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Abetalipoproteinemia

Cuanan, Marjorie Elsa


De Angel, Nicole Victoria
Delicana, Carmelaine
Objectives
By the end of the discussion, the students will be able to:
● Define lipoproteins and discuss the different types, their
composition and synthesis;
● Define what are apolipoproteins and discuss their significance;
● Discuss the transport of lipids in the blood;
● Define abetalipoproteinemia and discuss its underlying genetic
defect;
● Explain the accumulation of fats in intestinal and hepatic cells in
abetalipoproteinemia;
● Enumerate and discuss the manifestations and possible
complications of this disorder;
● Discuss the association of abetalipoproteinemia with fat-
soluble vitamin deficiency;
● Explain why patients with this disorder do not develop vitamin
D deficiency; and
● Enumerate other disorders that may arise from derangements
of lipoprotein function and discuss their genetic etiology and
clinical manifestations.
● Lipoproteins
● Apolipoproteins
● Transport of lipids in blood

Cuanan, Marjorie Elsa


What are lipoproteins? Discuss
the different types, their
composition and synthesis
Lipoproteins

● Assembly of lipids and


proteins that are used as
transport vehicle for fat
Four Types of Lipoproteins

● Chylomicron
● VLDL – Very Low Density
Lipoprotein
● LDL – Low Density
Lipoprotein
● HDL – High Density
Lipoprotein
Composition of Lipoproteins
Composition of Lipoproteins
Chylomicrons
● Largest
● Lowest in density due to high lipid ratio
● Contains high amount of TAGs; some cholesterol
VLDL
● Bad Cholesterol
● Highest in cholesterol as % of weight
● Contains few TAGs; mostly cholesterol
Composition of Lipoproteins

LDL
● 2nd Highest in TAGs as % of weight
● Has similar composition with chylomicron
HDL
● Good cholesterol
● Highest density due to high protein ratio
● Contains very few TAGs; mostly cholesterol
What are apolipoproteins?
What are their significance?
Apolipoproteins

● Forms the part of structure of lipoproteins


● Enzyme cofactors
● Ligands for binding to lipoprotein receptors
● Promote transport & uptake of Lipids
Transport of lipids in the blood
Chylomicrons
● A lipoprotein that is produced in the small intestine
● Contain mostly exogenous TAGs and some cholesterol
● Apoproteins:
○ Apo B48, Apo A
■ First acquired in the small intestine
○ Apo E, Apo C
■ Apoprotein acquired in the circulation
● Remnants are taken up by the Liver
● Half Life: 5-10mins
Formation and Secretion of Chylomicrons
● Apolipoprotein B, synthesized in the
RER, is incorporated into
lipoproteins in the SER.
● After the addition of carbohydrate
residues in Golgi Apparatus, they are
released from the cell by reverse
pinocytosis.
● Chylomicrons pass into the
lymphatic system.
Synthesis of Chylomicrons
Nascent Chylomicron
Mature Chylomicron

SRB1

Mature HDL
Very Low Density Lipoprotein
● Synthesized in the liver
● Contain mostly endogenous TAGs and some cholesterol from
the liver
● Predominant lipid present: Endogenous TAGs – comes from the
liver (from excess carbohydrates and proteins)
● Apoproteins:
○ Apo B100, Apo A - acquired in the liver
○ Apo E, Apo C - acquired in the circulation (from HDL)
● Half-life of VLDL: 15-60 minutes
Nascent Chylomicron
Mature Chylomicron

SRB1

Mature HDL
Low Density Lipoprotein

● Primary plasma carriers of cholesterol for delivery to cell


tissues
● Exclusive apoprotein: Apo B100
● Taken up by the cell via LDLR-mediated endocytosis
● Requires Apo B100
● Allows the peripheral tissues to take up all the cholesterol via
LDLR-mediated endocytosis
Nascent Chylomicron
Mature Chylomicron

SRB1

Mature HDL
High Density Lipoprotein
● Transport peripheral tissue cholesterol back to the liver
(reverse cholesterol transport)
● Major atheroprotective function
● Synthesized both from the liver and small intestines
● Free HDL sequesters macrophages from the peripheral tissues
and return those cholesterol back to the liver for degradation
into bile
Nascent Chylomicron
Mature Chylomicron

SRB1

Mature HDL
● Abetalipoproteinemia
● Fat accumulation in intestinal and hepatic cells
in abetalipoproteinemia
● Fat-soluble vitamin deficiency in
abetalipoproteinemia

De Angel, Nicole Victoria


Define “abetalipoproteinemia”.
What is the underlying genetic
defect?
Abetalipoproteinemia

● Also known as Bassen Kornzweig syndrome


● Rare autosomal recessive disorder that interferes with the
normal absorption of fats and fat-soluble vitamins
● Apo-B deficiencies found in Apo-B48 and ApoB-100 proteins
● It is caused by a mutation in Microsomal Triglyceride Transfer
Protein (MTP) gene, leading to an inability to load Apo-B with
lipids.
Prevalence of Abetalipoproteinemia

● It affects <1:1,000,000
● Affects both male and females
● There are no known racial or ethnic preferences for the
disorder
Microsomal Triglyceride Transfer Protein (MTP)
Gene
● Location: 4q24
● Present in the lumen of the endoplasmic reticulum.
● It is responsible for the transfer of TAGS and other lipids from
their site of synthesis in the endoplasmic reticulum into the
lumen
Microsomal Triglyceride Transfer Protein (MTP)
Gene
Microsomal Triglyceride Transfer Protein (MTP)
Gene Defect
● It is caused by missense mutations in the M subunit that results
in loss of lipid transfer activity
Microsomal Triglyceride Transfer Protein (MTP)
Gene Defect
Why are the intestinal and
hepatic cells accumulating
fats in this disorder?
Accumulation of fats in small intestine
Accumulation of fats in liver
Abetalipoproteinemia is
associated with fat-soluble
vitamin deficiency.
Vitamin A
● It is essential for vision, reproduction, growth, and maintenance
of epithelial tissues.
● It is packaged into chylomicron after absorption from the
lumen of intestine and stored in the liver
Vitamin K
● Required for the formation of functional blood clotting factors
Vitamin E
● Main function is free-radical trapping antioxidant in prevention
of non-enzymatic oxidation of cell components
● Manifestations and possible complications
● Explanation as to why patients with this
disorder do not develop vitamin D deficiency
● Other disorders that may arise from
derangements of lipoproteins

Delicana, Carmelaine
What are its manifestations
and possible complications?
Clinical Manifestations
● Fat malabsorption
○ Steatorrhea
○ Diarrhea
○ Vomiting
○ Distention of abdomen
○ Failure to gain weight
○ Failure to thrive
Clinical Manifestations
● Fat-soluble vitamins deficiency
○ Vitamin A deficiency
■ Decreased night vision
○ Vitamin K deficiency
■ Prolonged Prothrombin time
■ Problems with hemostasis
Clinical Manifestations
● Fat-soluble vitamin deficiency
○ Vitamin E deficiency
■ Hemolytic anemia
■ Retinitis pigmentosa
■ Neurologic abnormalities
● Decreased deep
tendon reflexes
● Loss of vibratory and
proprioceptive senses
● Peripheral neuropathy
Clinical Manifestations
● Hematologic abnormalities
○ Acanthocytosis
■ Anemia
■ Compensatory
reticulocytosis
■ Decreased sedimentation
rate
Clinical Manifestations
● Lipid accumulation in liver and intestines
Other Laboratory Findings

● Decreased Total Cholesterol


● Decreased Low-density lipoprotein (LDL)
● Decreased Triglyceride (TAG)
Possible Complications
● Neurologic abnormalities
→ Spinocerebellar degeneration
● Retinitis pigmentosa
→ Blindness
● Liver Steatosis
→ Steatohepatitis and fibrosis Liver cirrhosis
Why do patients with this
disorder do not develop
vitamin D deficiency?
Aside from abetalipoproteinemia,
what other disorders may arise
from derangements of lipoprotein
function? Discuss their genetic
etiology and clinical
manifestations.
Dyslipoproteinemias

HYPOLIPOPROTEINEMIA HYPERLIPOPROTEINEMIA

Tangier disease Familial lipoprotein lipase deficiency


Fish-eye disease (type I)
Apo-A-I deficiencies Familial hypercholesterolemia (type IIa)
Familial type III hyperlipoproteinemia
Hepatic lipase deficiency
Familial LCAT deficiency
HYPOLIPOPROTEINEMIAS
LIPOPROTEIN DISORDER GENETIC DEFECT CLINICAL MANIFESTATION

Tangier disease ABCA1 gene Orange tonsil


Cloudy cornea
Hepatosplenomegaly
Lymphadenopathy
Intermittent peripheral neuropathy
Fish-eye disease LCAT gene Cloudy cornea

Apo A-I deficiencies Apolipoprotein A-I Mild hepatomegaly


Cloudy cornea
Planar xanthoma
HYPERLIPOPROTEINEMIAS
LIPOPROTEIN DISORDER GENETIC DEFECT CLINICAL MANIFESTATIONS

Familial lipoprotein lipase LPL gene Eruptive xanthomas


deficiency (type I) Lipemia retinalis
**elevated CM & VLDL
Familial LDL receptor Tuberous xanthomas
hypercholesterolemia (type Planar xanthomas
IIa) Tendon & cutaneous xanthomas
**elevated LDL Atherosclerotic lesions
Arcus cornea
Familial type III Apolipoprotein E Xanthoma striata palmaris
hyperlipoproteinemia/ Tuberous lesions over elbows, knees,
Familial buttocks
Dysbetalipoproteinemia Achilles tendon xanthoma
**elevated CM & VLDL remnants

Hepatic lipase deficiency LIPC gene Xanthomas


**elevated HDL & VLDL

Familial lecithin:cholesterol LCAT gene Cloudy cornea


acyltransferase deficiency
**elevated nascent HDL
Summary
● Lipoproteins transport lipids (fats) such as triacylglycerol in blood

Chylomicrons VLDL LDL HDL

Intestines Liver VLDL Liver and intestines

Largest, least dense 2nd highest in TAG Highest in Smallest, most dense
Highest in TAG content cholesterol Highest in protein
content content

Apo B-48 Apo B-100 Apo B-100 Apo A-1

Transport Transports Transports dietary Reverse transport


exogenous TAG to endogenous TAG cholesterol to
hepatic and from liver to peripheral tissues
peripheral cells peripheral tissues
● Apolipoproteins serve as enzyme cofactors, receptor ligands, and lipid transfer
carriers that regulate the metabolism of lipoproteins and their uptake in tissues.
● Abetalipoproteinemia is caused by a mutation in Microsomal Triglyceride
Transfer Protein (MTP) gene, leading to an inability to load Apo-B with lipids.
● There are no Chylomicron and VLDL formed which are carriers of fats causing
accumulation in the small intestine and liver.
● Clinical manifestations of abetalipoproteinemia are steatorrhea,
acanthocytosis, neurologic dysfunction, retinitis pigmentosa, hematologic
abnormalities, and fatty liver.
● Abetalipoproteinemia is associated with fat-soluble vitamin deficiency. But
patients with this disorder do not develop vitamin D deficiency because it can
be synthesized in the skin.
● Inherited defects in lipoprotein metabolism lead to the primary condition of
either hypo- or hyperlipoproteinemia.
THE END