LIPIDS, DERIVED & LIPIDS, DERIVED & COMPLEX LIPIDS:COMPLEX LIPIDS:

-STRUCTURE -STRUCTURE - FUNCTIONS - FUNCTIONS

BIOCHEMISTRY

11

"BIOCHEMISTRY"BIOCHEMISTRY”?”?

Penelitian/Penelitian/ investigation investigation hubungan molekul-hubungan molekul-kehidupankehidupan

Menggunakan prinsip kimia untuk menjelaskan Menggunakan prinsip kimia untuk menjelaskan biologibiologi

Kita tahu bahwa "Semua organisme hidup Kita tahu bahwa "Semua organisme hidup mematuhi hukum-hukum kimia dan fisika yang mematuhi hukum-hukum kimia dan fisika yang sama. Hidup ini kompleks, dinamis, terorganisir sama. Hidup ini kompleks, dinamis, terorganisir dan mandiri. Hidup ini berbasis seluler dan dan mandiri. Hidup ini berbasis seluler dan informasi. Hidup beradaptasi dan berkembanginformasi. Hidup beradaptasi dan berkembang

22

GENERAL OBJECTIVES

By the end of this unit, students should be able to:By the end of this unit, students should be able to: Classify lipids according to their structuresClassify lipids according to their structures Relate the structure of lipids to their functionsRelate the structure of lipids to their functions

33

SPECIFIC OBJECTIVES1. Structure and Classification of Lipids At the end of this lecture, students should be able to: Give the general classification of lipid Describe lipid classification according to their structure Describe the structure of fatty acids Understand the nomenclature of fatty acids Describe the structure of triacylglycerol Describe the structure of phospholipids Describe the structure of sphingolipids; Describe the structure of Derived Lipids eg

eicosanoids/prostaglandins Describe the structure of different types of steroids,

cholesterol Describe the structure of Lipoproteins; ketone bodies

44

2. Functions of LipidsAt the end of this lecture, students should be able

to: Describe the functions of different types of lipids: Fatty acid Triacylglycerol Phospholipid; sphingolipids Cholesterol Eicosanoids/Prostanoids Lipoproteins; ketone bodies

55

Lipids : general informations Is third major classes of macromolecules. Water-insoluble organic compounds. High solubility in nonpolar organic solvents. Consist of a number of subclass: 1. Fatty acids and their derivatives, the eicosanoids. 2. Triacylglycerols. 3. Wax esters – important in external structure so no detailed

discussion 4. Phospholipids. 5. Sphingolipids; Phosphosphingolipids. 6. Isoprenoids: steroids; 7. Lipoproteins & ketone bodies Perform diverse functions. Examples: 1. Important structural components in cell membrane, controls flow

of materials 2. As fat (in adipose tissue), store energy efficiently. 3. Chemical signals (=hormones), vitamins or pigments

assisting/membantu biological process. 4. Outer coatings of various organism (the waxes).

Structural relationships of the major classes of lipids

77

Classifications according to main groups: Fatty acids ● Glycerides - saturated - neutral - unsaturated -phosphoglycerides

Complex lipids ● Nonglycerides - lipoproteins - sphingolipids - glycolipids - steroids - waxes

88

1.Fatty acids and their derivatives

Fatty acids (f.a): - - are long chain carboxylic acids, the common ones are C14- C20

- 2 kinds, saturated and unsaturated. Unsaturation can be mono, di or tri.

- Unsaturation normally begins at C9. In di unsaturation, the second is at C12. - The cis-isomer are the regular ones C= C R R - number of unsaturation is denoted by 2nd number in the symbol

to describe a fatty acid (xy:z) The presence of cis configuration causes an inflexible (rigid)

“kink” in the chain making unsaturated fatty acids loosely packed than saturated fatty acids thus melting point saturated f.a > unsaturated f.a. e.g at room temperature, palmitic acid (16:0)is a solid whereas palmitoleic acid (16:1) is a liquid.

maximum

99

Liquids at RT

1010

Polar head

Hydrophobic tail

1111

Mammals obtain most of their f.as from dietary sources. They can synthesize saturated f.as and small amount of monounsaturated f.as.

Two types: Nonessential FAs(= FAs can be synthesized) and Essential FAs – must be obtained from the diet.

Common Essential FAs are the di (18:2) and tri (18:3) unsaturated or generally referred as PolyUnsaturatedFatty Acids (PUFAs)

2 PUFAs : n-3 PUFAs and n-6 PUFAs n-3 PUFAs are the ω-3 and n-6 PUFAs are the ω-6 fatty acids Rich sources of essential FAs (EFAs) are veg. oil, nuts & seeds.

EFAs have several critical physiological functions. Individuals with deficiency of EFAs show symptoms of dermatitis, poor wound healing, reduced resistance to infection, alopecia and thrombocytopenia.

Linoleic(18:2) and linolenic(18:3) acids are precursor of several important metabolites.

Linoleic acid plays an important role in lowering cholesterol levels

1212

Myristic (14:0)and palmitic acids (16:0) (in eukaryotes) found covalently bonded to proteins, i.e acylated proteins. The f.a tail helps the protein membrane to interact with the hydrophobic environment.

F.as are transported from fat cell as acyl serum proteins to body cell via acyl transfer reactions.

In RCOO¯ form, -R interact with non-aqueous region and -COO¯ interact with aqueous, good as emulsifying agent

Arachidonic Acid (AA)

20 : 4 5,8,11,14-eicosatetraenoic acid

Liver fats

 EPA 20 : 5 5,8,11,14,17-eicosapentaenoic acid

 fish oil  

Behenic acid 22 : 0 docosanoic acid rapeseed oil

Erucic acid 22 : 1  13-docosenoic acid rapeseed oil

 DHA   22 : 6 4,7,10,13,16,19-docosahexaenoic acid

fish oil

1313

DHA (docosahexaenoic acid; 22:6) and AA (arachidonic acid 20:4)

- are both crucial to the optimal development of the brain and eyes. The importance of DHA and AA in infant nutrition is well established.

- both substances are routinely added to infant formulas. - Excessive amounts of omega-6 polyunsaturated fatty acids

and a very high omega-6/omega-3 ratio have been linked with pathogenesis of many diseases eg cardiovascular disease, cancer, and inflammatory and autoimmune diseases.

- The ratio of omega-6 to omega-3 in modern diets is approximately 15:1,

- ratios of 2:1 to 4:1 have been associated with reduced mortality from cardiovascular disease, suppressed inflammation in patients with rheumatoid arthritis, and decreased risk of breast cancer.

- may be better to increase the consumption of omega-3 fatty acids rather than decrease the consumption of omega-6 fatty acids because a reduction of polyunsaturated fats in the diet would increase the incidence of cardiovascular disease.

1414

When f.a molecules are added to water, the non-polar tails of the molecules clump into the center of a ball like structure called a micelle, because they are hydrophobic or "water hating".

The polar head of the molecule presents itself for interaction with the water molecules on the outside of the micelle

1515

Reactions: Fatty acid undergoes usual reaction of acids eg. - esterification RCOOH + R’CH2OH RCOOCH2R’ + H2O - acid –base RCOOH + NaOH RCOO+Na- + H2O In practical this reaction is Ξ acid number Reaction at C=C bonds. These reaction are used (at

industrial level) to produce a particular product i- for production of margerine: hydrogenation. OR ii- for quality control purposes a- Iodine value in practical b- saponification number

H+

1616

Eicosanoids: They are prostaglandins, prostacyclins, thromboxanes,

leukotrienes, and epoxyeicosatrienoic acids are derivatives from 3 different C20 multi-unsaturated EFAs

molecules. The 3 twenty-carbon(C20 ) EFAs: * Eicosapentaenoic acid (EPA), an ω-3 fatty acid with 5 double bonds; * Arachidonic acid (AA), an ω-6 fatty acid,with 4 double bonds; most

popular precursor. * Dihomo-gamma-linolenic acid (DGLA), an ω-6, with 3 double bondsSo there are 1 omega-3 (ω-3) and 2 omega-6(ω-6) EFAs. .

C20 multi unsaturated EFA (3 altogether)

EPA AA DGLA ωω-3-3

5 d.bnds5 d.bnds ωω-6-6

4 and 3 d.bnds4 and 3 d.bnds

Molecules formed from these 3 EFA through various reactions = eicosaniods 1717

Source of and compounds produced from arachidonate by various pathways. Prostanoids/prostaglandins H2 gave rise to 3 series of derivatives through 2 enzyme systems . Each series has 3-4 members.

Enzymes system producing the eicosanoids from parent molecule AA

1818

Prostaglandins eg PGE2 ( one of prostaglandins) A letter code is based on ring modifications (e.g.,

hydroxyl or keto groups). A subscript refers to the number of double bonds in the

two side-chains. • They are hormones.

They have specific effects on target cells close to their site of formation.

Synthesis and degradation pathways occurs in liver. They are rapidly degraded, so they are not transported to distal sites within the body.

Also involve in intracellular signal cascades.  Prostaglandins all have a cyclopentane ring. Thromboxanes

have a 6-member ring. affect other cells by interacting with plasma membrane G-

protein coupled receptors.  Depending on the cell type, the activated G-protein may

stimulate or inhibit formation of cAMP, or may activate a phosphatidylinositol signal pathway leading to intracellular Ca++ release. 1919

Structure of the major eicosanoidsStructure of the major eicosanoids

2020

Function of the eicosanoids : - Mediate physiological & pathophysiological action on the

liver, protecting the stomach lining, regulating blood pressure, mediating pain and inflammation, regulating the contraction and relaxation of smooth muscle, and the dilation and constriction of blood vessels.

When there is an injury to the body, prostaglandins cause blood vessels to dilate and increase their permeability to fluid and proteins. This results in swelling and increased temperature of the affected area. Prostaglandins also increase the sensitivity of nerve endings to pain.

- they control i) other hormones and ii) practically all important functions in the body, e.g. the central nervous system and the immune system.

- so they are also known as super hormones. Thus, they are very important for good health and well-being. There are both good and bad eicosanoids.

- have other various roles: blood clotting, immune system modulation, control of reproductive processes and tissue growth, and regulation of the sleep/wake cycle.

2121

exert their effects at very low concentrations and (2) usually act near their sites of synthesis.

TXA2 is made principally by platelets. It causes vasoconstriction and promotes platelet aggregation. These actions prevent excessive blood loss when a blood vessel is damaged or severed. PGI2 is made by the blood vessel wall and has the opposite effects. It prevents intravascular platelet aggregates from forming and obstructing blood flow.

Corticosteroids are anti-inflammatory because they prevent inducible Phospholipase A2 expression, reducing arachidonate release.

2222

Classified under Simple Glycerolipids or neutral lipids / neutral fats

consist of the trihydric alcohol glycerol esterified with 3 molecules of long-chain fatty acids (esters of glycerols with 3 FAs molecules).

The FAs are of varying lengths and may be saturated, unsaturated or a combination.

2. Triacylglycerols (TAG).

2323

Glycerol Back-bone

Fatty acids

1,3-diacylglycerol 1-monoacylglycerol

C18:1 ──C16:0

2424

2 types of TAG i)Simple Glycerides: When the 3 FAs are similar .

ii) Mix Glycerides. When the 3 FAs are different. Mix glycerides are more common.

TAG are also referred to as fats or oils. Fats are solid TAG at RT, contain large proportion of saturated FAs. Oils are liquid TAG at RT, contain high proportion of unsaturated FAs. TAGs have no charge. Glycerol esterified with 1 FAs (mono glyceride) or 2 FAs (diglyceride)

normally present only in small amounts. They are metabolic intermediates.

In fruits and seeds, TAGs are important energy reserve. Seed rich in oil include peanut, corn, palm and etc.

TAG store fatty acids as fats in animal bodies. Complete oxidation of 1 g of fat yield~ 38.9 kJ. Carhohydrates yields 17.2 kJ/g

Before fat can be oxidized, it must be hydrolysed to acid anion and glycerol.

Hydrolysis can be by i) Enzyme ( by lipases) ii) chemical, base eg NaOH => saphonification2525

CH2

CH

CH2

O

O

O CO

CO

CO

R3

R3

R3

3 NaOH

CH2

CHCH2

OHOHOH

+NaO C

OR3

a soap, Na or Ksalt of a fatty acid

3

Saphonification ( base hydrolysis of TAG)

** In the body, bile acid ( = natural soap) derived from cholesterol 2626

fat, play important role (i) as storage and transport of f.acids. Fat are stored in adipose tissue in cells called adipocytes. Fat is anhydrous (hydrophobic nature) therefore for an X quantity of energy only occupies 1/8 th of glycogen’s volume.

(ii) is to provide insulation in low temperatures due to its poor heat conductor property.

TAGs are lipid in human diet. Broken down/hydrolyse by lipases.

Lipases are synthesized in the pancreas and secreted into small intestine.

Pancreatic lipase catalyzes hydrolysis of the primary esters (at C1 and C3 of TAG).

TAG exhibit rancidity (change taste and smell) on long keeping. How? Cause can be by i) hydrolytic/enzyme

ii) oxidative ( more common with unsaturated f.as)

i) CH2-OCOR1 CH2OH CH-OCOR2 CHOH + 3 RCOOH CH2-OCOR3 CH2OH

Enz/H2O

μorgnsm

Responsible for change of taste/smell

2727

Oxidative rancidity: common at C=C in PUFAsii) CH2-OCOR1 CH2OCOR1o

CH-OCOR2 CHOCOR2o CH2-OCOR3 CH2OCOR3o

O2o

Free radical

Oxidized lipids

2828

A mixture of I and a number from 2

I I is esters of fatty acids and fatty alcohols

2

33. . WAXESWAXES

2929

A thin layer that cover the leaves of plants or provide a surface coating for insects or the skin of animals

Technologist referred to commercial products of mineral, marine, plant and insect origin that contain fatty materials of various kinds

A number of waxes are produced commercially in large amounts for use in cosmetics, lubricants, polishes, surface coatings, inks and many other applications. .

Examples: Beeswax; on leaves of plants( jojoba, carnauba); wool wax

waxy material from plant is microcrystalline in structure. It is the interface between the plant and the atmosphere. It serves many purposes, for example to limit the diffusion of water and solutes, while permitting a controlled release of volatiles that may deter pests or attract pollinating insects. The wax provides protection from disease and insects, and helps the plants resist drought.

3030

4.Phospholipids4.Phospholipids Is a fat derivatives, having hydrophobic and hydrophilic

domains. Also referred as phosphoglycerides its simplest form, one glycerol bonded to two fatty acids and

a phosphate group e.g (i) phosphotidic acid or (ii) phosphate group carrying one of several nitrogen-

containing molecules, choline e.g phosphatidylcholine (= phosphoglycerides)

A major component of the cell membranes. phospholipids are always needed for the formation of a

stable bilayer structure

3131

CH2

CH

CH2

O

O

O PO

CO

CO

R1

R2

OHO

Phosphatidic acid

=> phosphoacylglycerol Phosphoric acid

ester

CH2

CH

CH2

O

O

O PO

CO

CO

R1

R2

ORO

Phosphatidic ester

3232

CH2

CH

CH2

O

O

O PO

CO

CO

R1

R2

ORO

R=

CH2CH2NH3+

phosphatidylethanolamine

CH2CH2N(CH3)3+

phosphatidylcholine(lecithin)

CH2CHOH

CH2O PO

OOCH

CH2

OOCO

CO

R3R4

diphosphatidylglycerol(cardiolipin)

Phosphatidyl esters, egs.Phosphatidyl esters, egs.

3333

A phosphatidylcholine or lecithinA phosphatidylcholine or lecithin

3434

Phosphatidylcholine phosphatidylserine

Phosphatidylethanolamine Phosphatidylinositol

Various phosphoglycerides

3535

The phosphate carrying one of several nitrogen-containing molecules with presence of −ve and +ve charges usually is referred as hydrophilic polar head group and the 2 fatty acyl chains is referred as hydrophobic tail.

• suspended in water, they spontaneously rearrange into ordered structures

3636

When many phospholipid molecules are placed in water, their hydrophilic heads tend to face water and the hydrophobic tails are forced to stick together (basis for membrane structure), forming a bilayer (membrane) or ball-like structures called micelles.

/ bilayer vasicle

3737

• suspended in water, they spontaneously rearrange into ordered structures

3838

5. Sphingolipids5. Sphingolipids The sphingolipids, like the phospholipids, are

composed of a polar head group and two nonpolar tails. The core of sphingolipids is either the long-chain amino alcohol, sphingosine or its N-acyl derivative ( a ceramide)

are found in plants and animals, are common in the nervous system. Consist of 2 sub groups:i- sphingomyelinii- glycosphingolipids/ glycolipids (cerebrosides,

sulfatides, globosides and gangliosides ) They contain no phosphate. The carbohydrate ( glucose or galactose) is linked to the alcohol of the lipid via glycosidic bond. They are found in the cell membrane of nerve and brain cells 3939

4040

Sphingomyelins Sphingomyelins are

important structural lipid components of nerve cell membranes.

They are molecules of ceramide with phosphoester at C1 of the ceramide core structure

The predominant sphingomyelins contain palmitic or stearic acid N-acylated at carbon 2 of sphingosine.

4141

Structure of galactocerebrosides

4242

Gangliosides Are sphingolipids with one or more sialic residues Names include M-mono, D-di, T- tri (# residues) and

subscripts for number of sugars attached to the ceramide.

GM2

OCH2OH

OO

OH

O

SphOCH2OH

OH

OH

OOCH2OH

OHOH

NHC OCH3

OR

NH

OH

COO-CO

CH3 R = CH OHCH OHCH2OH

4343

Cardiac Glycosides are - :

- drugs used in the treatment of congestive heart failure and cardiac arrhythmia.

- are found as secondary metabolites in several plants, but also in some animals.

-increases the force of cardiac muscle contraction. . Eg Digitoxin from digitalis purpure

OCH3

OOH

O

O

CH3

CH3

3

4444

6.Isoprenoids

Are biomolecules that contain repeating 5-C structural units (isoprene units)

This class of lipids includes:i) Steroids only discuss this.ii) Terpenesiii) Lipid vitamines

4545

(i) STEROIDS Steroids are complex derivatives of triterpenes They are

characterized by a carbon skeleton consisting of four fused rings referred to as Cyclopentano perhydro phenanthrene. 

Steroids are nonpolar. The most abundant steroid is cholesterol. Cholesterol is the precursor for all steroids. It is a common

component of animal cell membranes and functions to help stabilize the membrane. Thus it is a crucial molecule in animals.

*high levels of it in the blood may contribute to atherosclerosis.

Cyclopentano perhydro phenanthrene 4646

They were made by joining together isoprene units, usually in a head-to-tail.

For cyclic compounds, the linkage is followed by the additional linkage to form the ring.

Terpene are classified according to the number of C they contain.

The body produces more cholesterol from diet that has high content of saturated fat.

Isoprene unit.(2-methyl-1,3-

butadiene),

4747

Structures of several steroids

Steroid hormones are chemical messanger.

Steroid hormones can be divided into 5 classes:1. glucocortocoids2. mineralocorticoids3. androgen4. estrogens5. progestins

4848

Ketones BodiesKetones Bodies Refer to 3 compounds: acetone, acetoacetate, and beta-

hydroxybutyrate Are toxic acidic chemicals. Are soluble in the body fluid. Formed in mitochondria of liver cell. its synthesis (≡ breakdown of fats, especially f.f.as) occurs in

response to low glucose/insulin in the blood or after exhaustion of glycogen.

Are formed when Acetyl-CoA is present in excess of the amount needed for TCA cycle (i.e ATP/NADH2 production cycle)

When only small amount of k.b are formed the phenomenon is referred to as KETOGENESIS

when excess accumulate, this abnormal state is called KETOSIS. This is not necessarily harmful.

Accumulation of large amounts of ketone bodies can lower body’s pH to dangerously acidic levels, this state is called KETOACIDOSIS.

Ketoacidosis is very rare, and, in general, happens only in untreated Type I diabetes

4949

KETOGENESISKETOGENESIS

3-hydroxy-3-methyl-glutaryl-CoA3-hydroxy-3-methyl-glutaryl-CoA5050

5151

Regulation When the body has no free carbohydrates (eg. glucose) available,

fat must be broken down into acetyl-CoA ie active β-oxidation of fatty acid occurs in order to get energy. But Acetyl-CoA is not being recycled through the citric acid cycle because the citric acid cycle intermediates (mainly oxaloacetate) have been depleted to feed the gluconeogenesis pathway, and the resulting accumulation of acetyl-CoA activates ketogenesis.

Diabetic patient

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Lipoproteins There are 2 main forms: Low density lipoproteins (LDL) High density lipoproteins (HDL) Low density lipoproteins (LDL) carry cholesterol from liver

to the cells High density lipoproteins (HDL) returns the extra

cholesterol that is not needed to the liver.

5353

LipoproteinsLipoproteins Is a conjugate (complex of one or more component

of lipids and apo- protein) rendering lipids solubility in the blood/cytosol. Generally, in particle form

The particles range in size from 10 to 1000 nm The proteins are in the surface layer and being

hydrophilic renders solubility to the conjugate. The lipids may be covalently or non- covalently

bound to protein Is the form by which various lipid

components( fig.1a,b&c) are transported within the body system either for special function or elimination

differ in the ratio of protein to lipids, and in the particular apoproteins and lipids that they contain

Density increases with increase % of protein 5454

The interaction of the proteins portion with (a) enzymes in the blood, (b) with each other and (c) with specific proteins on the surfaces of cells determine which lipid molecule will be added to or removed from the lipoprotein particles.

Abnormalities of the amounts or kinds of lipoproteins in blood or in many other arteries could lead to atherosclerosis

*atherosclerosis is sometimes referred to as hardening or narrowing of the arteries, cholesterol deposition, or arterial blockage. Atherosclerosis in the coronary arteries could lead to heart attack, angina or coronary pain, or sudden death, and atherosclerosis in many other arteries in the body could lead to stroke, aneurysm, or gangrene.

5555

Apoproteins Generally are Amphipathic α-helices (polar

along one surface of a helix and hydrophobic along the other side) are common structural alignment.

Types are: - Apolipoprotein A-I (apoA-I) found in HDL and

Chylomicron; consisting of N-terminal antiparallel 4-helix bundle & C-terminal α-helical chain.

-truncated apoA-I : shorter, lacks 1-43 amino acid of the native apoA-I. Also HDL associated

- Apoprotein B-48: major protein in nascent chylomicron

-Apoprotein B-100: found on VLDL, IDL and LDL ;major protein of LDL, recognizes and binds to LDL receptor on liver; one of the longest known proteins in human.

5656

- - Apoprotein CII : found on chylomicrons, activates Lipoprotein Lipase leading to hydrolysis of fatty acid from Tag.

- Apoprotein C I-III: found on VLDL, IDL and HDL, and Chylomicrons;

- Apolipoprotein E (apoE): found on VLDL, IDL and HDL and chylomicron, associated with late-onset Alzheimer's disease

CLASSIFICATION of Lipoproteins: As b-clam CONJUGATE As CHYLOMICRONS * As density-base LIPIDS: 4 types * i) VLDL ii) IDL iii) LDL iv) HDL

* these are 5 lipoproteins found in blood5757

b-clam Conjugate - Found within intestinal cells; are fatty acids bound

with the intestinal fatty acid binding protein (I-FABP) secluding f.acids from the cytosol. I-FABP are also found in several cell types, have a ''b-clam" structure.

The fatty acid is carried in a cavity between 2 approximately orthogonal β-sheets, each consisting of 5 antiparallel β-strands. 

* In blood, free fatty acids are transported bound to blood albumin

5858

As CHYLOMYCRON- assembled in the intestinal mucosa as a means to

transport dietary cholesterol and triacylglycerols (tag) and other lipid components, to organs and the rest of the body.

- Contain least amount of protein and largest amount of lipids: 1-2% protein, 85-88% triglycerides, ~8% phospholipids, ~3% cholesteryl esters and ~1% cholesterol. So tag is highest % of the lipids

- Largest in size and least dense of all lipoproteins - Secreted by intestinal epithelial cells, and

transported via the lymphatic system to the blood for transport to liver, skeletal muscle and adipose tissue.

5959

6060

-The apoproteins that predominate before the chylomicrons enter the circulation include apoB-48 and apoA-I, A-II andA- IV. ApoB-48 combines only with chylomicrons.

- In the bloodstream, chylomicrons acquire apoC-II and apoE from plasma HDLs.

in the capillaries of adipose tissue and skeletal muscle it is partly hydrolyzed to free fatty acids and glycerol by the action of lipoprotein lipase and remainder is chylomycron remnant

the free fatty acids are then absorbed by the cells and the glycerol is returned via the blood to the liver (and kidneys). The glycerol is then converted to the glycolytic intermediate DHAP.

6161

6262

++ B-48Apo A-I, A-II

A- IV

Chylomicron in lympatic systemtag ;;cholesterol

LiverLiver

Adipose Tissue

Skeletal Muscle

Apo C-II & E(from plasma HDL)

Mature Chylomicron in blood

bloodbloodlymphlymph

;;Diet

Intestinal tissues

1- dietary tag emulsified with bile salt → soluble2-degraded by pancreatic lipases(1 and 3 positions sequentially) generate free fatty acids and a mixtures of mono- and diacylglycerols(1,2-diacylglycerols and 2-acylglycerols)& lysophospholipid3-absorption of the products of pancreatic lipases by the intestinal mucosal cells4-resynthesis of triacylglycerols and phospholipid5-combine with specific protein→ chlomicron

phospholipids

f.f + glycerol + chylo remnt

+lipoprotein +lipoprotein lipaselipase

Key

6363

**Summary: chylomycron is a class of lipoproteins that transports (dietary) cholesterol and triglycerides from the small intestines to tissues after meals. Synthesised in the intestinal mucosa and carried via the intestinal lacteals and lymphatic system to the blood stream , they are then degraded to chylomicron remnants in the capillaries of muscles and adipose tissues through cleavage of the majority of their triglycerides by endothelial lipoprotein lipase. These remnants are rapidly cleared by the liver by receptor-mediated endocytosis .

6464

As Density-based lipid ( more proteins more dense). Types are:

- Very low density lipoprotein, VLDL, - Intermediate density lipoprotein, IDL- Low density lipoprotein, LDL- High density lipoprotein, HDL

1. VLDL - packet of triacylglycerols, tag (newly synthesized from

excess dietary fat and carbohydrates) released into lymphatic system/blood from liver for delivery to muscle and adipose tissue.

- Also contain some cholesterol and its esters and the apoproteins: apoB-100, apoC-I, apoC-II, apoC-III and apoE. VLDLs acquire apoCs and apoE from circulating HDLs.

-The fatty acid portion of VLDLs is released to adipose tissue and muscle through the action of lipoprotein lipase

- During its “life”, loses certain apoCs to HDL. ApoB-100 and apoE remain as predominant protein.

6565

2. IDL- is intermediate density lipoprotein.- is intermediate between VLDL and Low density

lipoprotein(LDL)- formed from VLDL. When VLDL loses the fatty acid

portion to the action of lipoprotein lipase, and loses portion of apoC (transferred to HDL)

- also referred to as VLDL remnant - Either forms LDL when more tag is lost- Or can be direct-uptake by the liver when

interacted with the LDL receptor through formation of complex then endocytosed. For LDL receptors in the liver to recognize IDLs requires the presence of both apoB-100 and apoE

6666

3. LDL Forms when IDL loses more tag Consist of highly-hydrophobic core of

polyunsaturated fatty acid linoleate and about 1500 cholesteryl ester molecules. This core is surrounded by a shell of phospholipids and cholesterol, and a single copy of B-100 protein

apolipoprotein B-100 is the exclusive apoprotein component. It is a 4536 a.a polypeptide chain

contains 20-22% protein, 10-15% triglycerides, 20-28% phospholipids, 37-48% cholesteryl esters and 8-10% cholesterol.

carry cholesterol from the liver to cells of the body for further use.

6767

The uptake of LDLs occurs predominantly in liver (75%), adrenals and adipose tissue.

In the uptake, the endocytosed membrane vesicles (endosomes) fuse with lysosomes, in which the apoproteins are degraded and the cholesterol esters are hydrolyzed to yield free cholesterol.

makes up more than half of the total lipoprotein in plasma

are the primary plasma carriers of cholesterol for delivery to all tissues

are taken up by cells via LDL receptor-mediated endocytosis

the interaction of LDLs with LDL receptors requires the presence of apoB-100

6868

The cholesterol is then incorporated into the plasma membranes as necessary. Excess intracellular cholesterol is re-esterified by acyl-CoA-cholesterol acyltransferase (ACAT), for intracellular storage. The activity of ACAT is enhanced by the presence of intracellular cholesterol.

Sometimes referred to as the “bad cholesterol" lipoprotein

6969

7070

7171

4. HDL are synthesized de novo in the liver and small

intestine, as primarily protein-rich disc-shaped particles free of any cholesterol and cholesteryl esters .

The primary apoproteins of HDLs are apoA-I, apoC-I, apoC-II and apoE

a major function is to act as circulating stores of apoC-I, apoC-II and apoE.

collects cholesterol from the body's tissues, and brings it back to the liver. Sometimes referred to as the "good cholesterol" lipoprotein

carry approximately one-fourth of the total amount of cholesterol in blood (the total cholesterol level measures blood cholesterol in all lipoproteins)

7272

Recommended Levels *Units: milligrams per deciliter (mg/dl). Lipoprotein Desirable High Desirableparameter in

atherosclerotic patient

Σ Cholesterol <200 >240 <200Triglycerides <200 >400 <200LDL Co’sterol <130 >160 <100

7373

In 1990 another lipoprotein, called lipoprotein(a) was discovered

In many people, it circulates in the blood in very small amounts.

20% and 30% of people in the U.S. have lipoprotein(a) levels high enough to raise coronary risk. Lipoprotein(a) levels are higher among black people than among people of white or Asian race.

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