College of Health Sciences

CHS

Metabolism of Lipid
MLS 218
 Objectives
CHS
1. To understand Lipid digestion and absorption.
2. To describe the mechanism of glycerol and fat oxidation.
3. Explain synthesis of phosphatidic acid and list different membrane
phospholipids
4. To become familiar with the amount of energy produced during the
oxidation of fat.
5. To describe process of digestion, absorption and synthesis of lipids
6. Describe the types and role of lipoproteins
7. Explain ketogenesis and ketosis
8. Explain cholesterol metabolism and its role in atherosclerosis
9. Desribe fatty liver and lipotropic factor
10.Explain the effects of hormones on lipid metabolism
11. Explain different types of hyperlipoproteinemia
12.Interpret the cases of various metabolic disorders
CHS
Metabolic Interrelationship

lipolysis

synthesis of lipids needs Acetyl CoA

breakdown gives Acetyl CoA
CHS Digestion of Triacylglyceroles
• Triacylglycerols (TAGs) pass through the mouth
unchanged and enter the stomach.
• The heat and churning action of the stomach break
lipids into smaller droplets.
• partially digested food leaves the stomach, it enters the
upper end of the small intestine (the duodenum).
• triggerring the release of pancreatic lipases, enzymes
for the hydrolysis of lipids.
• The gallbladder simultaneously releases bile.
• Bile contains bile acids and cholesterol. Cholic acid is
the major bile acid,which emulsify the lipid droplets so
they can be acted on by the pancreatic lipases.
TAG --- Stomach --- Heat and churning --- Small droplets --- duodenum
CHS
Digestion of Triacylglyceroles
• . Pancreatic lipase partially hydrolyzes the
emulsified triacylglycerols, producing mainly
mono- and diacylglycerols, plus fatty acids
and a small amount of glycerol
in the intestine
4 products free fatty acids

free glycerol
CHS cannot be transferred to the
Lipid absorption blood independently, it
needs proteins

Smaller fatty acids and glycerol are absorbed directly

through the surface of the villi that line the small intestine
and enter the bloodstream through capillaries.
The insoluble acylglycerols and larger fatty acids within
the intestine are packaged into the lipoproteins.
Chylomicrons "Lipoprotein" transports dietary lipids in intestine through blood to liver

by lipoprotein

directly

small bec less carbon

CHS Lipoprotein for lipid transport
• Lipids enter metabolism from three different sources:
– (1) the diet
– (2) storage in adipose tissue transported by different mechanism
– (3) synthesis in the liver
• Whatever their source, these lipids must eventually be
transported in blood.
• To become water-soluble, fatty acids released from
adipose tissue associate with albumin, a very large
protein that binds up to 10 fatty acid molecules.
• All other lipids are carried by lipoproteins of various
types.
CHS Lipoproteins
• contains a core of neutral
lipids, including
triacylglycerols and in the center "Core"

cholesteryl esters.
• Surrounding the core is a
layer of phospholipids in
which varying proportions
of proteins and cholesterol
are embedded.

intrinsic proteins= on the inside or half in half out

extrinsic= only on the surface

8
CHS
Lipoproteins
Tests done for liver profile:
total cholesterol
total glycerol
LDL
HDL
VLDL

Lipoprotein Density Diameter Protein % Phospholip Triacylglycero

class (g/mL) (nm) of dry wt id % l % of dry wt
HDL 1.063-1.21 5 – 15 33 29 8

LDL 1.019 – 1.063 18 – 28 25 21 24

IDL 1.006-1.019 25 - 50 18 22 31

VLDL 0.95 – 1.006 30 - 80 10 18 50

chylomicrons < 0.95 100 - 500 1-2 7 84

 Types of lipoproteins
CHS
• Chylomicrons, transport of lipids from the diet.
• Very-low-density lipoproteins (VLDLs) carry TAGs from the liver
to peripheral tissues for storage or energy generation
• Low-density lipoproteins (LDLs) transport cholesterol from the
liver to peripheral tissues, where it is used in cell membranes or for
steroid synthesis. LDL cholesterol can also cause formation of
arterial plaque (Bad cholesterol)

• High-density lipoproteins (HDLs) transport cholesterol from dead

or dying cells back to the liver, where it is converted to bile acids.
The bile acids are then available for use in digestion or are excreted
when in excess. HDL is also called good cholesterol ifliver,
cholesterol does not enter the
it stays in the blood
high LDL and low HDL is harmful causing blockage in arteries "
It should be normal amount of both heart diseases"

10
Pentose Phosphate Pathway
( HMP)
MLS 218
Objectives
 To understand the function of the
pentose phosphate pathway In production
of NADPH and precursors for nucleic
acid synthesis.
Introduction 4th option for glucose-6-phosphate to convert

 In most animal tissues, glucose is catabolized via

the glycolytic pathway into two molecules of
pyruvate. Pyruvate is then oxidized via the citric
acid cycle to generate ATP.
 There is another metabolic fate for glucose
used to generate NADPH and specialized
products needed by the cell. This pathway is
called the pentose phosphate pathway also
called as the hexose monophosphate shunt
(HMP shunt), or the phosphogluconate
pathway.
Cont..
 The pentose phosphate pathway produces NADPH
which is the universal reductant in anabolic pathways.
 In mammals the tissues requiring large amounts of
NADPH produced by this pathway are the tissues that
synthesize fatty acids and steroids such as the
mammary glands, adipose tissue, adrenal cortex and the
liver.
 Tissues less active in fatty acid synthesis such as
skeletal muscle are virtually lacking the pentose
phosphate pathway.

 The second function of the pentose phosphate

pathway is to generate pentoses, particularly ribose
which is necessary for the synthesis of nucleic acids.
Cont…
 The pentose phosphate pathway has
two distinct phases:
 the oxidative phase , which produces
NADPH and the pentose ribulose-5-
phosphate ; for biosynthetic pathways or nucleic acid synthesis

 the rearrangement phase ( non

oxidative phase ), which rearranges
pentose phosphates into Triose and
hexose phosphates , which can be returned
to the normal glycolysis sequence
should reconnect to glycolysis
Summary of HMP pathway
know them

glycolytic intermediates are formed

Regulation

 The first reaction is the irreversible and is the

committed step
 This reaction is catalyzed by glucose -6 –
phosphate dehydrogenase and is allosterically
regulated
 This enzyme is inhibited at high concentrations of
NADPH
G6PD deficiency
 Mutations present in some populations causes a deficiency in
glucose 6 ‐ phosphate dehydrogenase, with consequent
impairment of NADPH production.

 Reduced glutathione (GSH) protects the cell by destroying

hydrogen peroxide and hydroxyl free radicals. Regeneration of
GSH from its oxidized form (GS‐SG) requires the NADPH
no NADPH = No reduced glutathione
 Detoxification Of H2O2 is inhibited, and cellular damage results
‐ leads to erythrocyte membrane breakdown and hemolytic
anemia.
benign and asymptomatic
 Most G6PD ‐ deficient individuals are asymptomatic ‐ only in
combination with certain environmental factors (sulfa antibiotics,
herbicides, antimalarials, *divicine)do clinical Manifestations
occur.
Metabolism of Monosaccharides
and Disaccharides

MLS 218
OVERVIEW
 Glucose is the most common
monosaccharide consumed by humans, and
its metabolism has been discussed
extensively.
 However, two other monosaccharides—
fructose and galactose—occur in significant
amounts in the diet, and make important
contributions to energy metabolism.
 In addition, galactose is an important
component of cell structural carbohydrates.
 FRUCTOSE METABOLISM

 The major source of fructose is the

disaccharide sucrose, which, when cleaved
in the intestine, releases equimolar amounts
of fructose and glucose.

 Fructose is also found as a free

monosaccharide in many fruits, in honey, and
in high-fructose corn syrup which is used to
sweeten soft drinks and many foods.

 Fructose does not promote the secretion of

insulin.Natural sugars are better "Fructose" bec it does not increase glucose level. It enters glycolysis in stage 2 and disappears
from blood rapidly as the rate of metabolism is faster and that is why no insulin secretion
 PHOSPHORYLATION OF FRUCTOSE
 For fructose to enter the pathways of
intermediary metabolism, it must first be
phosphorylated

 Hexokinase phosphorylates glucose in all cells

of the body, and several additional hexoses can
serve as substrates for this enzyme. However, it
has a low affinity for fructose.

 Hence , Fructokinase provides the primary

mechanism for fructose phosphorylation

 It is found in the liver (which processes most of

the dietary fructose), kidney, and the small
intestinal mucosa, and converts fructose to
fructose 1-phosphate, using ATP as the
phosphate donor.
 CLEAVAGE OF FRUCTOSE 1-PHOSPHATE
 Fructose 1 -phosphate is cleaved by
aldolase B (also called fructose 1-phosphate
aldolase) to dihydroxy-acetone phosphate
(DHAP) and glyceraldehyde.

 DHAP can directly enter glycolysis or

gluconeogenesis, whereas glyceraldehyde
can be metabolized by a number of
pathways,

 The rate of fructose metabolism is more rapid

than that of glucose because the trioses
formed from fructose 1 -phosphate by pass
phosphofructokinase—the major rate-limiting
step in glycolysis.-This explains why
fructose disappears from blood more
rapidly than glucose
 2 fates:
enters into glycolysis
can also lead to formation of glucose

enters into glycolysis

Form glucose in (INDIRECT) formation of glucose (INDIRECT)
Direct pathway for fructose breaks down
(More convenient) bec both are glycolysis
intermediate as the enzyme is always there
the 2nd stage of glycolysis starts here

Trios isomerase
 DISORDERS OF FRUCTOSE METABOLISM
 Fructokinase deficiency-Essential fructosuria
✓ A deficiency of one of the key enzymes required for the entry of
fructose into intermediary metabolic pathways can result in this
benign condition
 Aldolase B deficiency (hereditary fructose intolerance, HFI),
✓ The first symptoms of HFI appear when a baby is weaned and begins
to be fed food containing sucrose or fructose.
✓ Fructose 1-phosphate accumulates, resulting in a drop in the level
of inorganic phosphate (Pi) and, therefore, of ATP.
✓ ATP falls, AMP rises. In the absence of Pi, AMP is degraded, causing
hyperuricemia. When conducting tests:
low inorganic phosphate which means low ATP
High uric acid

✓ The decreased availability of hepatic ATP inhibits gluconeogenesis

(causing hypoglycemia with vomiting), and protein synthesis
(causing a decrease in blood clotting factors and other essential
proteins).
✓ Diagnosis of HFI can be made on the basis of fructose in the urine.
In HFI, sucrose as well as fructose, must be removed from the diet to
prevent liver failure and possible death.
normally= normal amount of uric acid
MANNOSE METABOLISM
 Conversion of mannose to fructose 6-
phosphate
✓ Mannose, is an important component of
glycoproteins.
✓ Hexokinase phosphorylates mannose,
producing mannose 6-phosphate, which, in
turn, is (reversibly) isomerized to fructose
6-phosphate by phosphomannose
isomerase.
✓ There is little mannose in dietary
carbohydrates.
✓ Most intracellular mannose is synthesized
from fructose,
✓ Also exists as preexisting mannose produced
by the degradation of structural carbohydrates
Hexokinase Phosphomannose isomerase
Mannose Mannose-6-phosphate Fructose-6-phosphate
SYNTHESIS OF SORBITOL
Significance of Conversion of glucose to
fructose via sorbitol in seminal vesicles and
liver
• Aldose reductase reduces glucose, producing
sorbitol
Glucose Aldose reductase Sorbitol

• In cells of the liver, ovaries, sperm, and seminal

vesicles, there is a second enzyme, sorbitol
dehydrogenase, that can oxidize the sorbitol to
produce fructose
Sorbitol dehydrogenase
Sorbitol (Oxidized) Fructose

• The two-reaction pathway from glucose to

fructose in the seminal vesicles is for the benefit
of sperm cells, which use fructose as a major
carbohydrate energy source.
 The effect of hyperglycemia on sorbitol metabolism:

 Elevated intracellular glucose

concentrations and a adequate supply
of NADPH cause aldose reductase to
produce a significant increase in the
amount of sorbitol,

 When sorbitol dehydrogenase is low

or absent, for example, in retina, lens,
kidney, and nerve cells sorbitol
accumulates in these cells
excess glucose = excess sorbitol because even if the enzyme is there, it can't convert all sorbitol to
fructose. Sorbitol accumulates in the body (liver, eyes, kidneys....)

 Leading to cataract formation,

peripheral neuropathy, and vascular
problems leading to nephropathy and
retinopathy.
know the difference between
the two reactions
GALACTOSE METABOLISM_
A. Phosphorylation of galactose
Like fructose, galactose must be
phosphorylated before it can be further
metabolized. Most tissues have a specific
enzyme for this purpose, galactokinase,
which produces galactose 1-phosphate
galactokinase galactose 1-phosphate uridyltransferase
Galactose Galactose-1-phosphate UDP-galactose

B. Formation of UDP- galactose

Galactose 1-phosphate cannot enter the
glycolytic pathway unless it is first
converted to UDP-galactose .
The enzyme that catalyzes this reaction
is galactose 1-phosphate
uridyltransferase.
 Use of UDP- galactose as a carbon source
for glycolysis or gluconeogenesis
 For UDP- galactose to enter the mainstream
of glucose metabolism, it must first be
converted to UDP-glucose,
 This "new" UDP-glucose (produced from the
original UDP-galactose) can then participate
in many biosynthetic reactions,
Role of UDP-galactose in biosynthetic
reactions
 UDP-galactose can serve as the donor of
galactose units in a number of synthetic
pathways, including synthesis of lactose (see
below), glycoproteins, glycolipids, and gly-
cosaminoglycans.
for synthesis of complex carbohydrates

glycolysis "Energy generation"

 Disorders of galactose metabolism

Gatactose 1 -phosphate Uridyltransferase is

missing in individuals with classic
GALACTOSEMIA
 In this disorder, galactose 1 -phosphate and,
therefore, galactose accumulate in cells.

 The accumulated galactose leads to galactitol

production. This reaction is catalyzed by
aldose reductase, the same enzyme that
converts glucose to sorbitol. Can lead to
cataract formation
Aldose reductase
Galactose-1-phosphate Galactitol
 LACTOSE SYNTHESIS
 Lactose is a disaccharide that consists of a
molecule galactose attached by a β(1-»4)
linkage to glucose.
 Lactose, known as the "milk sugar,"

 Lactose is synthesized in the Golgi by

lactose synthase (UDP-galactose:glucose
galactosyltransferase),

 This enzyme is composed of two

proteins, A and B.

 Protein A is a β-D-gatactosyl
transferase, and is found in a number of
body tissues. In tissues other than the
lactating mammary gland, this enzyme
produces N-acetyl lactosamine— a N-
linked-glycoprotein. function not related to milk in other tissues
 Cont…
Protein B is found only in lactating
mammary glands. It is a-lactalbumin, and
its synthesis is stimulated by the peptide
hormone, prolactin.
Protein B forms a complex with the
enzyme, protein A, changing the
specificity of that transferase so that
lactose, rather than N-acetyl lactosamine,
is produced both proteins together
produce lactose