and VLDL.
➢ The protein exchange converts "nascent" particles to
"mature" particles.
Prof. Talal Alkawry
 Triacylglycerols Metabolism

➢ During fasting, fatty acids and glycerol are released

from adipose triacylglycerol stores.
➢ The glycerol travels to the liver and is used for
gluconeogenesis.

➢ Only the liver contains glycerol kinase, which is required

for glycerol metabolism.

Prof. Talal Alkawry

 Triacylglycerols Metabolism

Overview of triacylglycerol metabolism during fasting.

Prof. Talal Alkawry
 Triacylglycerols Metabolism

➢ The fatty acids form complexes with albumin in the blood

and are taken up by muscle, kidney, and other tissues,
where ATP is generated by their oxidation to CO2 and
water.
➢ Liver also converts some of the carbon to ketone bodies,
which are released into the blood
➢ Ketone bodies are oxidized for energy in muscle, kidney,
and other tissues during fasting, and in the brain during
prolonged starvation.
Prof. Talal Alkawry