Unit 5: Cardiovascular, Respiratory, Renal Systems

~ Patient-Oriented Problem Solving (POPS) ~

Lipidemia Disease

Suggested time Pages

Pre-Test: Answer Review .................. 10 min ..................... 2

The suggested total time for review of all 5 pre-test questions is 10 min.

Case 1................................................ 25 min* .............. 7-10

Case 2................................................ 25 min* ............ 11-12

Case 3................................................ 25 min** ............13-14

Case 4................................................ 25 min*............. 15-17

*The suggested total time for each case includes the problem solving exercises AND
review and discussion of the answers & explanations.

Post Test............................................. 10 min*............. 18-20

1
 Unit 5 POPS: Lipidemia Diseases

Pre-Test

This short pre-test is designed to help you review your mastery of subject matter
related to the POPS session, before that session.

The pre-test deals with topics in the related readings (see the Pre-Readings section
on the calendar for this POPS session) and in material from earlier sessions in the
Unit including several Interactive Lectures.

Please print-out or write down your answer choices and bring them with you to the
POPS session. The first part of the session involves review and discussion of the
correct answers for the pre-test questions among the students in your POPS group.

2
Question 1
Complete the following table:

Molecule Hydrophobic (H) or Amphipathic Location in lipoprotein (core or

(A) surface)

Fatty acid

Triacylglycerol

Phospholipid

Cholesterol

Cholesteryl ester

Apolipoprotein

Answers:

Molecule Hydrophobic (H) or Location in lipoprotein

Amphipathic (A) (core or surface)

Fatty acid A Present in lipoprotein only in

esterified form

Triacylglycerol H Core

Phospholipid A Surface

Cholesterol A Surface

Cholesteryl H Core
ester

Apolipoprotein A Surface

3
Question 2

Most lipids are not sufficiently soluble in aqueous solution to allow their transport in blood as
free solutes. What is the method for transport in each of the following situations?
A. Triacylglycerol from liver to adipose tissue
B. Triacylglycerol from the intestine to other tissues
C. Free fatty acids from one site to another
D. Cholesterol from the site of synthesis to sites of need
E. Glycerol (from hydrolysis of triacylglycerol) from one site to another
Answers:
A. VLDL.
B. Chylomicrons.
C. Albumin carries long chain fatty acids. Short and medium fatty acids travel
alone.
D. Picked up from extrahepatic tissues by HDL, esterified and transferred to VLDL,
IDL and LDL. For cholesterol synthesized in liver, some goes into newly
synthesized VLDL. Cholesteryl ester in LDL is delivered to extrahepatic tissues
(30%) and to the liver (70%).
E. Glycerol is soluble; it travels as a free solute in blood.

Question 3

Identify the apolipoprotein necessary for each of the following processes:

A. Uptake of remnant chylomicrons by the liver

B. Uptake of remnant LDL by the liver
C. Hydrolysis of triacylglycerol in capillaries of extrahepatic tissues
D. Esterification of cholesterol in plasma
E. Uptake of plasma cholesteryl ester by extrahepatic tissues
Answers:
A. Apo E
B. Apo B-100
C. Apo C-II
D. Apo A-I
E. Apo B-100 (it binds to LDL receptors)

4
Question 4

Cholesterol is distributed throughout the body with an equilibrium established between tissue
and plasma lipoprotein cholesterol and with maintenance of a rather constant level of
cholesterol. Explain the role of each of the following in these processes.

A. HDL
B. VLDL
C. LDL
D. LDL receptors
E. HMG-CoA reductase
F. ACAT
G. LCAT
H. ABCA1 transporter
I. SR-B1 receptor
J. Cholesterol ester transfer protein
K. Enterohepatic circulation
L. Dietary cholesterol

(Answers on next page)

5
Answers:
A. HDL picks up cholesterol from tissues and esterifies it.
B. VLDL, with loss of triacylglycerol from the action of lipoprotein lipase, becomes
IDL then LDL. Each receives cholesterol ester from HDL in exchange for
triacylglycerol.
C. LDL delivers cholesteryl ester to tissues.
D. LDL receptors are necessary for tissues to take up LDL with its cholesteryl
ester. The expression of LDL receptors is down-regulated by intracellular
cholesterol.
E. HMG-CoA reductase is the regulated enzyme of cholesterol synthesis; it is
inhibited by cholesterol.
F. AcylCoA:cholesterol acyl transferase (ACAT) esterifies cholesterol
intracellularly for storage.
G. Lecithin:cholesterol acyl transferase (LCAT) esterifies cholesterol in HDL in
plasma, using a fatty acid from lecithin (phosphatidylcholine).
H. The ABCA1 transporter is a plasma membrane protein which facilitates transfer
of cholesterol and phospholipids to pre-β HDL outside the cell membrane to
form discoidal HDL.
I. The SR-B1 receptor (scavenger receptor class B type I) is found on the surface
of hepatocytes where it picks up cholesteryl ester from HDL without taking up
HDL apolipoproteins. It is also found on the cell surface of steroidogenic tissues
where it has the same function.
J. Cholesterol ester transfer protein (CETP) mediates the transfer of cholesteryl
ester from HDL to VLDL, IDL and LDL, in exchange for triglycerides.
K. The enterohepatic circulation involves the synthesis of bile acids from
cholesterol. Bile acids plus cholesterol are secreted in the bile, the only means
of excretion of cholesterol or its major products. The bile acids and cholesterol
are, however, re-absorbed further down the G.I. tract, imposing little daily need
for newly synthesized cholesterol. This provides a means for pharmacological
intervention--by blocking re-absorption.
L. The role of dietary cholesterol is unclear. Day-to-day, it has little effect, but over
a long period of time, the level of dietary cholesterol may play a major role.
Some researchers believe that it resets the regulatory mechanisms. Reduction
of dietary cholesterol is always the first means of treatment of high cholesterol
levels.

6
Question 5

Write below the reactions for LCAT and ACAT.

Answer:
Phosphatidylcholine + cholesterol → lysophosphatidylcholine + cholesterol ester
(Lecithin:cholesterol acyl transferase, LCAT, on surface of HDL)

AcylCoA + cholesterol → CoASH + cholesteryl ester

(Acyl CoA:cholesterol acyl transferase, ACAT, inside cells)

7
 Case 1 (~25 min)
A six-year old was referred to a lipid clinic because of milky plasma and lab reports of very
high levels of plasma triglycerides. The parents reported that he had been an extremely colicky baby.
He has always been a finicky eater. He has frequently complained of abdominal pain, most often just
a general ache, but occasionally it was acute. On beginning school, his complaints of abdominal pain
increased in frequency and severity. His parents were confused - did he really have an organic
problem, or was he showing school phobia, rather common at this time of life?

Examination revealed a small child (15th percentile for his age and sex). There were few
notable features of the physical exam, except for moderate hepatomegaly and splenomegaly. It had
been requested that he come for his appointment after an overnight fast (his mother insisted he had
eaten nothing since bed time), but his plasma was very milky. His plasma triacylglycerol was 2200
mg/dL (normal fasting level is about 50 mg/dL). His cholesterol level was in the normal range for his
age.

Heparin was injected intravenously, and 15 minutes later a second sample of plasma was
obtained (also milky). Assays for lipoprotein lipase on both the patient’s post-heparin plasma, and on
a mixture of the patient’s post-heparin plasma and a plasma from a normal individual not treated with
heparin, showed no lipase activity. The child’s pre-heparin plasma was left in the refrigerator
overnight; a “cream” formed above a clear plasma.

QUESTIONS

1a. What makes normal plasma milky?

__________________________________________________________________________
__________________________________________________________________________

1b. In a normal person, when would milky plasma be present relative to eating? At what time after
eating would you not expect to see it?
__________________________________________________________________________
__________________________________________________________________________

1c. What does the “overnight refrigerator” test tell you?

__________________________________________________________________________
__________________________________________________________________________

1d. What metabolic processes must be normal to give milky plasma? Which ones might be
defective in this patient to produce the prolonged milky plasma?
__________________________________________________________________________
__________________________________________________________________________

1e. What is the rationale behind the heparin infusion?

__________________________________________________________________________
__________________________________________________________________________

1f. What is the rationale for the lipoprotein lipase assay with a mixture of the patient’s post-
heparin plasma and a normal plasma not treated with heparin? (If you cannot answer this, let it go
until after Case 2).

8
__________________________________________________________________________
__________________________________________________________________________

2a. Refer to the table describing lipidemias in the background “Pre-readings”. Which type of
hyperlipoproteinemia do you think this child has? What tests would you do for further determination of
the disease type?
__________________________________________________________________________
__________________________________________________________________________

2b. Based on your conclusions above, would you expect VLDL to be elevated?
__________________________________________________________________________
__________________________________________________________________________

2c. Can you suggest a treatment? What do you think the real, long-term problems with treatment
will be?
__________________________________________________________________________
__________________________________________________________________________

Case 1 (~25 min) — ANSWER KEY

QUESTIONS
1a. What makes normal plasma milky?
The milky effect is primarily due to chylomicrons formed in response to a fatty meal.

1b. In a normal person, when would milky plasma be present relative to eating? At what time after
eating would you not expect to see it?
In a normal person, milkiness would be present within an hour after a meal and remain for 1 - 4
hours, depending on how much fat was in the meal.

1c. What does the “overnight refrigerator” test tell you?

It confirms that the milkiness is due to chylomicrons. They are the major species with density
appreciably less than water and which therefore separate from water. VLDL can give a milky
appearance, but are not sufficiently lower in density to separate from water.

1d. What metabolic processes must be normal to give milky plasma? Which ones might be
defective in this patient to produce the prolonged milky plasma?
The digestion and absorption of lipids, including the assembly of chylomicrons, must be
reasonably normal. The transport of chylomicrons through the lymph to the blood must be
normal. The metabolism of chylomicrons (i.e., the hydrolysis of triacylglycerol by lipoprotein
lipase) is defective.

1e. What is the rationale behind the heparin infusion?

The heparin infusion releases lipoprotein lipase from the endothelial cell surface so that it can
be assayed in plasma.

1f. What is the rationale for the lipoprotein lipase assay with a mixture of the patient’s post-
heparin plasma and a normal plasma not treated with heparin? (If you cannot answer this, let it go
until after Case 2).

9
This assay allows the researchers to determine whether the Apo C-II cofactor required for
lipoprotein lipase activity is missing in the child’s blood. The normal plasma is not treated
with heparin and will not have lipoprotein lipase activity. It will supply Apo C-II for the assay. If
the child has normal lipoprotein lipase but lacks Apo C-II, then activity of the patient’s
lipoprotein lipase will be restored during the mixing experiment.

2a. Refer to the table describing lipidemias in the background “Pre-readings”. Which type of
hyperlipoproteinemia do you think this child has? What tests would you do for further determination of
the disease type?
Type I Familial Lipoprotein lipase deficiency, indicated by elevated chylomicrons and lack of
lipoprotein lipase activity. Electrophoresis should indicate which lipoproteins are elevated.

2b. Based on your conclusions above, would you expect VLDL to be elevated?
You would expect VLDL to be elevated. It is not and why this is so is not at all clear. There is
probably something fundamental we don’t know about lipoprotein metabolism, or there is
some type of compensatory mechanism. It is possible that there is insignificant amount of
fatty acid delivery to the liver for sustained high VLDL production.

2c. Can you suggest a treatment? What do you think the real, long-term problems with treatment
will be?
At this time the only treatment is a diet with very little fat. The requirement is actually for very
few long-chain fatty acids; as you know, short and medium-chain fatty acids are soluble and
absorbed directly from the G.I. tract. A low-fat diet will relieve symptoms and avoid the long-
term complications. The long term problem with the treatment is that a low-fat diet is pretty
hard to take for a lifetime.
The abdominal pain is due primarily to pancreatitis. The pancreas secretes pancreatic lipase
into the small intestine to digest dietary fat. Normally, a small amount of this enzyme leaks into
pancreatic capillaries. This is not a problem unless the triglycerides in the blood lipoproteins
are very high. Then they become a substrate for the capillary located enzyme and are
hydrolyzed. The free fatty acids released have detergent effects in the pancreatic vascular bed.
Cellular membranes are dissolved, releasing more pancreatic lipase and proteases. There is a
vicious cycle of injury and reinjury. Reducing the triacylglycerol level in the blood by dietary
means allows the injury to heal.
Hepatomegaly is found commonly, and splenomegaly is present, when levels of
triacylglycerol-containing lipoproteins are increased in the blood. This organomegaly occurs
as a result of the high levels of chylomicrons, which are taken up by macrophages. The
macrophages become foam cells. Organomegaly may rapidly regress when dietary fat intake
is decreased.

10
 Case 2 (~25 min)

A 59-year old man sought medical help because of chronic epigastric pain and diarrhea that
was getting progressively worse. He recalled that the pain began at the age of 18 years, when he left
his home in the Caribbean to become a Merchant Seaman. He attributed the distress to the rich food
aboard the freighter.

Physical examination revealed a slight man who had no other remarkable physical features.
He did have moderate anemia, very milky fasting plasma, and a plasma triacylglycerol level of 4700
mg/dL (normal = 50-150 mg/dL). Total cholesterol was 214 mg/dL (normal for his age). On his usual
diet with about 100 gm/day of fat, he had pronounced steatorrhea (fat in the stools). His post-heparin
lipase activity was barely detectable.

He was placed on a 2300 Calories/day diet with 5% of Calories from fat (that is an extremely
low-fat diet). The plasma triglyceride fell to 755 mg/dL after 3 weeks and to 200 mg/dL after six weeks.
He had no discomfort as long as he followed this diet, but he found it a difficult diet to sustain.

He returned to the clinic 6 months later with a plasma triglyceride level of 1750 mg/dL, but with
a substantially more serious anemia. It was decided to transfuse him to relieve his anemia before
further evaluation. The transfusion was followed by a decrease in his plasma triglycerides to 196
mg/dL and a post-heparin lipase activity that was 19% of normal. Over the next 10 days, the plasma
triglyceride levels increased to 1750 mg/dL and post-heparin lipase decreased to nearly zero again.

QUESTIONS
1a. How is this patient similar to the one in Case 1? How is he different?
__________________________________________________________________________
______________________________________________________ 1b. The anemia
confuses the situation (it is presumably unrelated to his lipemia), but the transfusion gave a surprising
result. What did it tell us? How does it focus the diagnosis?
________________________________________________________________

________________________________________________________________

2. From what you know about lipoprotein metabolism in general and what you know about this
patient, what additional biochemical assay might you wish to do to narrow the diagnosis in this case?
________________________________________________________________

________________________________________________________________

____________________________________________________

3. From this case report, there was no information to tell us about VLDL. In similar, subsequent
cases, VLDL was found to be elevated, but assembly of adipose tissue triacylglycerols appeared to be
nearly normal. Suggest a way fatty acids substrates for triacylglycerol assembly are supplied to
adipose tissue in these patients.
__________________________________________________________________________

__________________________________________________________________________

11
 Case 2 (~25 min) — ANSWER KEY
QUESTIONS

1a. How is this patient similar to the one in Case 1? How is he different?

They both have high levels of chylomicrons and plasma triacylglycerol that do not return
toward normal quickly even after a fast. The major difference is in the age of report of
symptoms. This could be in part due to responses by physicians or availability of health care,
but Case 2 patient did not even notice symptoms until he was 18. He may have thought
everyone had a belly ache, but he probably was able to adjust to a low-fat diet more easily until
he was on a regimented diet. In general, however, patients with Case 2's disease have less
severe, more easily controlled symptoms. See Answer 3 below for a possible reason.

1b. The anemia confuses the situation (it is presumably unrelated to his lipemia), but the
transfusion gave a surprising result. What did it tell us? How does it focus the diagnosis?

It tells us that something in the normal blood corrected the defect in our patient. From Case 1,
lipoprotein lipase at first seems a possibility, but if this was the case, then there should be no
lipase activity in unheparinized normal blood. What normally present plasma constituent is
required for lipoprotein lipase activity? Your answer will focus the diagnosis to Familial
Lipoprotein Lipase deficiency.

2. From what you know about lipoprotein metabolism in general and what you know about this
patient, what additional biochemical assay might you wish to do to narrow the diagnosis in this case?

The normal plasma component required for lipoprotein lipase activity is Apo C-II. A positive
effect of Apo C-II on a sample of the patient’s post-heparin plasma would reveal an Apo C-II
dependent lipase activity. Alternatively, an immunological test for Apo C-II might indicate its
absence from the patient’s plasma. If Apo C-II protein is present, then it might be defective.
Alternatively, there may be an inhibitor of lipase in the blood, each of which gives very similar
symptoms.

3. From this case report, there was no information to tell us about VLDL. In similar, subsequent
cases, VLDL was found to be elevated, but assembly of adipose tissue triacylglycerols appeared to be
nearly normal. Suggest a way fatty acids substrates for triacylglycerol assembly are supplied to
adipose tissue in these patients.

Elevation of VLDL is expected, since the same lipase and cofactor act on VLDL and
chylomicrons. Although VLDL levels are elevated in this disease, there may still be some
lipase activity. Apo C-II is a cofactor that lowers the KM of lipoprotein lipase for lipoprotein
triacylglycerols, and the very high levels of lipoproteins may be sufficient to give considerable
lipase activity without the cofactor. Adipose tissue can also synthesize fatty acids from
glucose or amino acids. Adipose tissue may be able to get some fatty acids from fatty acid-
albumin complexes. Perhaps hepatic lipase releases fatty acids, some of which bind to
albumin and go to adipose tissue. Perhaps there is something important we do not yet
understand.

12
 Case 3 (~25 min)

A 30-year old woman was admitted to the hospital with proteinuria, hyperlipidemia and
anemia. It was assumed that she had chronic nephritis, but kidney function proved to be normal. As
part of extensive lab tests, a detailed plasma lipoprotein/lipid analysis was done. Some of the results,
selected to focus you on her problem, follow. (Normal values from this hospital for women this age are
in parentheses.)

C CE/C TAG

VLDL 0.1 (0.1) 0.5 (0.8) 0.31 (0.22)

LDL 0.9 (0.6) 0.1 (2.1) 0.14 (0.07)
HDL 0.4 (0.5) 0.1 (2.8) 0.04 (0.05)

C = cholesterol; CE = cholesteryl ester; TAG = triacylglycerol

(The lipid units are: mole/mg protein.)

QUESTIONS

1. Consider overall lipoprotein metabolism (i.e., what goes from where to where). What appears
to be the defect in this case (e.g., LDL receptors, production of HDL, hydrolysis of triacylglycerol,.....)?
What additional assay could help you define this better?

__________________________________________________________________________

__________________________________________________________________________

__________________________________________________________________________

2. The anemia was attributed to a significantly shortened life span of red blood cells. Red blood
cells were found to have an exceptionally high amount of unesterified cholesterol in their membranes,
sufficient to account for their shortened survival. How is this woman’s defect (from the answer to
question 1) related to high cholesterol in red blood cell membranes? That is, does the high cholesterol
cause the defect, or does the defect cause the high cholesterol? What is the mechanism?

__________________________________________________________________________

__________________________________________________________________________

__________________________________________________________________________

3. HDL has the largest abnormality in CE/C, but essentially no abnormality in triacylglycerol. LDL
and VLDL have lesser abnormalities in CE/C, but significant increases in triacylglycerol. Can you
rationalize this?

__________________________________________________________________________

13
__________________________________________________________________________

14
 Case 3 (~25 min) — ANSWER KEY
QUESTIONS

1. Consider overall lipoprotein metabolism (i.e., what goes from where to where). What appears
to be the defect in this case (e.g., LDL receptors, production of HDL, hydrolysis of triacylglycerol,.....)?
What additional assay could help you define this better?

Cholesterol is normal, but cholesteryl ester is very low in HDL and LDL. For some reason,
cholesterol is not being esterified to cholesteryl ester. (Low cholesteryl ester in LDL could be
due to a defective transfer of cholesteryl ester from HDL to LDL, but this would not result in
low cholesteryl ester in HDL.) Esterification of cholesterol involves the transfer of a fatty acyl
group from phosphatidyl choline (lecithin) to cholesterol, catalyzed by Lecithin:Cholesterol
Acyl Transferase (LCAT). The products are lysophosphatidylcholine and cholesteryl ester.
LCAT is activated by apo A-I.
The obvious test is for LCAT or Apo A-I. (If there were no apo A-I, there would be no HDL.)
When LCAT was assayed, no activity was detected. LCAT was purified from normal plasma
and added to the patient’s plasma in a test tube; the expected LCAT activity was observed,
indicating no LCAT inhibitor in the patient’s plasma. This patient is LCAT deficient.

2. The anemia was attributed to a significantly shortened life span of red blood cells. Red blood
cells were found to have an exceptionally high amount of unesterified cholesterol in their membranes,
sufficient to account for their shortened survival. How is this woman’s defect (from the answer to
question 1) related to high cholesterol in red blood cell membranes? That is, does the high cholesterol
cause the defect, or does the defect cause the high cholesterol? What is the mechanism?

Normal lipoprotein metabolism involves HDL taking free cholesterol from cell membranes,
esterifying it to cholesteryl ester and transferring the cholesteryl ester to VLDL, IDL and LDL,
which ultimately go as LDL to the liver and extrahepatic tissues. HDL have a limited capacity
for polar lipids (they pack the non-polar lipids into their core, but a polar lipid needs to have a
face to the plasma). If HDL cannot esterify cholesterol, they cannot pick it up. Cell membranes
become very high in free (unesterified) cholesterol. In red blood cells, this leads to “floppy
cells” that have a shortened lifetime. It seems highly likely that the LCAT deficiency is primary.

3. HDL has the largest abnormality in CE/C, but essentially no abnormality in triacylglycerol. LDL
and VLDL have lesser abnormalities in CE/C, but significant increases in triacylglycerol. Can you
rationalize this?

If there is no lecithin cholesterol acyl transferase, then spherical HDL has no cholesteryl ester
to be exchanged for triacylglycerol with VLDL/ LDL by cholesterol ester transfer protein; thus,
the decreased CE/C ratio in all three lipoproteins, and the increased amounts of TAG in VLDL
and LDL. Note that some cholesteryl ester in VLDL will originate during synthesis in the liver.
Why TAG is not lower in HDL is not clear

15
 Case 4 (~25 min)
A 18-year old man was referred to a University Hospital for a worsening condition. Since birth
he had intermittent diarrhea and steatorrhea. Over the past few years his condition had become much
worse, with serious problems with anemia, which were partially relieved with iron and vitamin
supplementation, and neurological problems (poor coordination, muscle weakness, impaired vision).
His only treatment had been a diet with restricted fat and occasional vitamin supplementation.

Examination of the duodenal contents revealed normal amounts of pancreatic lipase activity
and normal bile acids. Prothrombin time (time for a clot to form after mixing plasma and Tissue Factor,
Ca2+, and phospholipids – a measure of extrinsic coagulation) was long. There were numerous red
blood cells with a peculiar “star-like” shape; the patient at this time was moderately anemic. The
patient’s plasma was unusually clear, even after a meal. Plasma cholesterol was 75 mg/dL (normal =
125-230); triacylglycerol was 33 mg/dL (normal = 40-150).

Post-heparin lipoprotein lipase activity in plasma was 25% of normal. There were no VLDL or
chylomicrons. Immunochemical assays of apoproteins were within limits except for the apo Bs; neither
B-48 nor B-100 could be detected.
QUESTIONS

1a. What do the steatorrhea and the clear plasma after a meal suggest?

__________________________________________________________________________

__________________________________________________________________________

1b. What do we learn from the pancreatic lipase activity and bile acids in the duodenum?

__________________________________________________________________________

__________________________________________________________________________

1c. What do you think is the underlying problem in this patient?

__________________________________________________________________________

__________________________________________________________________________

2a. Why has this condition led to such extensive and diverse symptoms? Why is there slowed
prothrombin time? Why vision problems? Why neurological problems?

__________________________________________________________________________

__________________________________________________________________________

2b. Compare/contrast this patient to the patients in Case 1 and Case 2. That is, they each have a
problem in the ability to deliver lipids from the intestine to tissues, but their symptoms seem quite
different. What is the explanation?

__________________________________________________________________________

16
 Case 4 (~25 min) — ANSWER KEY
QUESTIONS

1a. What do the steatorrhea and the clear plasma after a meal suggest?

Passage of lipids from the intestine to the blood must be defective.

1b. What do we learn from the pancreatic lipase activity and bile acids in the duodenum?

The duodenal contents tell us that he secretes pancreatic enzymes for digestion of lipids
normally. Bile acids are essential for solubilization and absorption of lipids from the intestines,
but his are normal. So his problem is unlikely to be due to events within the intestinal lumen.

1c. What do you think is the underlying problem in this patient?

He digests lipids, but they do not get to plasma. There is thus a problem either in resynthesis
of triacylglycerol in intestinal cells, in the assembly of chylomicrons or in secretion of
chylomicrons into the lymph. Two big clues help us. He also does not make VLDL. Since these
are made in the liver, and since they share with chylomicrons primarily the fact that they
contain as their major apoprotein a product of the apo B gene (B-48 for chylomicrons and B-
100 for VLDL), the presence of apo B is a logical place to look. It was confirmed, that among
the apoproteins, B-48 and B-100 were the only ones missing.
Two possibilities are: (a) there is an inherent problem in the gene for these proteins, and thus
no VLDL or chylomicrons, or (b), there is some other deficit in production of VLDL and
chylomicrons leading to no secreted lipoproteins, including apo B proteins.
We know now that the problem underlying his symptoms is a deficient microsomal
triacylglycerol transfer protein (MTP). He has abetalipoproteinemia. Typically at birth, persons
with this inherited disease are asymptomatic. Digestive signs appear during the months after
birth with a diet that is rich in lipids. Initially there is diarrhea, vomiting and abdominal
swelling. These digestive signs abate, in part because the patients themselves institute a lipid-
poor diet.

2a. Why has this condition led to such extensive and diverse symptoms? Why is there slowed
prothrombin time? Why vision problems? Why neurological problems?

Many of the problems are attributable to fat soluble vitamin deficiencies. The failure to take up
lipids means that deficiencies of fat soluble vitamins are likely. Thus, prothrombin deficiency
(vitamin K), red-cell hemolysis (in part due to vitamin E deficiency) and vision problems (in
part due to vitamin A deficiency) are present. Most of the neurological problems (vitamin E
deficiency) were markedly improved by vitamin supplementation. (Note that vitamin therapy
for these conditions is not normally appropriate unless some medical condition or clear
nutritional information suggests it. In this case, it is dictated by the failure to utilize properly
dietary fat.)

17
2b. Compare/contrast this patient to the patients in Case 1 and Case 2. That is, they each have a
problem in the ability to deliver lipids from the intestine to tissues, but their symptoms seem quite
different. What is the explanation?

Much of the problem with the patient in Case 4 is due to nutritional deficiencies that are absent
in Cases 1 and 2; Cases 1 and 2 can absorb lipids normally, they just cannot utilize the
triacylglycerol. The low level of plasma post-heparin lipoprotein lipase in Case 4 is probably
due to some form of feedback regulation on the synthesis of the lipase; in the absence of
substrates (VLDL and chylomicrons), there is less lipase.

18
LIPIDEMIAS POPS POST-TEST

QUESTION 1

A 7-year-old boy is brought to the physician by his mother because of digestive problems. His
mother says that he often experience severe abdominal cramps after eating a high-fat meal.
Diagnosis of a genetic defect resulting in a deficiency of lipoprotein lipase is made. Which of the
following substances is most likely increased in this patient's plasma following a fatty meal?

A. Albumin-bound free fatty acids

*B. chylomicrons
C. HDL
D. LDL

Correct Answer: B.
Lipoprotein lipase is involved in converting chylomicrons to chylomicrons remnants. A deficiency
in lipoprotein lipase leads to elevated circulating levels of chylomicrons. Lipoprotein lipase does
not affect albumin-bound free fatty acids. Elevated HDL is usually considered beneficial because
it picks up cholesterol accumulated in the blood vessels and delivers it to the liver. Elevated LDL
is associated with familial hypercholesterolemia.

QUESTION 2

A 25-year-old man has nodular masses (xanthomas) on the Achilles tendon and multiple yellow
patches on his eyelids. His father died at 35 years of age of an acute myocardial infarction. Which
of the following biochemical defects is most likely responsible for the physical findings?

A. Deficiency of apolipoprotein B48

B. Deficiency of apolipoprotein C-II
C. Deficiency of capillary lipoprotein lipase (CPL)
*D. Deficiency of LDL receptors

Correct Answer: D.
The patient has familial hypercholesterolemia (type II hyperlipoproteinemia), an autosomal
dominant disease with a deficiency of LDL receptors that causes an increase in serum LDL levels
and deposition of excess cholesterol in various tissues, including Achilles tendon and eyelids.
These patients usually die at an early age of MI or stroke. Deficiency of apoB-48 is associated
with decreased formation and secretion of chylomicrons from the small intestine. Deficiency of
apoC-II results in accumulation of chylomicrons and VLDLs loaded with triglycerides. Deficiency
of CPL increases chylomicrons. Which carry triglycerides and do not lead to lipid deposition in
tissues.

The patient has familial hypercholesterolemia (type II hyperlipoproteinemia), an autosomal

dominant disease with a deficiency of LDL receptors causing an increase in serum LDL. Since LDL

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is the primary vehicle for carrying cholesterol, these patients have extremely high serum
cholesterol levels. Cholesterol deposits commonly occur in the Achilles tendon (tendon
xanthomas) and eyelids (xanthelasma). Patients die at an early age of an acute myocardial
infarction or stroke.

QUESTION 3

A 45-year-old man, who is an alcoholic, has a blood specimen with a milky appearance. Which of
the following alterations in lipid metabolism is most likely responsible for the milky appearance
of the blood specimen?

A. Decrease in capillary lipoprotein lipase

B. Decrease in apolipoprotein C-II
C. Increase in cholesterol
D. D. Increase in chylomicrons

*E. Increase in very-low-density lipoprotein

Correct Answer: E
Explanation: Very-low-density lipoproteins (VLDLs) carry triglyceride (TG) synthesized in the
liver to peripheral tissues. Nascent VLDL particles formed in the liver contain apolipoprotein
B100, which is essential for assembly of the VLDL and its secretion into the blood. In alcohol
metabolism, there is an increase in NADH and acetyl CoA (substrate for fatty acid synthesis).
These substrates enhance the synthesis of TG by hepatocytes. For example, the increase in NADH
causes dihydroxyacetone phosphate to be converted to glycerol 3-phosphate. The addition of
three acetylated fatty acids to glycerol 3-phosphate produces TG. Increased triglycerides
produced are either stored as lipid droplets in hepatocytes producing fatty liver (steatosis) or
secreted to circulation producing hypertriglyceridemia or type IV hyperlipoproteinemia. An
increase in serum TG gives the blood a milky appearance.

QUESTION 4

Your patient is a 35-year-old male who presented with orange-yellow discoloration of palmar
creases and small clusters of yellowish papules on his elbows, knees, and buttocks.
Lab analysis suggested a lack of ApoE3 and ApoE4 in circulating lipoproteins.
Which of the following is most likely impaired in this patient?

A. Chylomiron secretion by the intestine

*B. Chylomiron remnant uptake by the liver cells
C. LDL particle uptake by hepatic and extrahepatic cells
D. Lipoprotein lipase activation

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E. Cholesterol esterification in the blood

Correct Answer: B.
Without ApoE3 or E4, the liver can not remove chylomicrons and VLDL remnants from
circulation properly. (A) is incorrect because ApoB-48 is responsible for chylomicron assembly
and secretion by enterocytes. (C) is incorrect because ApoB-100 handles LDL particle uptake by
hepatic and extrahepatic tissues. ApoB100 in LDL particles is recognized by LDL receptors
present in hepatic and extrahepatic tissues. (D) is incorrect because ApoC-II is linked to
Lipoprotein Lipase Activation.

QUESTION 5

Which of the following substance is responsible for LCAT activation and cholesterol
esterification?

*A. ApoA-I
B. ApoB-48
C. ApoB-100
D. ApoC-II
E. ApoE3

Correct Answer: A
The key functions of important lipoproteins is summarized below:
ApoA-I: LCAT activation (cholesterol esterification)
ApoB-48: Chylomicron assembly and secretion by enterocytes
ApoB-100: VLDL assembly and secretion by the liver and LDL particle uptake by tissues
ApoC-II: Lipoprotein Lipase Activation
ApoE3 and ApoE4: VLDL and Chylomicron remnant uptake by liver cells

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