Lipoproteins- structure, classification, metabolism and clinical significance

Lipoproteins- Structure, classification, metabolism and significance

Biochemistry for Medicswww.namrata.co

04/11/23 Biochemistry for medics 1

Lipids absorbed from the diet and synthesized by the liver and adipose tissue must be transported between various cells and organs for utilization and storage.Lipids are insoluble in water, the problem of transportation in the aqueous plasma is solved by associating nonpolar lipids (triacylglycerols and cholesteryl esters) with amphipathic lipids (phospholipids and cholesterol) and proteins to make water-miscible lipoproteins.

General Structure of Lipo proteinsGeneral Structure of Lipo proteins

Lipoproteins consist of a nonpolar core and a single surface layer of amphipathic lipids

The nonpolar lipid core consists of mainly triacylglycerol and cholesteryl ester and is surrounded by a single surface layer of amphipathic phospholipid and cholesterol molecules

These are oriented so that their polar groups face outward to the aqueous medium.

The protein moiety of a lipoprotein is known as an apolipoprotein or apoprotein.


General Structure of Lipo proteinsGeneral Structure of Lipo proteins

Some apolipoproteins are integral and cannot be removed, whereas others can be freely transferred to other lipoproteins.


Classification of LipoproteinsClassification of Lipoproteins

Lipoproteins can be classified in three ways-1)Based on density- They are separated by

Ultracentrifugation. Depending upon the floatation constant (Sf), Five major groups of lipoproteins have been identified that are important physiologically and in clinical diagnosis.

(i) Chylomicons, derived from intestinal absorption of triacylglycerol and other lipids; Density is generally less than 0.95 while the mean diameter lies between 100- 500 nm



1) Based on density (contd.)(ii) Very low density lipoproteins (VLDL),

derived from the liver for the export of triacylglycerol; density lies between 0.95- 1.006 and the mean diameter lies between 30-80 nm.

(iii) Intermediate density lipoproteins (IDL) are derived from the catabolism of VLDL,with a density ranging intermediate between Very low density and Low density lipoproteins i.e. ranging between 1.006-1.019 and the mean diameter ranges between 25-50nm.


Classification of LipoproteinsClassification of LipoproteinsBased on density (contd.)iv) Low-density lipoproteins (LDL),

representing a final stage in the catabolism of VLDL; density lies between 1.019-1.063 and mean diameter lies between 18-28 nm

(iv) High-density lipoproteins (HDL), involved in cholesterol transport and also in VLDL and chylomicron metabolism. Density ranges between 1.063-1.121 and the mean diameter varies between 5-15 nm.



Lipoproteins with high lipid content will have low density, larger size and so float on centrifugation. Those with high protein content sediment easily, have compact size and have a high density.


Classification of LipoproteinsClassification of Lipoproteins2) Based on electrophoretic mobilitiesLipoproteins may be separated according to

their electrophoretic properties into - α, pre β, β, and broad beta lipoproteins.

The mobility of a lipoprotein is mainly dependent upon protein content.

Those with higher protein content will move faster towards the anode and those with minimum protein content will have minimum mobility.



Lipoproteins may be separated according to their electrophoretic properties into - α, pre β, β, and broad beta lipoproteins.


Classification of LipoproteinsClassification of Lipoproteins2) Based on electrophoretic mobilities (contd.)HDL are -α , VLDL pre- β, LDL-β , and IDL are

broad beta lipoproteins. Free fatty acid and albumin complex although not

a lipoprotein is an important lipid fraction in serum and is the fastest moving fraction.

Chylomicrons remain at the origin since they have more lipid content.

VLDLs with less protein content than LDL move faster than LDL, this is due to nature of apoprotein present.



As the lipid content increases, density decreases and size increases, that is why Chylomicrons are least dense but biggest in size, while HDL are rich in proteins , hence most dense but smallest in size.



3) Based on nature of Apo- protein contentOne or more apolipoproteins (proteins or

polypeptides) are present in each lipoprotein. The major apolipoproteins of HDL (α-lipoprotein)

are designated A. The main apolipoprotein of LDL (β -lipoprotein) is

apolipoprotein B (B-100), which is found also in VLDL.

Chylomicons contain a truncated form of apo B (B-48) that is synthesized in the intestine, while B-100 is synthesized in the liver.

Apo E is found in VLDL, HDL, Chylomicons, and chylomicron remnants.


Functions of Apo proteinsFunctions of Apo proteins(1) They can form part of the structure of the

lipoprotein, e.g. apo B, structural component of VLDL and Chylomicons

(2) They are enzyme cofactors, e.g. C-II for lipoprotein lipase, A-I for lecithin: cholesterol acyl transferase (LCAT), or enzyme inhibitors, eg, apo A-II and apo C-III for lipoprotein lipase, apo C-I for cholesteryl ester transfer protein

(3) They act as ligands for interaction with lipoprotein receptors in tissues, e.g. apo B-100 and apo E for the LDL receptor, apo A-I for the HDL receptor.


Metabolism of chylomicronsMetabolism of chylomicrons

Chylomicrons are found in chyle formed only by the lymphatic system draining the intestine.

They are responsible for the transport of all dietary lipids into the circulation.

Synthesis of Chylomicrons 1) Synthesis of Apo B48Chylomicrons contain Apo B48, synthesized in

the rough endoplasmic reticulum (RER). The synthesis of apo B48 is the result of RNA

editing process. Coding information can be changed at the mRNA

level by RNA editing.


Synthesis of ChylomicronsSynthesis of Chylomicrons

The synthesis of apo B48 is the result of RNA editing process.



Synthesis of ChylomicronsIn liver, the single apo B gene is transcribed into

an mRNA that directs the synthesis of a 100-kDa protein, apoB100.

In the intestine, the same gene directs the synthesis of the primary transcript; however, a Cytidine deaminase converts a CAA codon in the mRNA to UAA at a single specific site.

Rather than encoding glutamine, this codon becomes a termination signal, and a 48-kDa protein (apoB48) is the result.

ApoB100 and apoB48 have different functions in the two organs



Clinical Significance- In Abetalipoproteinemia (a rare disease), lipoproteins containing apo B are not formed and lipid droplets accumulate in the intestine and liver(Due to non formation of VLDL)04/11/23 Biochemistry for medics 18

Apolipoprotein B, synthesized in the RER, is incorporated into lipoproteins in the SER, the main site of synthesis of triacylglycerol. After addition of carbohydrate residues in G, they are released from the cell by reverse pinocytosis.Chylomicrons pass into the lymphatic system.

Synthesis of Chylomicrons (contd.)

2) Synthesis of lipids and formation of lipoproteinLong-chain fatty acids are esterified to yield to

triacylglycerol in the mucosal cells and together with the other products of lipid digestion, are incorporated into lipoproteins in the SER, the main site of synthesis of triacylglycerol.

3) Addition of Carbohydrate-Carbohydrate residues are added in the golgi apparatus.

4) Release of Chylomicrons- After addition of carbohydrate residues in golgi apparatus, they are released from the cell by reverse pinocytosis.

5) Transportation of Chylomicrons- Chylomicrons pass into the lymphatic system and eventually enter the systemic circulation.


Catabolism of ChylomicronsCatabolism of Chylomicrons

Chylomicrons are acted upon by the enzyme lipoprotein lipase .

Reaction with lipoprotein lipase results in the loss of approximately 90% of the triacylglycerol of chylomicrons and in the loss of apo C (which returns to HDL) but not apo E, which is retained.

The resulting chylomicron remnant is about half the diameter of the parent chylomicron and is relatively enriched in cholesterol and cholesteryl esters because of the loss of triacylglycerol.



Chylomicron remnants are taken up by the liver by receptor-mediated endocytosis, and the cholesteryl esters and triacylglycerols are hydrolyzed and metabolized.

Uptake is mediated by apo E .Hepatic lipase has a dual role: (1) it acts as a

ligand to facilitate remnant uptake and (2) it hydrolyzes remnant triacylglycerol and phospholipid.

The products released are re utilized for the synthesis of VLDL.


Metabolism of VLDLMetabolism of VLDL

There are striking similarities in the mechanisms of formation of chylomicrons by intestinal cells and of VLDL by hepatic parenchymal cells

Apart from the mammary gland, the intestine and liver are the only tissues from which particulate lipid is secreted.

Newly secreted or "nascent" VLDL contain only a small amount of apolipoproteins C and E, and the full complement is acquired from HDL in the circulation

Apo B 100 is essential for VLDL formation.



VLDL are secreted into the space of Disse and then into the hepatic sinusoids through fenestrae in the endothelial lining.


Catabolism of VLDLCatabolism of VLDL

Catabolism of VLDL is similar to chylomicronsBoth phospholipids and apo C-II are required

as cofactors for lipoprotein lipase activity, while apo A-II and apo C-III act as inhibitors.

Hydrolysis takes place while the VLDLs are attached to the enzyme on the endothelium.

Triacylglycerol is hydrolyzed progressively through a diacyl glycerol to a monoacylglycerol and finally to free fatty acids plus glycerol.

Some of the released free fatty acids return to the circulation, attached to albumin, but the bulk is transported into the tissue .


Catabolism of VLDLCatabolism of VLDLReaction with lipoprotein lipase results in the loss of approximately

90% of the triacylglycerol of VLDLs and in the loss of apo C (which returns to HDL) but not apo E, which is retained.

These changes occurring to VLDL, lead to the formation of VLDL remnants or IDL (intermediate-density lipoprotein)

After metabolism to IDL, VLDL may be taken up by the liver directly via the LDL (apo B-100, E) receptor, or it may be converted to LDL.

Only one molecule of apo B-100 is present in each of these lipoprotein particles, and this is conserved during the transformations.

Thus, each LDL particle is derived from a single precursor VLDL particle.

In humans, a relatively large proportion of IDL forms LDL, accounting for the increased concentrations of LDL in humans compared with many other mammals.


Metabolism of LDLMetabolism of LDLThe liver and many extra hepatic tissues express

the LDL (apo B-100, E) receptor. It is so designated because it is specific for apo B-

100 but not B-48, which lacks the carboxyl terminal domain of B-100 containing the LDL receptor ligand, and it also takes up lipoproteins rich in apo E.

This receptor is defective in familial hypercholesterolemia.

Approximately 30% of LDL is degraded in extra-hepatic tissues and 70% in the liver.

A positive correlation exists between the incidence of coronary atherosclerosis and the plasma concentration of LDL cholesterol.



The liver and many extrahepatic tissues express the LDL (apo B-100, E) receptor. It is so designated because it is specific for apo B-100 but not B-48, which lacks the carboxyl terminal domain of B-100 containing the LDL receptor ligand, and it also takes up lipoproteins rich in apo E.


Metabolism of HDLMetabolism of HDL

Synthesis of HDLHDL is synthesized and secreted from both

liver and intestine .However, apo C and apo E are synthesized in

the liver and transferred from liver HDL to intestinal HDL when the latter enters the plasma.

A major function of HDL is to act as a repository for the apo C and apo E required in the metabolism of chylomicrons and VLDL.

Nascent HDL consists of discoid phospholipid bilayer containing apo A and free cholesterol.


Metabolism of HDLMetabolism of HDLLCAT and the LCAT activator apo A-I—bind to

the discoidal particles, and the surface phospholipid and free cholesterol are converted into cholesteryl esters and lysolecithin .

The nonpolar cholesteryl esters move into the hydrophobic interior of the bilayer, whereas lysolecithin is transferred to plasma albumin.

Thus, a nonpolar core is generated, forming a spherical, pseudomicellar HDL covered by a surface film of polar lipids and apolipoproteins.

This aids the removal of excess unesterified cholesterol from lipoproteins and tissues .


Metabolism of HDLMetabolism of HDL

Role of LCATLCAT( Lecithin Cholesterol Acyl Transferase)

enzyme catalyzes the esterification of cholesterol to form Cholesteryl ester. The reaction can be represented as follows-

Lecithin + Cholesterol Lysolecithin + Cholesteryl Ester


Reverse cholesterol transportReverse cholesterol transport

The cholesterol efflux is brought about by esterification of cholesterol under the effect of LCAT. The cholesteryl ester rich HDL (HDL2) gains entry through Scavenger

receptor (SR-B1)


Metabolism of HDLMetabolism of HDLThe class B scavenger receptor B1 (SR-B1)

has been identified as an HDL receptor with a dual role in HDL metabolism.

In the liver and in steroidogenic tissues, it binds HDL via apo A-I, and cholesteryl ester is selectively delivered to the cells, although the particle itself, including apo A-I, is not taken up.

In the tissues, on the other hand, SR-B1 mediates the acceptance of cholesterol from the cells by HDL, which then transports it to the liver for excretion via the bile (either as cholesterol or after conversion to bile acids) in the process known as reverse cholesterol transport 04/11/23 Biochemistry for medics 33

HDL- cycleHDL- cycleHDL3, generated from discoidal HDL by the

action of LCAT, accepts cholesterol from the tissues via the SR-B1 and the cholesterol is then esterified by LCAT, increasing the size of the particles to form the less dense HDL2.

HDL3 is then reformed, either after selective delivery of cholesteryl ester to the liver via the SR-B1 or by hydrolysis of HDL2 phospholipid and triacylglycerol by hepatic lipase. This interchange of HDL2 and HDL3 is called the HDL cycle.

Free apo A-I is released by these processes and forms pre -HDL after associating with a minimum amount of phospholipid and cholesterol.04/11/23 Biochemistry for medics 34

Metabolism of HDLMetabolism of HDL A second important mechanism for reverse

cholesterol transport involves the ATP-binding cassette transporter A1 (ABCA1).

ABCA1 is a member of a family of transporter proteins that couple the hydrolysis of ATP to the binding of a substrate, enabling it to be transported across the membrane.

ABCA1 preferentially transfer cholesterol from cells to poorly lipidated particles such as pre -HDL or apo A-1, which are then converted to HDL3 via discoidal HDL

Pre -HDL is the most potent form of HDL inducing cholesterol efflux from the tissues.


Functions of HDLFunctions of HDLScavenging action- HDL scavenges extra cholesterol

from peripheral tissues by reverse cholesterol transport

HDL, with the help of apo E competes with LDL for binding sites on the membranes and prevents internalization of LDL cholesterol in the smooth cells of the arterial walls

HDL contributes its apo C and E to nascent VLDL and chylomicrons for receptor mediated endocytosis

HDL stimulated prostacyclin synthesis by the endothelial cells, which prevent thrombus formation

HDL also helps in the removal of macrophages from the arterial walls .


Summary of formation and fate of Summary of formation and fate of lipoproteinslipoproteins Chylomicrons is a

transporter of dietary lipids whereas VLDL is a transporter of endogenous lipids(mainly TGs).

LDL transports cholesterol to peripheral cells while HDL transports cholesterol from peripheral cells back to liver.04/11/23 Biochemistry for medics 37

Role of HDL in receptor mediated Role of HDL in receptor mediated endocytosisendocytosis

HDL contributes its apo C and E to nascent VLDL and chylomicrons for receptor mediated endocytosis


Clinical Significance of lipoprotein Clinical Significance of lipoprotein metabolismmetabolismFatty Liveris an abnormal accumulation of certain fats

(triglycerides) inside liver cells. Hepatic triacylglycerol synthesis provides the

immediate stimulus for the formation and secretion of VLDL.

Impaired VLDL formation or secretion leads to nonmobilization of lipid components from the liver, results in fatty liver.


Fatty Liver (contd.)Fatty Liver (contd.)

Fatty livers fall into two main categories-A)More synthesis of Triglycerides High carbohydrate dietHigh fat feeding StarvationDiabetes mellitusHigh carbohydrate diet stimulates de novo fatty

acid synthesis by providing excess of Acetyl CoA and high fat feeding provides more flux of fatty acids from the diet that can be esterifies to provide excess triglycerides.



B) Defective VLDL synthesis -The second type of fatty liver is usually due to a metabolic block in the production of plasma lipoproteins, thus allowing triacylglycerol to accumulate. The lesion may be due to –(1)A block in apolipoproteins synthesisa) Protein energy Malnutritionb) Impaired absorptionc) Presence of inhibitors of endogenous protein synthesis e.g.- Carbon tetra chloride, Puromycin, Ethionine , Heavy metals etc.d) Hypobetalipoproteinemia- Defective apo B gene can cause impaired synthesis of apo B protein.



(2) A failure in provision of phospholipids that are found in lipoproteins

a)A deficiency of choline, a lipotropic factor can cause impaired formation of phosphatidyl choline (Lecithin),a glycerophospholipid.

b)Methionine deficiency can also cause impaired choline synthesis

c)Inositol deficiencyd)Deficiency of essential fatty acids can also

cause impaired PL synthesis04/11/23 Biochemistry for medics 42


(3) Impaired Glycosylation- Orotic acid also causes fatty liver; it interferes with glycosylation of the lipoprotein, thus inhibiting release, and may also impair the recruitment of triacylglycerol to the particles. In conditions of orotic aciduria(disorder of pyrimidine nucleotide biosynthesis), fatty liver can be observed.

4) Impaired secretion of VLDL- oxidative stress is a common cause for membrane disruption of lipoproteins.


Fatty Liver (contd.)Fatty Liver (contd.)2) Alcoholic fatty liverAlcoholism leads to fat accumulation in the

liver, hyperlipidemia, and ultimately cirrhosis. The fatty liver is caused by a combination of

impaired fatty acid oxidation and increased lipogenesis, which is thought to be due to changes in the [NADH]/[NAD+] redox potential in the liver,

and also to interference with the action of transcription factors regulating the expression of the enzymes involved in the pathways.


Fatty Liver and Lipotropic agentsFatty Liver and Lipotropic agents

Lipotropic agents- Agents such as- CholineInositol Methionine and other essential amino acids, Essential fatty acids, Anti oxidant vitamins, Vitamin B12, folic acid and Synthetic antioxidants which have the apparent

effect of removal of fats from the liver cells, and thus prevent the formation of fatty liver are called lipotropic agents.


Primary Disorders of Plasma Lipoproteins Primary Disorders of Plasma Lipoproteins (Dyslipoproteinemias)(Dyslipoproteinemias)Inherited defects in lipoprotein metabolism lead

to the primary condition of either hypo- or hyperlipoproteinemia .

In addition, diseases such as diabetes mellitus, hypothyroidism, nephrotic syndrome, and atherosclerosis are associated with secondary abnormal lipoprotein patterns that are very similar to one or another of the primary inherited conditions.

All of the primary conditions are due to a defect at a stage in lipoprotein formation, transport, or degradation.


Primary Disorders of Plasma Lipoproteins Primary Disorders of Plasma Lipoproteins (Dyslipoproteinemias)(Dyslipoproteinemias)

Name Defect Characteristics

Hypolipoproteinemias

Abetalipoproteinemia No chylomicrons, VLDL, or LDL are formed because of defect in the loading of apo B with lipid.

Rare; blood acylglycerols low; intestine and liver accumulate acylglycerols. Intestinal malabsorption.

Familial alpha-lipoprotein deficiency

All have low or near absence of HDL.

Hypertriacylglycerolemia due to absence of apo C-II, Low LDL levels. Atherosclerosis in the elderly.

Tangier disease

Fish-eye disease

Apo-A-I deficiencies04/11/23 Biochemistry for medics 48

Primary Disorders of Plasma Lipoproteins Primary Disorders of Plasma Lipoproteins (Dyslipoproteinemias)(Dyslipoproteinemias)Name Defect Characteristics

Hyperlipoproteinemia

Familial lipoprotein lipase deficiency (type I)

Hypertriacylglycerolemia due to deficiency of LPL, abnormal LPL, or apo C-II deficiency causing inactive LPL.

Slow clearance of chylomicrons and VLDL. Low levels of LDL and HDL. No increased risk of coronary disease.

Familial hypercholesterolemia (type II a)

Defective LDL receptors or mutation in ligand region of apo B-100.

Elevated LDL levels and hypercholesterolemia, resulting in atherosclerosis and coronary disease.


Primary Disorders of Plasma Lipoproteins Primary Disorders of Plasma Lipoproteins (Dyslipoproteinemias)- contd.(Dyslipoproteinemias)- contd.Name Defect Characteristics

Familial type III hyperlipoproteinemia (broad beta disease, remnant removal disease, familial dysbetalipoproteinemia)

Deficiency in remnant clearance by the liver is due to abnormality in apo E.

Increase in chylomicron and VLDL remnants , Causes hypercholesterolemia, xanthomas, and atherosclerosis.

Familial Hypertriacylglycerolemia (type IV)

Overproduction of VLDL often associated with glucose intolerance and hyperinsulinemia.

High cholesterol, VLDL, Subnormal LDL and HDL. Associated with Alcoholism, diabetes mellitus and obesity.

Hepatic lipase deficiency

Deficiency of the enzyme leads to accumulation of large triacylglycerol-rich HDL and VLDL remnants

Patients have xanthomas and coronary heart disease.


Atherosclerosis

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For further detailsFor further detailsReferA Case Oriented Approach Towards

Biochemistryby: Namrata Chhabra, Sahil Chhabra

http://www.jaypeedigital.com/BookDetails.aspx?id=9789350901885&sr=1And visit our web site-http://www.namrata.co/category/metabolism-lipids/subjective-questions-metabolism-lipids/


Lipoproteins- structure, classification, metabolism and clinical significance

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