333
DISEASES OF LIPID METABOLISM
LECTURE NOTES ONLY
(no video associated clips)
Topic Outline
A.
B.
C.
D.
E.
F.
G.
Fatty Acids
F.A. Synthesis
Lipid Degradation
Eicosanoids
Glycerolipids
Sphingolipids
Lipoproteins / Cholesterol
__________________________________________________
A. Fatty Acids
Dietary notes: 1. Most saturated (and mono-unsaturated) fats are from animal products
but a considerable amount is derived from coconut and palm oils
2. Poly-unsaturated (ω - 6) are present in corn, soybean and safflower oils
3. Poly-unsaturated (ω - 3) are found in canola (rape-seed) and fish oils
4. Human breast milk is rich in long-chain fatty acids: 16:0 / 18:1 / 18:2
which are required for proper brain development
5. Cow=s milk is rich in short / medium chain fatty acids but is deficient in
long-chain fatty acids (hence, poor for infant development)
6. Milk lipids are present in the form of triglycerides. Thus, a lipase is
required to free the fatty acids. The infant pancreas is low in pancreatic
lipase. However, infant salivary and gastric secretions are good
sources of lipase. In addition, human milk also contains lipase activity.
These lipases are able to tolerate the low pH of the infant stomach.
7. The apparent optimal triglyceride diet should contain no more than 30%
triglyceride. However, the Awestern diet@ consists of more than 40%
triglyceride.
8. The proportions of various lipids in the Awestern diet@ is approximately:
a. 35% saturated
b. 40% unsaturated
c. 15% poly-unsaturated but>should be 25-35%@
9. At least 3% of the total dietary calories should be 18:2 (linoleic acid,
ω-6) to avoid fatty acid deficiency
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Fat Malabsorption Syndromes: (most dietary lipid is absorbed in the small intestine)
Causes:
1. Shortened bowel Syndrome (due to surgical removal of a portion of the
bowel (eg., Crohn=s, cancer, obstruction)
2. Whipple=s Disease (a GI mucosal disease)
3. Crohn=s Disease (ileal problem accompanied by decreased bile
reuptake)
4. Zollinger Ellison (hyper-acidity which overwhelms neutralization of the
duodenal contents; therefore pancreatic lipase is inactive
5. Blocked lymphatic drainage prevent chylomicrons from reaching the
thoracic duct
Effects: (fat malabsorption can result in EFA - essential fatty acid - deficiencies)
1. Skin problems include
- dry, flaky skin due to loss of moisture;
- ecchymoses, large reddish patches due to bleeding from the
capillary beds due to lack of the fat soluble Vit K vitamin
2. Increased occurrence of kidney stones rich in oxalates
- many fruits are rich in oxalates
- normally, dietary oxalates are eliminated in feces by chelating with
divalent cations like Ca++, Zn++ and Mg++. However, when lipids are
not absorbed by the GI mucosa, the fatty acids tend to bind the
divalent cations and leave the oxalate to be absorbed into the blood.
Once there, they tend to precipitate out, especially in the urine they
become less soluble in the low pH of the urine. This results in oxalate
stone deposition.
3.
Because free fatty acids are able to chelate divalent cations like Ca++,
Zn++ and Mg++, these cations are also lost in the feces which can lead
to reduced blood levels of these essential minerals.
TRANS-Fatty Acids
Structures:
Most dietary oils (corn, soy, safflower) are poly-unsaturated fatty
acids. These fatty acids have naturally occurring cis-double-bonds.
The cis-bonds block Atight-packing@ of the fatty acid chains - hence
the oily property of these lipids. They are liquid at room temperature.
In an attempt to make these oils mimic the consistency of butter, the
food industry Ahydrogenates@ the oils - that is, attempts to reduce
some of the cis-double bonds to single bonds which make the fatty
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acids more saturated. This process renders the fatty acids less fluid
at room temperature. However, the process of Ahydrogenation@
also converts many of the cis-double bonds to trans-bonds. The
newly made Atrans-fatty acids@ also pack more tightly that cis-fatty
acids, they contribute to the solidification of the oils.
The Apartially hydrogenated@ oils can be up to 50% cis-trans (racemic
mixture) and because of their solidifying properties are used in baking,
especially for pies, cooking and deep frying.
By comparison, the trans-fatty acid composition of various lipids:
naturally occurring butter
= 2-7 % trans
margarine (tub-type)
= 10 % trans
margarine (stick-type) = 30 % trans
frying lards (deep frying)
= 40 % trans
While the trans-fatty acids are better for cooking, they have an undesirable
metabolic effect.
Problems with TRANS-FATTY ACIDS:
1.  LDL cholesterol in serum and contributes to coronary artery disease
(C.A.D.)
(The proposed mechanism is that the trans-fatty acids  synthesis of Apo A
which results in a  in HDL production. (Recall, the HDL is used to activate
LCAT and the transfer of cholesterol from LDLs to HDLs.)
2.  in serum triglycerides
(The mechanism is thought to be due to incorporation of the trans-fatty acids
into the mitochondrial membranes and endoplasmic reticulum. This results
in reduced mitochondrial β-oxidation of fatty acids (hence, increased serum
TG) and reduced activity of the Δ6 desaturase enzyme in the smooth
endoplasmic reticulum. This enzyme is used in the conversion of 18:2 ω6 to
arachidonic acid and therefore a decrease in the desaturase could mimic an
essential fatty acid deficiency.
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Omega - 3 Fatty Acids
Notes:
1.
2.
3.
4.
Are long-chain (22-26) polyunsaturated fatty acids
Found in high concentration in retina, brain (cortex), testes, and sperm
Supplied to infants in breast milk - also as ADHA@ formula supplements
Role in vision:
a. The retina requires highly fluid membranes into which rhodopsin is
embedded. The ω-3 (PUFA) apparently contribute to this fluidity.
b. Patients with Retinitis Pigmentosa have reduced ω-3 fatty
content in their retinas. This disease has a mild form (autosomal
recessive) and a severe form (sex-linked recessive). The genetic
component may result from an inability to elongate and/or desaturate
PUFAs or with tailoring of retinal membrane phospholipids. The
disease is characterized by a loss of peripheral vision, loss of night
vision and blindness.
B.
F.A. Synthesis
1. General Notes:
A.
B.
C.
In humans, the liver synthesizes more fatty acids than do the adipocytes.
The opposite is true in rats.
The principle substrate for FA synthesis is carbohydrate (glucose)
Diseases of FA synthesis are extremely rare. When present, the diseases
are due to problems with control rather than with defects in the F.A.
Synthase enzyme.
1.
Regulation of FA synthesis
a. Availability of Carbohydrates: (recall synthesis)
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b. Note that glucose is a good substrate BUT also notice that
fructose (from sucrose and fruit) would be an even better
substrate because:
1. Citrate from the TCA cycle blocks PFK I of glycolysis
2. Fructose metabolism bypasses the regulation of PFK I
Thus, people desiring to loose weight by eating more fruit
and fruit juices may actually be contributing to their obesity by
enhancing de novo fatty acid synthesis.
c. The key regulatory step of FA synthesis is the conversion of
acetyl~CoA to malonyl~CoA by acetyl~CoA carboxylase
(malonyl~CoA synthetase)
NOTE: If biotin is absent in the diet (very rare), or more commonly, if
raw eggs are eaten (which contain Aavidin@ - a biotin binding
protein) or if a Abiotinidase deficiency@ exists which biotin is not
recycled, then the carboxylation reaction cannot occur.
If this should happen, the acetyl~CoA is shunted toward cholesterol
biosynthesis and can lead to Ahypercholesterolemia.@
d. Branched and odd chain fatty acids can be present in the diet.
While rare, they do exist and are metabolized via propionyl~CoA
into succinyl~CoA similar to the pathway for the branched chain
amino acids. This pathway requires Vitamin B12 for conversion of
methyl malonyl~CoA into succinyl~CoA by methyl malonyl mutase.
If a Vitamin B12 deficiency occurs and if odd-chain and/or branched
chain fatty acids are ingested, it is possible to have an accumulation
of the propionic acid appearing in the urine.
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2. Dietary intake of lipids inhibits F.A. Synthase
Increases in serum free fatty acids (due to dietary sources as well as due to release from
adipocyte triglycerides during fasting) inhibit acetyl~SCoA carboxylase.
A.
Low Serum Free Fatty Acids + High Synthesis: After a meal low in lipid, any
available fatty acids appear in the chylomicrons as triglycerides. However,
as the dietary lipid intake exceeds 10%, there is a marked decrease in fatty
acid synthesis. Under these conditions, virtually no carbohydrate
conversion to fatty acid takes place.
B.
High Serum Free Fatty Acids + Lowered Synthesis: Occurs during a
transition from well-fed to fasting. The increase in free fatty acids comes
from adipocyte triglyceride mobilization. Fatty acid synthesis is most
sensitive to inhibition by free fatty acids at this time.
C.
Low Serum Free.Fatty Acids +- Low Synthesis: Occurs during moderate severe fasting. Although adipocyte fatty acids are being mobilized,
peripheral tissues are consuming the fatty acids for energy and are sparing
their glucose - hence, little fatty acid synthesis takes place. Inhibition of
FAS occurs at two levels: (a) allosteric inhbition of acetylCoA carboxylase
and (b) genetic inhibition of FAS transcription.
3. Hormonal Regulation of F.A. Synthesis
Insulin=s effect on Fatty Acid Synthesis:
 glucose uptake (in adipocyte)
 [DHAP] for TG asembly
 pyruvate for de novo synthesis
 PDH activity (adipocyte only)
 acetyl~CoA carboxylase
activity via dephosphorylation
f.  cAMP (inhibits HSL / lipolysis)
g.  synthesis (at genetic level) of
fatty acid synthease and
acetyl~CoA carboxylase
a.
b.
c.
d.
e.
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4. Obesity is an extremely complex subject.
A. Genetic component:
B. Virtually all (>99%) of obesity is due to excessive caloric intake and is
NOT due to de novo biosynthesis defects.
C. The number of adipocytes increases until the end of adolescence
(hyperplasia). After this time, the size of the adipocytes will continue to
increase (hypertrophy).
D. Weight reduction leads to a  in the size of adipocyte cells not  in number.
E. However, weight reduction also leads to an  in the amount of lipoprotein
lipase which leads to more efficient extraction of lipids from chylomicrons
and VLDL=s.
5. Disease processes related to de novo lipid biosynthesis
A.  Production of Apo B48 and Apo B100
These apolipoproteins are required for the proper synthesis of chylomicrons
and VLDLS in the intestine and liver, respectively. The absence of these
Apo B proteins is known as Aabetalipoproteinemia@ and is characterized by
serious neural defects and RBC deformities.
B.  Production of LPL (Lipo-Protein Lipase)
Once chylomicrons and VLDLs are assembled, their triglycerides are
extracted in peripheral tissues by the action of LPL found attached to
endothelial cells of capillaries.
If this enzyme is deficient, chylomicrons and/or VLDLs will accumulate in
the serum. This can lead to eruptive xanthomas on the hands, feet and
buttocks.
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C. Lipid Degradation
1. TG mobilization from adipocytes
a. This is ATHE@ control step in lipid (fatty acid) degradation. Triglycerides are
mobilized by increased activity of the hormone sensitive lipase. This enzyme is
inhibited by insulin (well-fed-conditions) but is stimulated by glucagon (fasting),
epinephrine (stress), ACTH (stress), and growth hormone. Control over the
hormone sensitive lipase occurs by cAMP/protein kinase phosphorylation similar to
that of the glycogen degradation cascade.
b. Triglyceride degradation in the adipocyte results in the release of glycerol and
three fatty acids. The reaction is not reversed because re-esterification of the
glycerol requires that it be phosphorylated into α-glycerol phosphate. Since
adipocytes do not possess a glycerol kinase, the glycerol is Aforced@ to leave the
adipocyte along with the three fatty acids. This prevents a Afutile cycle@ from
taking place as triglycerides are degraded. The glycerol is relatively soluble in
water and is transported to the liver which does contain glycerol kinase. Hence, the
glycerol moiety of the triglyceride enters glycolysis (via DHAP) in the liver.
c. The free fatty acids released from the adipocyte triglyceride are Apicked up@ by
serum albumin. This is necessary because of the hydrophobic nature of the fatty
acids. Under conditions when serum albumin levels are low (i.e., during severe
starvation or malnutrition), the release of free fatty acids will contribute to a low
serum pH.
d. A condition has been identified called Aanalbuminemia@ in which patients make
little or no serum albumin. While one would expect these patients to exhibit high
concentrations of free fatty acids in the serum plus a severely decreased serum pH,
frequently the patients are Aasymptomatic.@ The explanation for their lack of
symptoms is that other serum proteins are capable of carrying the free fatty acid
released from the adipocytes.
e. Once albumin-bound free fatty acids reach the liver, a cytosolic fatty acid binding
protein Apicks-up@ the fatty acids and holds them within the hepatocyte.
Presumably, other peripheral tissues, such as skeletal muscle have a similar
binding protein.
2. FA Activation
a. Hepatic degradation of fatty acids requires that they be Aactivated@ as
acyl~SCoA. This reaction is catalyzed by Acyl~CoA synthetase.
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b. Fatty acid activation is required for all fatty acids. However, the long and very
long chain fatty acids are activated by a cytosolic enzyme, whereas the short and
medium chain fatty acids can be activated by an cytosolic as well as mitochondrial
enzyme.
c. There are no diseases known that are related to a deficiency in this enzyme.
3. FA Transport into mitochondria requires carnitine
a. Carnitine synthesis requires two essential amino acids, lysine and methionine. If
either amino acid is deficient in the diet (eg, malnutrition, starvation or Kwashiorkor)
and if carnitine is not supplied in the diet, fatty acids cannot be utilized for energy.
b. Recall that carnitine is utilized as a carrier for fatty acid transport into the
mitochondrion. The transport process is not energy dependent but it does rely
upon three enzymes - carnitine acyl (palmitoyl) transferase I and II (CPT I, CPT II)
and a translocase.
A number of diseases have been identified where these enzymes are deficient. In
each case, fatty acid degradation is impaired. Defects have been shown in:
TISSUE
RESULTING EFFECT
liver
hypoketotic hypoglycemia
muscle
heart
muscle pain, loss of muscle tissue,
myoglobinuria, renal failure
cardiomyopathy, calcification in and
around ventricles
These diseases demonstrate the importance of fatty acid degradation in these
tissues. Occasionally, treatment of these patients with excess amounts of dietary
carnitine will have a beneficial effect.
4. Fatty Acid β-Oxidation
a. The first reaction of fatty acid β-oxidation is catalyzed by FAD dependent
dehydrogenases. There is a different dehydrogenase for each Alength@ of fatty
acid:
short, medium, long and very long chain fatty acid
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.
b. Defects related to the acyl dehydrogenase have been identified. Each defect
leads to an intracellular accumulation of lipid, especially in the brain and the liver.
c. MCAD is decreased in patients with SIDS (Sudden Infant Death Syndrome
d. REYE=S Disease (Syndrome) can occur spontaneously (without known cause)
and can be induced in infants treated with aspirin. In both instances, the MCAD
appears to be defective. Liver problems are associated with increased intracellular
lipid accumulation and increased levels of SGPT (ALT) and SGOT (AST). Brain
problems are manifested as seizures, coma and death due to cerebral edema.
There is no cure for Reye=s Syndrome. However, patients are often treated with
hypertonic IV solutions in order to remove fluid from the brain and with mechanical
respiration.
D. Eicosanoids (Prostaglandins and Leucotrienes)
Review Notes:
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E. Glycerolipids - focus on their role in lung surfactant
(Hyaline membrane disease - Infant Respiratory Distress Syndrome)
1. Glycerolipids differ from sphingolipids in that the backbone structure of the glycerolipids
is a glycerol molecule. Most often, each of two adjacent hydroxyl groups on the glycerol
are esterified with a fatty acid. Glycerophospholipids also contain a phosphate (ester) and
frequently a nitrogen containing moeity (also esterified) on the third hydroxyl group of the
glycerol. The most common glycerolipids are phosphatidyl choline, phosphatidyl serine,
phosphatidyl ethanolamine and phosphatidyl inositol.
2. The glycerolipids play a number of roles in addition to forming the bilayer structure of
cellular membranes. Some of these roles include providing the precursor arachidonic acid
for prostaglandin and leukotriene biosynthesis and they also provide second messengers
such as diacyl-glycerol (DAG) and inositol polyphosphate (IP 3).
3. Due to the amphipathic (polar + nonpolar) properties of the phospholipids, they also
play an extremely important role as detergents, especially in the developing fetal/infant
lung. Because the detergent properties of the phospholipids increases the surface area of
oil-water interfaces, a collection of these molecules is called Asurfactant@.
4. In the developing lung, surfactant is produced by Type II pneumocytes. The surfactant
consists of a mixture of phosphatidyl glycerol, sphingomyelin, cholesterol and proteins.
However, the major component (>80%) is dipalmitoyl-phosphatidyl-choline (DPPC). The
DPPC is one of the last components to be added to the surfactant mixture and is essential
for preventing alveolar wall cohesion.
5. During the last several days of a full term pregnancy, the stress experienced by the
fetus results in the secretion of fetal and maternal cortisol. This hormone stimulates a
large increase in DPPC (surfactant) production. Delivery of premature infants, however,
results in lesser amounts of surfactant production. The following graph demonstrates the
relative production of two important surfactant components, DCCP and sphingomyelin.
343 a
6. At 34 weeks, the L:S ratio is approximately 2:1. This is the minimum composition of
surfactant for normal lung inflation. As the ratio increases toward term (40 wks), the
surfactant increases in effectiveness. Prior to 34 wks, however, the lower ratio can be
predictive of infantile respiratory distress. For example, amniotic fluid analysis done at 34
wks resulting in an L:S: ratio of 1.5 - 1.9 : 1 can predict respiratory distress syndrome
(RDS) with 40% accuracy. If, however, the ratio is less than 1.5 : 1, the predictability
increases to 75% accuracy.
7. Lung samples of premature infants with low levels of surfactant exhibit lamellar membranous bodies within the pneumocytes. Since the lamellae resemble the hyaline
cartilage in shape, the condition was initially called Ahyaline membrane disease@.
However, this name has been replaced with respiratory distress syndrome. The lamellar
bodies appear to result from aggregation of phospholipids into concentric layers
resembling intracellular membranes.
8. Treatment of respiratory distress in premature infants occurs on two fronts. In utero,
maternal injections of cortisol (usually betamethasone) can induce maturation of the
pneumocytes and the production of DPPC. This takes 24-72 hrs for a full effect to be
observed. Post-delivery, however, the newborn infant is generally intubated and an
artificial preparation of surfactant (AExosurf@) is introduced into the lung to facilitate lung
inflation.
F. Sphingolipids
1. Review of synthesis
2 Ceramides are converted into cerebrosides by the addition of various sugars. Some
of the GALACTO-cerebrosides give rise to the ABO blood group substances. For
example, a transferase enzyme can add either an N-acetyl-Gal, a Gal or neither to a short
chain of carbohydrates on the ceramide. The addition of the N-acetyl-Gal produces the
AA@ substance, addition of plain Gal gives rise to the AB@ substance, and adding neither
results in the AO@ substance of the ABO blood groups. NOTE: Not all blood groups are
determined by sphingolipids. For example, while the ABO and Lewis blood groups are
determined by various sphingolipids, the MN blood groups are determine by the presence
of various membrane proteins. The specificity of the transferase for the various additions
is determined by the presence or absence of the AA@, AB@ or Anull@ alleles. The various
Asubstances@ are incorporated into RBC membranes.
343 b
2. Sphingolipidoses
a. All are due to deficiencies in lysosomal enzymes that degrade sphingolipids
b. All result in the accumulation of sphingolipipds
c. All are autosomal recessive except the sex-linked Fabry=s
d. Almost all result in neurological (mental retardation) problems
e. None are treatable except for Gaucher=s
f. In the following diagram, the BOLD arrow represents the defective enzyme. In
each case the arrow represents an enzyme that degrades the prior sphingolipid.
g. LEARN THESE DEFECTS:
1.
2.
3.
Niemann-Pick
Tay Sach=s
Fabry=s
= sphingomyelinase deficiency
= hexoamidase deficiency (GM2 accumulates)
= galactoside deficiency (sex-linked)
343 b
G. Lipoproteins / Cholesterol
1. Hypolipoproteinemias (missing/defective Apo proteins)
a. Abetalipoproteinemia : unable to make chylomicrons or VLDLs
b. Alpha apo-lipoprotein defect: unable to make functional HDLs. Leads to high
LDL accumulation and atherosclerosis
2. Hyperlipoproteinemias
TYPE DEFECT
TREATMENT
DISEASE
I
No LPL for chylomicrons
(hyperchylomicronemia)
 detary fat
no atherosclerosis
II
 Apo-B100 or receptor
(hypercholesterolemia)
 dietary cholesterol
Statin therapy
 atherosclerosis
III
 Apo E - unable to clear
chylomicrons and VLDL=s
(Abroad beta disease@)
IV
hypersentivity to insulin
(glucose, alcoholism, obesity)
( VLDL production)
V
Defective LPL for chylo=s
and VLDL=s
 atherosclerosis
xanthomas
 carbohydrate intake
 atherosclerosis
 atherosclerosis
Summary: Lipoproteins and Heart Disease
Chylomicrons
VLDL  IDL  LDL
HDL
-
high density lipoprotein
carries cholesterol
used for transporting cholesterol
removes cholesterol from capillary walls and other lipoproteins
serves as Arespository@ for apo-proteins as lipoproteins are degraded
LDL
- ABAD@ cholesterol
HDL
- AGOOD@ cholesterol