Abetalipoprotienemia..Final..group 3

GROUP 3

Kavita NarulaArsenio Reblando

Jinky HarveyShila Lacia

Dexcel Petty

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ABETALIPOROTIENEMIAABETALIPOROTIENEMIAABETALIPOROTIENEMIAABETALIPOROTIENEMIA

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Lipoproteins• Lipoproteins are protein-lipid complexes.• Spherical in structure

– Inner core lipids triglycerides and cholesteryl esters

– surface layer of phospholipids and unesterified cholesterol

– Specific proteins (apolipoproteins) attached to the outer lipid layer through their specific lipophilic domains

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Lipoproteins

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Lipoproteins• lipoprotein classes• on the basis of density and size• four groups • differ primarily in the amounts of

cholesterol, trigyleride, phospholipids, and types of apolipoproteins they contain

•Chylomicrons •Very low density lipoproteins (VLDL)•Low density lipoproteins (LDL)•High density lipoproteins (HDL)

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Density (g/mL)

ClassDiameter (nm)

% protein

% cholesterol

% phospholipid

% triacylglycerol

>1.063 HDL 5-15 33 30 29 8

1.019-1.063

LDL 18-28 25 50 21 4

1.006-1.019

IDL 25-50 18 29 22 31

0.95-1.006

VLDL 30-80 10 22 18 50

<0.95Chylomicrons

100-1000 <2 8 7 84

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Lipoproteins • Exogenous pathway (dietary fat),

metabolism of chylomicrons• Endogenous pathway (lipids

synthesized by the liver)– Metabolism of VLDL– Metabolism of LDL

• HDL metabolism (apolipoprotein transfer, cholesteryl ester transfer, reverse cholesterol transport)

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Chylomicrons• Assembled in Assembled in intestinal mucosal cellsintestinal mucosal cells• Surface Monolayer Surface Monolayer

– Phospholipids (5%), Free Cholesterol Phospholipids (5%), Free Cholesterol (1%), Protein (1%)(1%), Protein (1%)

• Hydrophobic CoreHydrophobic Core– TriglycerideTriglyceride (93%), Cholesteryl Esters (93%), Cholesteryl Esters

(1%)(1%)

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Chylomicrons• Synthesis of apolipoproteins -Apo

B48 – Rough endoplasmic reticulum– Unique to chylomicrons– Constitutes N-terminal 48 % of apoB100– Post transcriptional editing in mRNA

cytosine replaced by uracil nonsense codon

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Chylomicrons• Assembly of chylomicrons• in the Golgi apparatus• Absorbed Fatty acids are reesterified in the

enterocyte • Apo B48 the structural protein of the chylomicron

contains the majority of cholesterol (as cholesteryl ester)

• Reesterified TAG are added to the chylomicron precursors by a microsomal TAG transfer protein.

• Apo CII is also added. • Nascent chylomicrons released to the lymphatic

system.

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VLDL• Surface Monolayer Surface Monolayer


• Hydrophobic CoreHydrophobic Core– Triglyceride (65%) Cholesteryl Esters Triglyceride (65%) Cholesteryl Esters

(8%)(8%)

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VLDL• formed in the liver • as nascent VLDL (contains only

triglycerides, apoE and apoB)• primarily during the fed state. • Circulating concentrations of VLDL

triacylglycerol increase after a carbohydrate rich meal.

• The cholesterol esters present in VLDL are from de novo synthesis

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VLDL• Release into circulation• As nascent VLDL with apoB100• ApoC’s and ApoE are acquired from

HDL in circulation• ApoC-II activates lipoprotein lipase

which catalyses the hydrolysis of TAG• Apolipoproteins are transferred back to

HDL

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VLDL• TAG’s transferred to HDL in

exchange for cholesteryl esters• Mediated by Cholesteryl ester

transfer Protein (CETP)• Converted to VLDL remnant (IDL)• Then to LDL

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VLDL• Fate of IDL• The remnant particle (IDL), if it

contains apoE, can be taken up by the apoE/remnant receptor

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LDL• Surface Monolayer Surface Monolayer


• Hydrophobic CoreHydrophobic Core– Triglyceride (5%) Triglyceride (5%) Cholesteryl EstersCholesteryl Esters

(35%)(35%)

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LDL• Primary function transport

cholesterol to peripheral tissues • Returns to liver

– By binding to LDL receptors apoB100/apoE receptors

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LDL

LDL are taken up by the LDL Receptor into clathrin-coated pits pits

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LDLDissociates from the receptor; the

receptor recycles to the membrane

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LDL

In the lysosome, lipids are deseterified are hydrolyzed

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LDL

• Increase in free cholesterol decrease cholesterol synthesis and uptake & increase cholesterol esterification– Inhibition of HMG CoA Reductase– Inhibition of synthesis of new LDL

receptors– Esterification by Acyl CoA:Cholesterol

acyl transferase

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HDL• Surface Monolayer Surface Monolayer

– PhospholipidsPhospholipids (25%), Free Cholesterol (25%), Free Cholesterol (7%), Protein (45%)(7%), Protein (45%)

• Hydrophobic CoreHydrophobic Core– Triglyceride (5%) Cholesteryl Esters Triglyceride (5%) Cholesteryl Esters

(18%)(18%)

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HDL• Smallest of the lipoproteins• Synthesized by intestine and liver as nascent

cholesterol-poor lipoprotein• Accumulates cholesterol and cholesteryl

esters through interactions with peripheral cells and other lipoproteins

• Participates in reverse cholesterol transport, removal of excess cholesterol from peripheral cells and delivery to the liver for metabolism

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HDL• HDL is secreted in the liver and intestine• Serve as circulating reservoir of apoCII and

apoE• ABC1-mediated lipid efflux from cells initial

lipidation; • LCAT-mediated esterification of cholesterol

generates spherical particles that continue to grow on ongoing cholesterol esterification HDL2

• Cholesterol ester transfer protein moves some Cholesteryl esters to VLDL

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HDL• Reverse cholesterol Transport• Transport of cholesterol from

tissues to HDL and from HDL to Liver

• Mediated by Scavenger receptor

APOLIPOPROTIENS

Protiens that bind to fats (lipids).They form liporotiens, which transport

dietary fats through the bloodstream The fatty, oily components of lipoprotiens

are not soluble in waterBecause of their detergent-

like,amphipathicProperties, apolipoprotiens can dissolve

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APOLIPOPROTIENS

Also serve as enzyme co factors, receptor ligands, and lipid transfer carriers that regulate metabolism of lipoprotiens and their uptake in tissues

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Apo E• Present in 3 isoforms• E2, E3, E4• Is found in Chylomicrons and IDL that

binds to a specific receptor on liver cell• It is essential for the normal catabolism

of triglyceride-rich lipoprotien constituent

• E2 binds poorly to receptors homozygous poor clearance of chylomicron remnants and IDL

• E4 associated with increased susceptibility to late onset of Alzheimer’s disease

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Apo A1

• Major protien component of HDL in plasma

• It promotes cholesterol efflux from tissue to the liver for excretion

• It is a co-factor for LCAT (Lecithin cholesterolacyltransferase)

Apo B

Is the primary apolipoprotiens of LDL “bad cholesterol,” which is responsible for carrying cholesterol in the tissue

It acts as a ligand for LDL receptors in various cells throughout the body

High Apo B can lead to plaques that cause vascular disease leading to heart disease

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Apoproteins • Diverse functions

Apoprotein

Lipoprotein

Function

B48 CM Carry cholesterol esters

B100 VLDL,IDL,LDL

Binds LDL receptor

C-II All Activate LPL

C-III All Inhibit LPL

Apo E CMremn., VLDL,IDL

Binds remnant receptor

Apo AI HDL,CM Activates L-CAT

3. Review the transport of lipids in the blood

Lipids Carried in Blood as Lipoproteins

•••• Lipids are hydrophobic compound . Thus, when they are ingested, they must be carried in blood combined with proteins as Lipoproteins. • All LPs have a central hydrophobic core of triglycerides & cholesterol. • Phospholipids (charged heads) and proteins are at the surface.

Types of blood lipoproteins

• Chylomicron (formed in cells of the small intestine) transfers dietary lipids from the intestine into the liver.• VLDL (formed in the liver) transfers lipids from the liver by blood to extra-hepatic tissues.• IDL (formed in circulation) is an intermediate LP of VLDL breakdown• LDL (formed in circulation) transfers lipids from blood into tissues.• HDL (formed in the liver and small intestine) transfers lipids from extra-hepatic locations to the liver.

Lipids are insoluble in water. When dietary fats are digested and absorbed into the small intestine, they eventually re-form into triglycerides, which are then packaged into lipoproteins.

Dietary fats, including cholesterol, are absorbed from the small intestines and transported into the liver by lipoproteins called chylomicrons. Chylomicrons are large droplets of lipids with a thin shell of phospholipids, cholesterol, and protein.

Once chylomicrons enter the bloodstream, an enzyme called lipoprotein lipase breaks down the triglycerides into fatty acid and glycerol. After a 12- to 14-hour fast, chylomicrons are absent from the bloodstream.

The liver removes the chylomicron fragments, and the cholesterol is repackaged for transport in the blood in very low-density lipoproteins (VLDLs), which eventually turn into low-density lipoproteins (LDL). LDL cholesterol (LDL-C)—the "bad cholesterol"—consists mainly of cholesterol. Most LDL particles are absorbed from the bloodstream by receptor cells in the liver.

Cholesterol is then transported throughout the cells. LDL particles are also removed from the bloodstream by scavenger cells, or macrophages. Scavenger cells prevent cholesterol from reentering the bloodstream, but they deposit the cholesterol in the inner walls of blood vessels, eventually leading to the development of plaque.

High-density lipoproteins (HDLs) are a separate group of lipoproteins that contain more protein and less cholesterol than LDL. HDL cholesterol (HDL-C) is also called "good cholesterol." HDL is produced primarily in the liver and intestine, and it travels in the bloodstream, picks up cholesterol, and gives the cholesterol to other lipoproteins for transport back to the liver.

4. Define “abetalipoproteinemia”.

What is the underlying genetic defect?

Abetalipoproteinemia• Abetalipoproteinemia, or Bassen-Kornzweig

syndrome is a rare autosomal recessive disorder that interferes with the normal absorption of fat and fat-soluble vitamins from food.

• Genetic disease characterized by lack of ApoB-100.• Thus patients cannot synthesize chylomicrons, VLDLs

and LDLs.• Symptoms:

– Malabsorption of fat.– Accumulation of lipid droplets within cells of the

small intestine.– Spiny shaped red cells– Neurological disease (i.e. ataxia and retardation)

• Mutations in the microsomal triglyceride transfer protein (MTTP) gene has been associated with this condition.

• The MTTP gene provides instructions for making a protein called microsomal triglyceride transfer protein, which is essential for creating beta-lipoproteins. These lipoproteins are both necessary for the absorption of fats, cholesterol, and fat-soluble vitamins from the diet and necessary for the efficient transport of these substances in the bloodstream. Most of the mutations in this gene lead to the production of an abnormally short microsomal triglyceride transfer protein, which prevents the normal creation of beta-lipoproteins in the body.

• MTTP-associated mutations are inherited in an autosomal recessive pattern, which means both copies of the gene must be faulty to produce the disease.

5. Why are the intestinal and hepatic 5. Why are the intestinal and hepatic cells accumulating fats in this disorder? cells accumulating fats in this disorder?

6. What is its manifestations and 6. What is its manifestations and possible complications?possible complications?

• The enterocytes of intestinal cells and hepatic cells have accumulation of fats because of the absence of Apo B which is the major structural protein of chylomicrons that acts like a detergent in maintaining the solubility of lipids in the plasma. Therefore this cause fat deposition (engorgement of enterocytes in the small intestines) in abetalipoprotenemia.

The signs and symptoms of abetalipoproteinemia appear in the first few months of life.

They can include failure to gain weight and grow at the expected rate; diarrhea; abnormal star-shaped red blood cells (acanthocytosis); and fatty, foul-smelling stools (steatorrhea). The stool may contain large chunks of fat and or blood.

Other features of this disorder may develop later in childhood and often impair the function of the nervous system. They can include poor muscle coordination, difficulty with balance and movement (ataxia), and progressive degeneration of the light-sensitive layer (retina) at the back of the eye that can progress to near-blindness.

Adults in their thirties or forties may have increasing difficulty with balance and walking. Many of the signs and symptoms of abetalipoproteinemia result from a severe vitamin deficiency, especially vitamin E deficiency, which typically results in eye problems with degeneration of the spinocerebellar and dorsal columns tracts.

Signs and symptoms• Often symptoms will arise that indicate the body is

not absorbing or making the lipoproteins that it needs. These symptoms usually happen all together, all the time. These symptoms come as follows:

• Failure to grow in infancy• Fatty, pale stools• Foul smelling stools• Protruding abdomen• Retinitis Pigmentosa

• Mental retardation/developmental delay

• Muscle weakness• Slurred speech• Scoliosis (curvature of the spine)• Progressive decreased vision and• Balance and coordination problems

7. Abetalipoproteinemia is associated with fat soluble vitamin deficiency. Explain

this statement.

7. Abetalipoproteinemia is associated with fat soluble vitamin deficiency. Explain

this statement.

Abetalipoproteinemia is an inherited disorder that affects the absorption of dietary fats, cholesterol, and fat-soluble vitamins. People affected by this disorder are not able to make certain lipoproteins, which are particles that carry fats and fat-like substances (such as cholesterol) in the blood. Specifically, people with abetalipoproteinemia are missing a group of lipoproteins called beta-lipoproteins.

An inability to make beta-lipoproteins causes severely reduced absorption (malabsorption) of dietary fats and fat-soluble vitamins (vitamins A, K, and E) from the digestive tract into the bloodstream. Sufficient levels of fats, cholesterol, and vitamins are necessary for normal growth, development, and maintenance of the body's cells and tissues, particularly nerve cells and tissues in the eye.

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Patients with abetalipoproteinemia develop severe vitamin E deficiency because they are defective in three steps in this pathway: First, along with other fat soluble vitamins, the fat malabsorption decreases the absorption of vitamin E

Second, the small amount of vitamin E that maybe absorbed can not be efficiently secreted by the intestine because of the defect in the chylomicron secretion.

Third, any vitamin E that is delivered to the liver also can not be secreted because of the defect in the VLDL secretion

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Vitamin A and K Aare also packaged in to chylomicrons after absorption from the lumen of the intestine, but unlike vitamin E , they have a separate transport system in the blood and are not dependent on VLDL for their transport. Because the absorption of these vitamins is affected only at steps 2 and 3. that’s why deficiency of these fat soluble vitamins are not severe.

8. Why do patients with This disorder do not develop vitamin D deficiency?

Vitamin D is a fat-soluble vitamin, meaning it is able to be dissolved in fat. While some vitamin D is supplied by the diet, most of it is made in the body. To make vitamin D, cholesterol, a sterol that is widely distributed in animal tissues and occurs in the yolk of eggs, as well as in various oils and fats, is necessary. Once cholesterol is available in the body, a slight alteration in the cholesterol molecule occurs, with one change taking place in the skin. This alteration requires the energy of sunlight (or ultraviolet light). Vitamin D deficiency, as well as rickets and osteomalacia, tends to occur in persons who do not get enough sunlight and who fail to eat foods that are rich in vitamin D.

Once consumed, or made in the body, vitamin D is further altered to produce a hormone called 1,25-dihy-droxy-vitamin D (1,25-diOH-D). The conversion of vitamin D to 1,25-diOH-D does not occur in the skin, but in the liver and kidney. First, vitamin D is converted to 25-OH-D in the liver; it then enters the bloodstream, where it is taken-up by the kidneys. At this point, it is converted to 1,25-diOH-D. Therefore, the manufacture of 1,25-diOH-D requires the participation of various organs of the body—the liver, kidney, and skin.

The purpose of 1,25-diOH-D in the body is to keep the concentration of calcium at a constant level in the bloodstream. The maintenance of calcium at a constant level is absolutely required for human life to exist, since dissolved calcium is required for nerves and muscles to work. One of the ways in which 1,25-diOH-D accomplishes this mission is by stimulating the absorption of dietary calcium by the intestines.

Approximately 80% is absorbed into the lymphatic system. Vitamin D is bound to vitamin D-binding protein in the blood and carried to the liver where it undergoes its first hydroxylation into 25-hydroxyvitamin D. This is then hydroxylated in the kidney into 1,25(OH)2D. When there is a calcium deficiency, parathyroid hormone is produced, which increases the tubular reabsorption of calcium and renal production of 1,25(OH)2D. The 1,25(OH)2D travels to the small intestine and increases the efficiency of calcium absorption. That is why vitamin D deficiency is not manifested in this disorder because it is not solely dependant on lipoproteins.

9. Aside from abetalipoproteinemia, what other

disorders may arise from derangements of lipoprotein

function? Discuss their genetic etiology and clinical

manifestations.

9. Aside from abetalipoproteinemia, what other

disorders may arise from derangements of lipoprotein

function? Discuss their genetic etiology and clinical

manifestations.

1.Hepatic lipase deficiency :Hepatic lipase is a member of the same gene family as LPL

and hydrolyzes triglycerides and phospholipids in remnant lipoproteins and HDL. HL deficiency is a very rare autosomal recessive disorders characterized by elevated plasma cholesterol and triglycerides mixed hyperlipidemia due to accumulation of lipoprotein remnants. HDL-C is normal or elevated.

Gene defect: LPLClinical findings: premature atherosclerosisLab. Findings: increased VLDL remnant

Familial Dysbetalipoproteinemia

( Type III Hyperlipoproteinemia or familial broad B disease

• Familial, dysbetalipoproteinemia is characterized by a mixed hyperlipidemia due to accumulation of remnant lipoprotein particles. ApoE is present in multiple copies of chylomicrons and VLDL remnants and mediates their removal via hepatic lipoprotein receptors. FDBL is due to genetic variations in apoE that interfere with its ability to bind lipoprotein receptors.

• Gene defect: ApoE.• Clinical Findings: palmar and tuberoeruptive

xanthomas CHD, PVD

FH is an autosomal codominant disorder characterized by elevated plasma LDL-C with normal triglycerides, tendon xanthomas, and premature coronary atherosclerosis . FH is caused by more than 750 mutations in the LDL receptor gene and has a higher incidence in certain populations such as Afrikans, christian, Lebanese and french canadian, due to the founder effect. The elevated levels of LDL- C in FH are due to delayed catabolism of LDL and its precursor particles from the blood, resulting in increased rates of LDL production.

Gene defect: LDL receptor LDLR) Clinical Findings: Tendon xanthomas, CHD

Familial defective Apo B – 100( FDB)

FDB is a dominantly inherited disorder that clinically resembles heterozygoes FH. The ds. Is char: by elevated plasma LDL-C levels with normal triglycerides, tendon xanthomas, and an increase incidence of premature ASCVD. FDB is caused by mutatins in the LDL receptor- binding domain of apo B-100. Almost all pts. With FDB have a sustitution of glutamine for arginine at position 3500 in apoB 100, although other rarer mutations have been reported to cause this ds. As a consequence of the mutation in apoB-100, LDL binds the LDL receptor with reduced affinity and LDL is removed from the circulation at a reduced rate.

Familial Defective ApoB-100

• Gene defect: ApoB-100 • Clinical man8ifestations: Tendon

xanthomas, CHD. Lab. Finding: Elevated LDL

Autosomal recessive hypercholesterolemia

• Autosomal recessive Hypercholesterolemia- autosamal recessive hypercholesterolemia (ARH) is a rare disorder except in (Sardinia) due to mutations in a protein (ARH) clinically resemble homozygous FH and is char: by hypercholesterolemia, tendon xanthomas, and premature coronary artery disease. The hypercholeterolemia tends to be intermediate between the levels seen in FH homozygotes and FH heterozygotes.

• Gene defect:ARH• Lab. Findings: increase LDL• Clinical manifestations: Tendon Xanthomas, CHD

Sitosterolemia• Sitosterolemia is a rare autosomal recessive disease caused by

mutations in one of two recessive diseases. Caused by mutations in one of two members of the adenosine triphosphate (ATP)- binding casstte transporter family, ABCG5 and ABCG8. These genes expressed in the intestine and liver, where they form a functional complex to limit intestinal absorption and promote biliary excretion of plant and animal derived neural sterols. In sitosterolemia, the intestinal absorption of plant sterols is increased and biliary excretion of the sterols is reduced, resulting in increased plasma levels of sitosterol and other plant sterols.

• Gene Defect: ABCG5 and ABCG8• Lab. Findings. Elevated LDL• Clinical manifestations: Tendon xanthomas, CHD

THE END

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Abetalipoprotienemia..Final..group 3

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