Lipid Metabolism

SYAHRIJUITA
BIOCHEMISTRY DEPT OF MEDICAL FACULTY
HASANUDDIN UNIVERSITY
2015
 Topic
2

A. DIGESTIONS AND ABSORPTIONS OF FATS

B. TRANSPORT AND STORAGE OF FATS
C. OXIDATION OF FATS
D. KETOGENESIS
E. BIOSYNTHESIS OF FATS
F. METABOLISM OF LIPOPROTEIN
G. METABOLISM OF KOLESTEROL
H. METABOLISM OF EIKOSANOID
 Introduction

“Biological molecules that are insoluble in aqueous solutions and soluble

in organic solvents, have some relation to fatty acids as esters, and have
potentiality of utilization by living organisms are classified as lipids.”

They perform four major physiological functions:

1. Serve as structural components of biological membranes

2. Provide energy reserves, predominantly in the form of
triacylglycerols
3. Both lipids and lipid derivatives serve as vitamins and
hormones
4. Lipophilic bile acids aid in lipid solubilization
 Classification
Bloor’s Classification
A. Simple lipid - ester of fatty acids with various alcohols
1. Natural fats and oils (triglycerides)
2. Waxes
(a) True waxes: cetyl alcohol esters of fatty acids
CH3 CH3 CH3

(b) Cholesterol esters E E E E

OH

(c) Vitamin A esters CH3

CH3

(d) Vitamin D esters

B. Compound lipid - esters of fatty acids with alcohol plus other groups
1. Phospholipids and spingomyelin: contains phosphoric acid and
often a nitrogenous base
2. Spingolipids (also include glycolipids and cerebrosides):
contains aminoalcohol spingosine, carbohydrate, N-base;
glycolipids contains no phosphate
3. Sulfolipids : contains sulfate group
4. Lipoproteins : lipids attached to plasma/other proteins
5. Lipopolysaccharides: lipids attached to polysaccharides
 Classification cont.
C. Derived lipids – hydrolytic products of A & B with lipid characters
1. Saturated & unsaturated fatty acids
2. Monoglycerides and diglycerides
3. Alcohols (b-carotenoid ring, e.g., vitamin A, certain carotenoids)
D. Miscellaneous lipids
1. Aliphatic hydrocarbons: found in liver fat and certain
hydrocarbon found in beeswax and plant waxes
2. Carotenoids
3. Squalene : found in shark and mammalian liver and in
human sebam; an important intermediate in biosynthesis
of cholesterol
4. Vitamin E and K
 Structure of lipids

The figure is found at http://courses.cm.utexas.edu/archive/Spring2002/CH339K/Robertus/overheads-2/ch11_lipid-struct.jpg

(Jan 2007)
7
 Phospholipids

 They are first and for most structural components

of membranes
 Serves as emulsifying agents and surface active
agents
 They are amphipathic molecules
 They are of two types : phosphoglycerides and
spingomyelins (contains spingosine instead of
glycerol)
 Ceramide is the core structural unit of spingolipids
which is a fatty acid amide derivative of spingosine
Major Classes of Phospholipids
 Figure 48

Components of Sphingolipid
I. LIPID: PENGERTIAN & KLASIFIKASINYA
 Lipid merupakan kelompok
11 heterogen dari
senyawa yang lebih berkerabat karena sifat
fisiknya dibandingkan sifat kimianya.
 Sifat umum lipid :
- Relatif tidak dapat larut di dalam air
- Larut di dalam pelarut non polar seperti eter,
kloroform, dan benzen.
 Pengetahuan tentang biokimia lipid amat penting
untuk memahami banyak bidang biomedis
mutakhir, seperti obesitas, aterosklerosis, dan
peran asam lemak tak jenuh ganda pada bidang
gizi & kesehatan.
12
 Lipases
name source location of function properties
its action
acid stable stomach stomach hydrolysis of TAG stability in
lipase composed of short low pH
chain fatty acids
pancreatic pancreas small hydrolysis of TAG needs
lipase intestine to 2 fatty acids pancreatic
and colipase
2-monoacylglycerol
lipoprotein extra- inner hydrolysis of TAG activated
lipase hepatic surface of found in VLDL by
tissues blood and chylomicrons apoC-II
vessels
hormon adipocytes cytoplasm hydrolysis of activated
sensitive of reserve by
lipase adipocytes triacylglycerols phosphory-
lation
acidic lipase various lysosomes hydrolysis of TAG acidic pH-
tissues optimum
 Releasing of free
fatty acids from TAG
of fatty tissue
and their followed
transport
to target cells

The figure is found at

http://courses.cm.utexas.edu/archive/Spring2002/CH339K/Robertus/o
verheads-3/ch17_lipid-adipocytes.jpg (Jan 2007)
The figure was accepted from the book: Grundy, S.M.: Atlas of lipid disorders, unit 1. Gower Medical Publishing,
New York, 1990.
 Metabolism

The hydrophobic and highly reduced structure of

triglycerols allows them to serve as a compact and
rich source of energy (e.g., in average U.S. diet, 30 –
40% of calories are provided by fat). The metabolism
of lipids include the degradation and synthesis and
regulation of these processes. A major emphasis is
placed on the role of the central metabolite in lipid
metabolism: acetyl-CoA.
Metabolisme LIPID
 Metabolism of LIPID

Degradation of Lipid  Oksidation of FA

b-oksidations of FA
 Ketogenesis

Biosintesis Lipid
 Biosynthesis of FA
 Biosynthesis of triasilgliserol
 Biosynthesis of fosfolipid
 Biosynthesis of Lipoprotein
 Biosynthesis of cholesterol and steroid
 Biosynthesis of Eichosanoid
 β oxidations

Why beta-
oxidations?
 β oxidations of FA

substrate: acyl-CoA
product: n acetyl-CoA, n NADH + H+, n FADH2
function: gain of energy from fatty acids
subcelullar location: matrix of mitochondria
organ location: liver, skeletal muscles and
other tissues with expection to CNS
regulatory enzyme: carnitine acyltransferase
I

23
24
Transfer of acyl-CoAs from cytoplasm to the mit. matrix is
performed by a carnitine transporter

25
β-oxidation of fatty acids

26
27
 Ketone Bodies

Most of the acetyl-CoA product during fatty acid oxidation is

utilized by the citric acid cycle or in isoprenoid synthesis. In
a process called ketogenesis, acetyl–CoA molecules are used
to synthesize acetoacetate, b-hydroxy butyrate and acetone, a
group of molecules called the ketone bodies

Ketone body formation occurs within mitochondria

Ketone bodies are used to generate energy by several

Tissues, e.g., cardiac and skeletal muscle and brain
Synthesis of ketone bodies (ketogenesis)

 substrate: acetyl-CoA
 product: acetoacetate, 3-hydroxybutyrate, acetone
 function: energy substrate for extrahepatal tissues
 subcelullar location: matrix of mitochondria
 organ location: liver

Excessive production of ketone bodies is typical during

starvation or diabetes mellitus:
↑ lipolysis → ↑ FA → β-oxidation of FA → excess of
acetyl-CoA → ↑ ketogenesis
Ketone Body Formation
Ketogenesis

31
Conversion of Ketone Bodies to Acetyl-CoA
 Ketosis
In normal metabolic pathway, acetoacetate and b-
hydroxybutyrate are the ketone bodies which are
converted to acetyl - CoA. However, during starvation and
in uncontrolled diabetes, conc. of acetoactate is very high
and supply of oxaloacetate (a TCA component) is
insufficient, thus acetoacetate spontaneously
decarboxylated to acetone - KETOSIS

 A 4-carbon acid (oxaloacetate) is needed to react with excess acetyl-CoA

and form citrate
 When OAA is not available excess acetyl - CoA in liver are condensed to
form ketone bodies
 OAA is limited during scarcity of glucose for glycolysis. In starvation and
diabetes, glycogen is broken down. Fatty acids of fat depots are
metabolized to supply ATP needs producing excess of the ketone bodies
34
BIOSYNTHESIS OF FATS
35
36
37
38
Metabolism of lipoproteins

Figure was assumed from www.media-2.web.britannica.com/eb-media/42/96842-...

40
 Lipoproteins

● Chylomicrons carry TAG (fat) from the intestine to the liver and
adipose tissue
● VLDL carry (newly synthesized) TAG from the liver to peripheral
tissues
● IDL are intermediate between VLDL and LDL
● LDL carry cholesterol from the liver to cells of the body
● HDL collects cholesterol from body´s tissues and brings it back to
the liver
Figure was assumed from http://http://www.britannica.com/EBchecked/topic-art/720793/92254/Cutaway-view-of-a-low-
density-lipoprotein-complex-The-LDL
 A Summary of the Relative Amounts of Cholesterol,
Cholesteryl Ester, Phospholipid, and Protein in Four
major Classes of Plasma Lipoproteins
Lipoproteins are Responsible for Transport and
Mobilization of Fat
Fig. 17-2 Lehninger POB 4th Ed.

 Chylomicrons are formed

from fat absorption
 VLDL secreted by liver
have analogous (but not
identical) structure
i.e. phospholipid shell with
apolipoproteins (and
varying amounts of
cholesterol) and TAG core
 Function “differs” –
chylomicrons from meals,
VLDL between meals
 Chylomicrons vs. VLDL

 Made by intestine  Made by liver

 90-1000 nm  30-90 nm diameter
diameter  Density 0.95-1.006
 Density <0.95  7-10% protein
 1-2% protein  56% TAG
 88% TAG  20% PL
 8% PL  15% CE
 3% CE  8% C
 1% C  1% FFA
 trace FFA
45
46
 Lipoproteins
 Low Density Lipoproteins (LDL) – is
made by the liver and is comprised of
cholesterol that is delivered to the cells in
the body
 High levels of LDL is strongly correlated
with heart disease
 High Density Lipoproteins (HDL) - made
by the liver and picks up cholesterol from
the cells fro recycling or excretion
 High levels of HDL is inversely
correlated with heart disease
 It is protective
 Synthesis of cholesterol
 substrate: acetyl-CoA
 product: cholesterol
 function: de novo synthesis of endogenous cholesterol
 subcelullar location: cytosol and endoplasmic reticulum
 organ location: liver, intestine, adrenal cortex, ovaries,
testes and placenta make the largest contributions to
the body´s cholesterol pool

Cholesterol is a constituent of cellular

membranes and it is present in all animal
tissues.
 Cholesterol
 Plant and animal food contain sterols but only
animal food contain cholesterol
 Why? Cholesterol is made in the liver and plants
do no have a liver
 Cholesterol is needed to make bile, sex
hormones, steroids and vitamin D.
 It is the constituent of cell membrane structure
 Dietary recommendation - <300 mg/d
 Sources – egg yolks, liver, shellfish, organ foods
50
 Regulation of cholesterol synthesis
 reduction of HMG-CoA to mevalonic acid is catalyzed
by HMG-CoA reductase – rate-limiting and key
regulatory step
 expression of HMG-CoA
reductase gene is inhibited
by cholesterol

● activity of HMG-CoA
reductase is increased
by insulin and thyroxine
but glucagone has the opposite effect
Figure was adopted from textbook T. M. Devlin et al.: Textbook of Biochemistry With Clinical
Correlations, 4th ed.
52
53
 Blood levels for Lipids

 Total Cholesterol:
 <200 mg/dl = desirable
 200-239 mg/dl = borderline
hyperlipidemia
 >240 mg/dl = hyperlipidemia

 LDL < 130 mg/dl is favorable

 HDL > 35 mg/dl is favorable
VI. EIKOSANOID
56
57
Selected Examples of Eicosanoids
 Key Features of Eicosanoids

 Prostaglandins contains a cyclopentane ring with hydroxy

group at C - 11 and C - 15 (pain, fever, ovulation, uterine
contraction, gastric secretion inhibition)
 Thromboxanes possess a cyclic ether in their structures; TxA2 is
the most prominent member of this group and is primarily
produced by platelet (clotting)
 Leukotrines are hydroxy derivatives possessing conjugated
trienes ; early discovery was in leukocites. LTC4, LTD4
and LTE4 are “ slow - releasing substance of anaphylaxis ” (
SRS - A ) , cause fluid leakage from blood vessels to inflamed
area. LTB4 is a potent chemotactic agent
Biological Actions of Selected
Eicosanoid Molecules
61
62
H) Effects of Eicosanoids (Fig. 17-25) – KNOW ALL OF THESE!!
1) many varied effects
2) Tromboxane A2 (TXA2) – promotes blood clots by causing platelet
aggregation and vasoconstriction. Prostacyclin (PGI 2) inhibits
platelet aggregation and causes vasodilation, and inhibits
thrombogenesis, by acting on nucleated endothelial cells. Aspirin
blocks both by covalently attaching to COX-1 and inactivating it
(Fig. 17-24). But endothelial cells can synthesize more COX-1 and
make PGI2, while
anucleated platelets
cannot synthesize
more TXA2. Basis for
low-dose aspirin
therapy for lowering
stroke and heart attack
risk by lowering
thrombi formation.
3) COX-2 inhibitors may
cause increased risk
of heart attack and
stroke (Vioxx recall).

63
Lipid Metabolism
Lipid Metabolism
Integrasi Metabolisme Lipid

66
 Lipids Disorder

 Lipids deficiency (Shortage

in Lipids intake)
 Lipids exceeding
(Overtaking in Lipids intake)
 Hasil Pemeriksaan Lipid Darah yang Ideal
(Setelah puasa minimal 12 jam)
68

 Kolesterol total = 120-200 mg/dl

 Kilomikron = negatif
 VLDL = 1-30 mg/dl
 LDL = 60-160 mg/dl
 HDL = 35-65 mg/dl
 Perb. LDL / HDL = < 3,5
 Triasilgliserol = 10-160 mg/dl
 Lipids Deficiency

 Fat should comprise of 3% of total

calories to prevent fatty acid
deficiency
 Fatty acid deficiency syndromes
 Dry scaly skin, dermatitis (Linoleic
acid deficiency)
 Hand tremors (Prostaglandin
deficiency)
 Inability to control blood pressure
 Lipids Exceeding

 Fat should comprise not more than

30% of total calories to prevent lipids
exceeding
 To prevent overtaking, we should
consume fat breakdown (% total
calories)
 <8% from saturated fat
 10% from polyunsaturated fat
 10-15% from monounsaturated fat
 Body Mass Index

 Current best single gauge for body fat

 BMI =(Weight in Kg)/((Height in cm )(Height in
cm)) X 10,000

BMI Weight Status

Below 18.5 Underweight
18.5 – 24.9 Healthy Weight
25.0 – 29.9 Overweight
30.0 and Above Obese
 Health Problems

 Energy Intake > Energy needed =

Lipids overtaking
 Develop medical problem
 Cancer
 Heart disease
 Diabetes
 Obesity
 High blood pressure
 High blood cholesterol
 Fredrickson’s Classification of
Hyperlipoproteinemias - Robbins page 508
 Type I

 Hyper TG
 Chylomicrons
 Serum milky
 High cholesterol
 High TG
 < 1%
 No Atherosclerosis
 Rx:Diet, No alcohol
 Type I

 Hyper TG
 Chylomicrons
 Serum milky
 High cholesterol
 High TG
 < 1%
 No Atherosclerosis
 Rx:Diet, No alcohol
 Type I

 Hyper TG
 Chylomicrons
 Serum milky
 High cholesterol
 High TG
 < 1%
 No Atherosclerosis
 Rx:Diet, No alcohol
 Type I

 Hyper TG
 Chylomicrons
 Serum milky
 High cholesterol
 High TG
 < 1%
 No Atherosclerosis
 Rx:Diet, No alcohol
Type II

 High cholesterol
 Clear serum
 Xanthelasma
 Corneal Arcus
 Atheroscler. +++
 4 genetic
Conditions
Autosomal Dominant
Type II

 Tendon &
Tuberous Xanthomas
 10% IIA
Only cholesterol
 40% IIB (!!!)
Both chol & TG
 Rx Diet, drugs
A 40 year-old man
to the ER for
evaluation of chest
pain AND severe
“heartburn”.

The Achilles
tendons bilaterally
have painless,
fleshy, faintly yellow
lesions:

DIAGNOSIS?
 Primary vs. Secondary
Hypercholesterolemias

Cholesterol elevated in:

 Cholestasis, intra- or extra-hepatic
 Nephrotic Syndrome
 Hypothyroidism
 Oral Contraceptives
 Normal Pregnancy
 Acute Intermittent Porphyria (AIP)
 Macroglobulememia … & other conditions
 Type III

 Rare electrophoretic pattern of abnormal LP

 Atherosclerosis +++ (atherogenic)
 Remnant chylomicrons & IDL Intermediate
 Mutation in apolipoprotein E
 TG & cholesterol both greatly elevated
 Uncommon not rare < 1 % of primary LP
 Rx : Diet & reduction in weight
 Type IV (2 different genetic)

 Increase in VLDL & TG

 Possibly atherogenic
 Common: 45% of cases (Rx diet & drugs)
 Example: mutation in LP lipase gene
 Secondary hypertriglyceridemias in:
Non-fasting specimen (most common)
Diabetes, Acute alcoholism,Oral contraceptives,
Nephrotic syndrome, CRF, Steroids, Acute
pancreatitis, Gout, Gram negative infections,etc.
 Type IV (2 different genetic)

 Increase in VLDL & TG

 Possibly atherogenic
 Common: 45% of cases (Rx diet & drugs)
 Example: mutation in LP lipase gene
 Secondary hypertriglyceridemias in:
Non-fasting specimen (most common)
Diabetes, Acute alcoholism,Oral contraceptives,
Nephrotic syndrome, CRF, Steroids, Acute
pancreatitis, Gout, Gram negative infections,etc.
 Type IV (2 different genetic)

 Increase in VLDL & TG

 Possibly atherogenic
 Common: 45% of cases (Rx diet & drugs)
 Example: mutation in LP lipase gene
 Secondary hypertriglyceridemias in:
Non-fasting specimen (most common)
Diabetes, Acute alcoholism,Oral contraceptives,
Nephrotic syndrome, CRF, Steroids, Acute
pancreatitis, Gout, Gram negative infections,etc.
 Type
V

 Pancreatitis
 Eruptive
Xanthomas
 Adults
 ? atherosclerosis
 5% of total
 DM,Alcohol
 Rx Diet,drugs
 Hypolipidemia

 Hypolipidemia (Hypoproteinemia) - rare

familial disorders or secondary to
hyperthyroidism, malabsorption, malnutrition e.g.
AIDS, cancers
 Hypo-alphalipoprotenemia (Low HDL)
associated with increased CAD: genetic or
secondary to obesity, sedentary, cigarettes,
diabetes, nephrotic syndr., medications (beta-
blockers, diuretics, steroids, progestationals,..)
lack of red wine…
In about 10 % of population - important
 Hypolipidemias (continued)

 Hypo-beta-lipoproteinemia, rare inherited

reduced LDL gene mutation of apo B
 Total cholesterol 70-120 mg/dl
 Decreased CAD & so called together with familial
hyper-alpha lipoprotenemia … “longevity syndr”
 Familial alpha-Lipoprotein Deficiency or Tangier’s
disease (see next slide)
 A-beta-lipoproteinemia or Bassen-Kornzweig
Syndrome (see slide after that)
Ketone Bodies
 Sphingolipidoses

Disorder Lipid Accumulation Enzyme Deficiency Primary Organ Involvement

Generalized Ganglioside GM1 GM1 ganglioside: brain, liver, skeleton

Gangliosidosis b -galactosidase

Tay-Sachs Disease Ganglioside GM2 b -Hexosaminidase A brain

Gaucher Disease Glucocerebroside Glucocerebrosidase brain, liver, spleen

Metachromatic b-Sulfogalactocerebroside Arylsulfatase A brain

Leukodystrophy

Krabbe Disease Galactocerebroside Galactosylceramide brain

b -galactosidase

Sandoff-Jatzkewitz Globoside and b -Hexosaminidase brain

Disease Ganglioside GM2 A and B

Fabry Disease Ceramide trihexoside a-Galactosidase A kidney

Niemann-Pick Disease Sphingomyelin Sphingomyelinase brain, liver, spleen

Farber Disease Ceramide Ceramidase joints, liver, spleen

Fucosidosis Pentahexosylfucoglycolipid a-Fucosidase brain, nerves, skin

91
 Prevention of Lipid Disorder

 Reduce fat
 Cut down on high fat foods
 E.g. butter, margarine, oil,
mayonnaise
 Consume small amounts of
unsaturated fats
 Donot eliminate fat completely
since it is high in calories
 Prevention of Lipid Disorder
 Limit added sugar and alcohol
 Added sugar and alcohol are ‘empty
calories’
 Watch portions of all food
 ‘fat free’ ≠ ‘calorie-free’
 Drink at least 8 glasses of water
everyday
 Water is calorie-free, refreshing, and
filling
 Prevention of Lipid Disorder

 Increase intake of vegetables,

fruits, and whole grains
 Loaded with fiber
 Contain high amounts of vitamins,
minerals, and phytonutrients
 Include low-fat protein-rich food
with every meal
 E.g. tofu, beans, eggs, and fish
 Prevention of Lipid Disorder

 Slow down when eating

 Toofast eating will exceed calorie
needs before realizing we are full
96

Thank
you