9. Lipids and Lipoproteins

8/14/2019 9. Lipids and Lipoproteins

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LIPID CHEMISTRY

AND

METABOLISM



Contents

1. Lipid Chemistry

2. Lipid Classes

3. Lipid Synthesis4. Metabolism

5. Lipid Disorders

6. Lipid and Lipoprotein Analyses



Lipid Chemistry

Introduction

Composed of mostly carbons-hydrogen (C-H) bonds

Classification of Medically Important lipids:

1. Fatty acids2. Triglycerides

3. Cholesterol

4. Phospholipids

Transported by lipoproteins (VLDL, LDL, HDL)



Classes of lipids in General

Classes of Lipids

By Function By Structures

torage Messenger Simple Sterol Derived

Membrane Compound Miscellaneous

Fats/Oil Waxes

Phospholipids Glycolipids



Lipid Chemistry

1. Fatty Acids

1. Fatty Acids

• Linear chains of C-H bonds that terminated with -COOH

1. Fatty Acids


• Classifications:

a. unesterified bound to albumin

b. esterified constituent of triglycerides/phospholipids

1. Fatty Acids


• Classifications:

a. unesterified bound to albumin

b. esterified constituent of triglycerides/phospholipids

g. saturated no double bonds

h. monosaturated

one double bondi. polyunsaturated ≥double bonds



Lipid Chemistry

1. Fatty Acids

Linear chains of C-H bonds that terminated with -COOH



Lipid Chemistry

2. Triglyceride

a. Contain 3 FA attached to one molecule of glycerol

2. Triglyceride


b. Contain saturated fatty acids or unsaturated fatty acids

2. Triglyceride


b. Contain saturated FA’s or unsaturated f=FA’s

c. No charged groups, water insoluble, neutral lipid



Lipid Chemistry

3. Phospholipids3. Phospholipids

a. Contain 2 FA’s attached to one molecule of glycerol

3. Phospholipids


b. Third position contain phospholipid head groups

3. Phospholipids


b. Third position contain phospholipid head groups

c. Amphipathic



Lipid Chemistry

3. Phospholipids

a. Contain 2 FA’s

attached to one

molecule ofglycerol

b. Third position

contain

phospholipidhead groups

c. Amphipathic

Lecithin



Lipid Chemistry

4. Cholesterol4. Cholesterol

a. Unsaturated steroid alcohol contain four rings

4. Cholesterol


b. Amphipathic

4. Cholesterol


b. Amphipathic

c. Classifications:

4. Cholesterol


b. Amphipathic

c. Classifications:

i. unesterified free cholesterol (amphipathic)

ii. esterified cholesteryl ester (neutral lipid)



Lipid Chemistry

4. Cholesterol4. Cholesterol

Converted to:

4. Cholesterol

Converted to:

a. Bile salts

4. Cholesterol

Converted to:

a. Bile salts

b. Steroid hormones

4. Cholesterol

Converted to:

a. Bile salts

b. Steroid hormones

c. Vitamin D and Cell membrane



Lipid Chemistry

Chemical Structure of Lipids



Lipoprotein Structure

COMPONENTS

Lipids and proteins

COMPONENTS

Lipids and proteins

Composition:

COMPONENTS

Lipids and proteins

Composition:

a. Free cholesterol and

phospholipids are on

the surface

COMPONENTS

Composition:

a. Free cholesterol and

phospholipids are on

the surface

b. Triglycerides and

cholesteryl esters are

in the core regions




Apolipoprotein

Apo A-I

Apo A-II

Apo A-IV

Apo B-100

Apo B-48

Apo C-I

Apo C-II

Apo C-III

Apo E

Apo(a)

Characteristics of the Major Human ApolipoproteinsApolipoprotein Major LPP Location

Apo A-I HDL

Apo A-II HDL

Apo A-IV Chylos, VLDL, HDL

Apo B-100 LDL, VLDL

Apo B-48 Chylos

Apo C-I Chylos, VLDL, HDL

Apo C-II Chylos, VLDL, HDL

Apo C-III Chylos, VLDL, HDL

Apo E VLDL, HDL

Apo(a) Lp(a)

Apolipoprotein Major LPP Location Function

Apo A-I HDL LCAT activator, ABCA1 lipid acceptor

Apo A-II HDL inactivates LCAT

Apo A-IV Chylos, VLDL, HDL

Apo B-100 LDL, VLDL LDL receptor ligand

Apo B-48 Chylos Remnant receptor ligand

Apo C-I Chylos, VLDL, HDL

Apo C-II Chylos, VLDL, HDL LPL cofactor

Apo C-III Chylos, VLDL, HDL LPL inhibitor

Apo E VLDL, HDL LDL receptor Ligand

Apo(a) Lp(a) plasminogen inhibitor




MAJOR TYPES

1. Chylomicrons

2. VLDL

3. LDL

4. HDL

http://upload.wikimedia.org/wikipedia/commons/d/d1/Chylomicron.svg




Characteristics of the Major Human Lipoproteins

Characteristics

Density (g/mL)

Diameter (nm)

Total lipid (%)

Triglyceride (%)

Cholesterol (%)

Major Protein

Characteristics Chylo.

Density (g/mL) <0.93

Diameter (nm) 80-1,200

Total lipid (%) 98

Triglyceride (%) 84

Cholesterol (%) 7

Major Protein Apo B-48

Characteristics Chylo. VLDL

Density (g/mL) <0.93 0.93-1.006

Diameter (nm) 80-1,200 30-80

Total lipid (%) 98 89-96

Triglyceride (%) 84 44-60

Cholesterol (%) 7 16-22

Major Protein Apo B-48 Apo B-100

Characteristics Chylo. VLDL LDL

Density (g/mL) <0.93 0.93-1.006 1.019-1.063

Diameter (nm) 80-1,200 30-80 18-30

Total lipid (%) 98 89-96 77

Triglyceride (%) 84 44-60 11

Cholesterol (%) 7 16-22 62

Major Protein Apo B-48 Apo B-100 Apo B-100

Characteristics Chylo. VLDL LDL HDL

Density (g/mL) <0.93 0.93-1.006 1.019-1.063 1.063-1.21

Diameter (nm) 80-1,200 30-80 18-30 5-12

Total lipid (%) 98 89-96 77 50

Triglyceride (%) 84 44-60 11 3

Cholesterol (%) 7 16-22 62 19

Major Protein Apo B-48 Apo B-100 Apo B-100 Apo A-1




MAJOR TYPES

1. Chylomicrons

• Largest and least dense

• Produced in the intestine

• Delivery of dietary lipids to hepatic and peripheral cells

Tube of turbid plasma

left overnight in a

refrigerator at 4OC




MAJOR TYPES

2. Very Low Density Lipoproteins

• Pre-β- lipoprotein

• Produced in the Liver

• Transfer triglycerides from the liver to peripheral tissue

Tube of turbidplasma left

overnight in a

refrigerator at

4OC




MAJOR TYPES

3. Low Density Lipoproteins (LDL)

• β-lipoprotein or bad cholesterol

• Formed from lypolysis of VLDL to IDL then to LDL

• Transfer dietery cholesterol to peripheral tissues




MAJOR TYPES

4. High Density Lipoproteins (HDL)

• α-LPP or good cholesterol

• Produced in the Liver and the Intestine

• Transfer cholesterol from peripheral cells back to the liver




MINOR TYPES

5. Lipoprotein(a)

• LDL lipoprotein like particle

• ↑ Confers increased risk for premature coronary heartdisease and stroke.




MAJOR TYPES

1. Chylomicrons

2. VLDL

3. LDL

4. HDL

http://upload.wikimedia.org/wikipedia/commons/d/d1/Chylomicron.svg



Analyte Reference RangeConversion

Factor (mmol/L)

Total cholesterol 140-200 mg/dL 0.026

HDL cholesterol 40-75 mg/dL

LDL cholesterol 50-130 mg/dL

Triglyceride 60-150 mg/dL 0.011

Adult reference ranges for Lipids




Liver Adipose tissues Skeletal muscle

Dietary lipid

Digestion (bile)

Fatty acid + monoglyceride

Absorption

Triglyceride

Chylomicrons

Transport

Overview of Lipid Metabolism



Ketone bodies Formation

Ketone bodies, also known as ketones,are water-soluble compounds that areproduced as by-products of fatty acidsoxidation.The

The three endogenous ketone bodiesare

Acetoacetic acid

Acetone,

Beta-hydroxybutyric acid.

Production of these compounds is calledketogenesis.

Ketone bodies are synthesized from theAcetyl CoA molecules produced

from the β-oxidation of fatty acid Glycolysis. Instead of entering the

citric acid cycle, some acetyl-CoA isconverted to ketone bodies in the livermitochondria.



Ketone bodies Formation

Step 3: Ketone bodies aretransported to other tissuessuch as brain, muscle and heartwhere they are converted backto acetyl-CoA to serve as sourceof energy.

Normally, the brain uses only glucose for energy, butduring starvation and high-fat/low carbohydrate diet,the glucose level becomes low. In this condition,ketone bodies can become the main energy source forthe brain.

When excess ketone bodies accumulate in the blood,the condition is called ketonemia.

This condition decreases the blood pH to acidic levels

which could lead to a state called ketoacidosis. T The accumulation of the ketone bodies in the blood

which lead to ketonemia and ketoacidosis is generallyreferred to ketosis.

This condition happens most often in untreated Type Idiabetes mellitus. A diabetic person has



Metabolic Fate of Ketone Bodies

Ketone bodies are transported from the liver to other

tissues such as brain, muscle and heart.

The acetoacetate and beta-hydroxybutyrate can be

reconverted to acetyl-CoA to produce energy via thecitric acid cycle.

Acetone cannot be converted back to acetyl-CoA, so it

is excreted in the urine or exhaled because of its

characteristic high vapor pressure.

Therefore, acetone is responsible for the characteristic

"fruity" odor of the breath of persons in ketoacidosis.

Comparison of Fatty Acid Catabolism and



Fatty Acid Catabolism Fatty Acid Anabolism

Occurs in mitochondrial matrix Occurs in the cytoplasm

Acetyl CoA – product Acetyl CoA - precursor

Malonyl CoA – not involved Malonyl CoA – source of 2 carbon

Biotin not required Biotin required

Oxidative process Reductive process

Requires NAD and FAD Requires NADPH

Produce ATP Require ATP

Form thioesters with CoA-SH Form thioesters with acyl carrier proteins (ACP-SH)

No ordered aggregate of enzymes With ordered multienzyme complex

β-hydroxyacyl intermediates have L-

configuration

β-hydroxyacyl intermediates have D-configuration

Comparison of Fatty Acid Catabolism and

Anabolism



Fatty Acid Anabolism

Fatty acids are synthesized from acetyl CoA.

The major source of acetyl CoA is the carbohydrates.

Therefore excess intake of carbohydrate can be converted to fats.

Acetyl CoA is needed in the synthesis of fatty acid and fatty acid is needed in thesynthesis of triglyceride which is the storage form of lipids in the body.

This complex process of biosynthesis of fats is referred to as lipogenesis.

The reductive synthesis of fatty acids is a cytoplasmic process carried out by amultienzyme complex called the acyl carrier protein (ACP).

The reduction-oxidation steps require nicotinamide adenine dinucleotide

phosphate (NADPH). There are series of steps: ACP Formation, Condensation, Hydrogemation,

Dehydration, and hydrogenation.



Steps in fatty acid biosynthesis

Acp Complex Formation

Step 1: Transfer of acetylgroup to acyl carrierprotein (ACP) with noenergy input. Thereaction is catalyzed byacetyltransferase andmalonyl CoA. .

Step 2: Malonyl CoA isadded to the ACP which iscatalyzed bymalonyltransferase and

malonyl –ACP is formed..



Steps in fatty acid Biosynthesis

Elongation Chain

Step 3: Acetyl group is transferred to the malonyl

group with the release of carbon dioxide which is

catalyzed by β-ketoacyl-synthase and Acetoacetyl-ACP is formed.




Step 4: Keto group is reduced to a hydroxyl group

by the beta-ketoacyl reductase activity to form

Beta-hydroxybutyryl-ACP




Step 5: Beta-hydroxybutyryl-ACP is dehydrated toform a trans- monounsaturated fatty acyl groupcatalyzed by β-hydroxyacyl dehydratase in the formof crotonyl-ACP and oxidized NADP and water.

Step 6: Double bond is reduced by NADPH, yielding

a saturated fatty acyl group (Butyryl –ACP) twocarbons longer than the initial one. It is catalyzedby enoyl-reductase.



Regulation of Fatty Acid Metabolism.

Fatty acid metabolism is regulated by theaction of hormone, feedback inhibitionand feed-forward activation.

The free fatty acids from the adiposetissue are used as energy when insulinlevel is low. Insulin controls the storageand release of fatty acids in and out ofthe adipose tissue.

When there is low insulin level and highglucagon level, the fatty acids will bereleased from the adipose tissue.

Then it will be converted into ketonebodies in the liver.

Therefore, fatty acid oxidation and

ketone body synthesis is activated byglucagon.



Metabolic Fate of Fatty Acid

Fatty acids are stored in the form of triglyceride primarily inadipose tissue.

Triglycerides must be hydrolyzed to release the fatty acids whichare oxidized to acetyl CoA for energy.

Fatty acids can also be converted to ketone bodies which can beused as source of energy for extrahepatic tissues.

They also attach to a phosphate group to form thephospholipidsthat composed the cell membranes.Fatty acids are

used for the biosynthesis of bioactive molecules such asarachidonic acid and eicosanoids.Cholesterol, steroids and steroidhormones are all derived from fatty acids.



ANABOLISM OF CHOLESTEROL

Cholesterol is widely distributed in the body because of its variousroles. It is a biosynthetic precursor of bile acids, vitamin D andsteroid hormones.

Cholesterol is abundant in the tissue of the brain and nervoussystem where it contributes to the functioning of ‘synapses' which

allow nerves to communicate with each other.

Exogenous cholesterol is derived in the diet while endogenous arethose synthesized by the body.

Cholesterol is produced in the liver and stored in the gallbladder.Cholesterol biosynthesis involved five major steps:

o es ero osyn es s nvo ve ve



o es ero osyn es s nvo ve vemajor steps:

1. Acetoacetyl-CoA is converted to 3-hydroxy-3-

methylglutaryl-CoA (HMG-CoA) which is catalyzed

by HMG-CoA synthase.



Steps in biosynthesis of Cholesterol

2. HMG-CoA is converted to mevalonate which is catalyzed by HMG-CoA

reductase

3. Mevalonate is converted to isopentenyl pyrophosphate (IPP) with the

release of CO2

.



4. IPP is converted to squalene.



5. Squalene is converted to cholesterol.



Fate of Cholesterol

Cholesterol can be stored in thegall bladder or transported tothe cell membranes where it canbe used to synthesize or repairthe membranes.

Stored cholesterol in the

gallbladder can be concentratedand lead to the formation of gallstones.

Since the body synthesizesenough cholesterol, excessendogenous cholesterol may

builds up in the walls of arteriesand form hard structures calledplaques.

The hardening of the arteries isknown as atherosclerosis

Cholesterol can be recycled backto the liver, therefore only asmall amount is excreted.

The cholesterol that is excretedis first converted to the watersoluble bile acids or bile salts.

Cholesterol that is not excretedcan be used in the synthesis ofvarious classes of steroidhormones.

There are five groups of steroid hormones synthesized from



cholesterol which perform various metabolic functions:

Steroid hormones Metabolic Function

Glucocorticoid Stimulation of gluconeogenesis

Enhance the expression of enzymes involved in gluconeogenesis

Mobilization of amino acids from extrahepatic tissues

Inhibition of glucose uptake in muscle and adipose tissue

Stimulation of fat breakdown in adipose tissue

Mineralocorticoids Aldosterone acts on the kidneys to provide active reabsorption of

sodium and an associated passive reabsorption of water, as well as

the active secretion of potassium

Androgens Inhibit the ability of some fat cells to store lipids by blocking a

signal transduction pathway that normally supports adipocyte

function

Estrogen Increase hepatic production of binding proteins

Progestogens Precursors to other steroids



Steroidogenesis is the process of steroid hormone production in living organisms. This

process requires several oxidative enzymes located in both mitochondria and endoplasmic

reticulum.The biosynthetic pathway for different steroid hormones is depicted in Figure

13.7

na o sm o omp ex an er ve



na o sm o omp ex an er velipid

Complex lipids include the glycerolipids, for which

glycerol is the backbone, and sphingolipids, which

are built on a sphingosine backbone.

The phospholipids, which include both

glycerophospholipids and sphingomyelins, are

crucial components of membrane structure.



The biosynthetic precursor of glycerolipids is phosphatidic acid. Phosphatidic acid

is derived from the phosphorylation of glycerol to form glycerol-3-phosphate

which is catalyzed by glycerokinase.

It is also synthesized from dihydroxyacetone phosphate (DHAP) which

can be reduced to glycerol-3-phosphate by glycerol-3-phosphate dehydrogenase.

Another way is the addition of first acyl chain to the DHAP catalyzed by

acyltransferase.

It is followed by reduction of the backbone keto group by

acyldihydroxyacetone phosphate reductase, using NADPH as the reductant. Then

the phosphatidic acid is converted directly to glycerolipids which is catalyzed by

phosphatidate cytidyltransferase.



Sphingolipid Biosynthesis

Sphingolipids are present in myelinsheath that insulates nerve axons.

The initial reaction, which involvescondensation of serine and palmitoyl-CoA with release of bicarbonate, iscatalyzed by 3-ketosphinganine

synthase. Reduction of the ketone product to form

sphinganine is catalyzed by 3-keto-sphinganine reductase, with NADPH as areactant.

Then sphinganine is acylated to form N-

acyl sphinganine, which is thendesaturated to form ceramide.Ceramide is the building block for allother sphingolipids. (Figure 13.16)



Eicosanoid Biosynthesis

Eicosanoids arecyclopentanoic acids derivedfrom the fatty acid which isthe arachidonic acid.

They include prostaglandins,

thromboxanes,prostacyclins,andleukotrienes.

Eicosanoids are not storedwithin cells, but aresynthesized whenever the

body needs them. Usually theyare release in the

body during inflammation.



Prostaglandinisoriginally shown to be synthesized



g g y y

in the prostate gland. One of the important function of

prostaglandin is the contraction and relaxation of smooth

muscle tissue.Prostaglandins are autocrine or paracrine

hormones which exert effect on the immediate vicinity of

the site of their secretion.

Prostacyclin is produced in endothelial cells from prostaglandinby the action of the



y p p g y

enzyme prostacyclin synthase. (Figure 13.17) Prostacyclin inhibits platelet

activation thus preventing the formation of the platelet plug which is involved in

blood clot formation.

Thromboxaneisproduced by activated platelets from prostaglandin by the



Thromboxaneisproduced by activated platelets from prostaglandin by the

action of the enzyme thromboxane synthase. It act as vasoconstrictorand it

facilitate platelet aggregation. (Figure 13.17)

Leukotriene was first found in leukocytes It is produced in the



Leukotriene was first found in leukocytes. It is produced in the

body from arachidonic acid by the activity of the enzyme 5-

lipoxygenase.(Figure 13.17) It triggers contractions in the smooth

muscles lining the trachea and their overproduction is a majorcause of inflammation in asthma and allergic rhinitis.

9. Lipids and Lipoproteins

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