1

…Úrsula on the other hand, held a bad memory of that visit, for she had entered the room just as Melquíades had carelessly broken a flask of bichloride of mercury. “It’s the smell of the devil,” she said. “Not at all,” Melquíades corrected her. “It has been proven that the devil has sulphuric properties and this is just a little corrosive sublimate.” …

Gabriel García Márquez, One Hundred Years of Solitude.

2

LIPID METABOLISM• Lipids serve as a source of energy and for the synthesis

of membranes and biologically active molecules• Fatty acids are the preferred source of energy for the

heart, the liver and for the skeletal muscles (during rest and prolonged activity)

• Fatty acids can be obtained from the diet or they can be synthesized from excess carbohydrates and proteins (mainly in the liver and the adipose tissue) and stored in the adipose tissue

• advantages to having triacylglycerides as storage lipids: they have high energy content because they are

highly reduced they form aggregates because of their non-polar

nature; osmolality is not raised and there is no solvation stability of the C-C bonds

3

human milk, on the other hand, is rich in long-chain fatty acids which are essential for the development of the brain some amount of lipases is also released along

with the milk• The insolubility of lipids in water poses a problem

for their digestion lipid-digesting enzymes are water-soluble they can access only the outer surface of the lipid aggregates this problem is solved by bile salts which emulsify the lipids and increase the surface area that is exposed to the enzymes

• Bile salts are amphipathic molecules synthesized from cholesterol by the liver and stored in the gall bladder

4

The digestion and transport of lipids • Although the main lipids in the diet are

triacylglycerides, small amounts of phospholipids, cholesterol and cholesterol esters are present

• Most of the digestion of lipids in the intestine and produces free fatty acids, 2-monoacylglycerols, cholesterol and lysophospholipids (phospholipids with a fatty acid removed from carbon 2)

• Lingual and gastric lipases are relatively active in infants and children

the enzymes cleave short and medium-chain ( < 12 carbons) fatty acids from triacyglycerides

short and medium-chain fatty acids are abundant in cow milk

5

• Secretion of bile salts and cholesterol into the bile is the only way of excreting cholesterol

• Bile salts enclose pieces of triacylglyceride• Colipase binds with TAG and lipase; removes bile salts

and the lid that was covering the active site of lipase• Lipase breaks triacyglycerides down into two free fatty

acids and 2-monoacyglycerol• Cholesterol esterase produces free cholesterol and a

fatty acid molecule• Phospholipase A2 gives a lysophospholipid and a fatty

acid lysophospholipids are powerful detergents assist in the emulsification process

Some amount of lecithin (phosphatidylcholine) is secreted in the bileBee and cobra venoms contain phospholipase A2

6

7

•Short and medium-fatty acids are absorbed directly into the intestinal epithelial cells •Once in the cells, they are bound with intestinal

fatty acid binding protein (I-FABP)

8

• From the intestine they pass to the portal veins and they travel to the liver bound with albumin the function of I-FABP and albumin is to increase

solubility and prevent the damage to cell membranes that could be brought by the detergent properties of free fatty acids

• The absorption of the remaining products of lipid digestion is through the formation of mixed micelles that are made up of amphipathic molecules: bile salts, lysophospholipids, long-chain fatty acids, 2- monoacyglycerol , cholesterol and fat-soluble vitamins

• Except for the bile salts, the rest are absorbed by the duodenal and jejunal epithelial cells

in the epithelium triacylglycerides, phospholipids and some cholesterol ester are resynthesized

• > 95 % of the bile salts reabsorbed in the ileum and returned to the liver (enterohepatic circulation) to be recycled; the rest is excreted

9

Absorp

tion of t

he

products

of lipid digesti

on

10

Enterohepatic circulation of

bile salts

11

oSteatorrhea or the excretion of undigested lipids could result from the deficiency of pancreatic lipase or bile salts

• the digestion and absorption of fat-soluble vitamins is also impaired

• If the resynthesized TAG were to enter the blood directly, they would have formed aggregates and blood flow would have been blocked

• This problem is solved through the synthesis of chylomicrons – one type of lipoproteins

• The idea behind lipoproteins is to transport hydrophobic lipids by sequestering them in the core of the particle and covering them with a hydrophilic layer made up of proteins

• The core of chylomicrons consists of TAG, cholesterol esters and vitamins; the surface is made of proteins and the polar groups of cholesterol and phospholipids

12

The resynthesis of TAG

• The main apoprotein of chylomicrons is Apo B-48 and is produced by the rough endoplasmic reticulum

• TAG resynthesized by the smooth ER; TAG and Apo B-48 are packed into chylomicrons in the Golgi complex

• Other proteins in chylomicrons include Apo-CII and Apo-E• Of the lipoproteins, chylomicrons are the biggest in the size

and the lowest in density (smallest amount of proteins)

13

14

• Nascent chylomicrons (containing only Apo B-48) are exocytosed into the lymph and then join the blood stream

• While in the circulation, they receive the other apoproteins from high density lipoprotein (HDL) and become mature chylomicrons

• a fat-rich meal gives the blood a milky appearance• Chylomicrons are destined mainly for the adipose,

muscles (especially cardiac muscles) and lactating mammary glands

• These tissues produce lipoprotein lipase (LPL)• LPL is found associated with the proteoglycans in the

basement membranes of the endothelial cells of the capillaries serving these tissues

• The LPL isozyme from the adipose has a higher Km and is most active after meals when there is much TAG in the blood

• insulin stimulates the synthesis of adipose LPL

15

• LPL is activated by Apo CII and removes fatty acids from the TAG of the chylomicrons

• The free fatty acids travel bound with albumin until they are absorbed

• The fatty acids are used as energy sources in the muscles

• In the adipose they are reesterified and stored while in the mammary glands they are incorporated into milk fat

• The glycerol that was produced through the action of LPL travels to the liver and could be used for TAG synthesis in the fed-state

• When most of the TAG has been removed, chylomicrons shrink and become chylomicron remnants

• Chylomicron remnants are endocytosed by the liver (through recognition of Apo E) and their contents are degraded in the lysosomes

16

17

Mobilization of triacylglycerides from the adipose• The adipose stores mainly TAG and steroid hormone –

synthesizing tissues like the adrenal cortex, ovaries and testes store cholesterol esters

• The lipids are stored in the form of lipid droplets: a core of TAG or cholesterol esters surrounded by a single layer of phospholipids and perilipin proteins

• Perilipins prevent the untimely mobilization of lipids• The release of glucagon in the fasting state or

epinephrine in the fight or flight response increases the level of cAMP – a secondary messenger – in the adipose

• cAMP activates protein kinase A which in turn phosphorylates perilipin

• The phosphorylated perilipin allows hormone-sensitive lipase (HSL) to move to the surface of the lipid droplet

18

• HSL also is phosphorylated by protein kinase A; but the main factor for the massive increase in mobilization is the phosphorylation of perilipin

• HSL breaks TAG down into fatty acids and glycerol• The glycerol travels to the liver and is used for

gluconeoge.• Some of the fatty acids travel-bound with albumin-

to the cardiac and skeletal muscles and the renal cortex; provide energy

• About 75 % of the fatty acids released by lipolysis are reesterified

• This is known as the triacylglycerol cycle • the fatty acids are reesterified while they are still in

the adipose or after they have travelled to the liver• The cycle operates even during starvation

19

20

• In the adipose tissue, dihydroxyacetone from glycolysis is changed to glycerol-3-phosphate for TAG synthesis; the liver can make use of glycerol

• But glucagon and epinephrine inhibit glycolysis and DHAP would not be available in the adipose for TAG synthesis

o What is the source of the DHAP used for the synthesis of TAG in the adipose during starvation? glyceroneogenesis is a shortened version of

gluconeogenesis that produces DHAP from gluconeogenic substrates like alanine, aspartate and malate the adipose has two gluconeogenic enzymes –

pyruvate carboxylase and PEP carboxykinase – even though it does not produce glucose

21

• Glyceroneogenesis supports TAG synthesis in the liver during starvation

• Natural and artificial glucocorticoids induce the synthesis of the liver isozyme of PEP carboxykinase while inhibiting the adipose isozyme little reesterification in the adipose; more fatty

acids will be released to the blood stream but esterification in the liver will be more active

and reestablish the 75 %• Excess levels of fatty acids in the blood have been

implicated in the development of insulin resistance thiazolidinediones are drugs that induce the

synthesis of the adipose isozyme of PEP carboxykinase used in the treatment of type 2 diabetes mellitus

22

The

tria

cylg

lyce

rol c

ycle

Thiazolidinediones

23

FATTY ACID CATABOLISM/β- OXIDATION• Fatty acids released from the adipose have their

origins in the diet or synthesis in the liver• The most common dietary fatty acids are palmitate

(16:0), stearate (18:0), oleate (18:1) and linoleate (18:2)

• Animal fat contains mostly saturated and monounsaturated fatty acids while vegetable oils contain linoleate and longer polyunsaturated fatty acids

• Fatty acids enter cells both by diffusion and sodium- dependent transport

• As shown by Lehninger and Kennedy, the oxidation of fatty acids takes place in the mitochondria

• Short and medium-chain fatty acids can freely enter into and be activated in the mitochondria

24

• long chain fatty acids, on the other hand, are first activated in a reaction with CoA; form a high energy thioester

the acyl-CoA synthetase is present in the ER and the outer membranes of the mitochondria and the peroxisomes . It shows little or no activity with short, medium and very long chain (>22C) fatty acids

25

• The fatty acyl-CoA can be used either in the synthesis of TAG and membrane lipids or transported into the mitochondria and used for energy production

• Transport by the carnitine shuttle Carnitine reacts with fatty acyl-CoA and gives

acyl- carnitine; commits the fatty acids to oxidation the enzyme responsible is carnitine

acyltransferase I (CAT I) which is located on the outer mitochondrial membrane

Acylcarnitine crosses the inner membrane through a translocase

In the mitochondria CAT II changes acylcarnitine to fatty acyl-CoA

Carnitine returns to the cytosol through the translocase

26

Acylcarnitine

27

• As the name indicates, β-oxidation is a set of reactions aimed at forming a carbonyl group on the β-carbon

• The presence of two carbonyl groups weakens the otherwise stable Cα-Cβ bond and acetyl-CoA groups are removed successively

• One cycle of β-oxidation consists of four reactions 1. The oxidation of the Cα-Cβ bond • Catalyzed by acyl-CoA dehydrogenases - a family

of three isozymes specific for short, medium and long-chain FA

• Contain non-covalently (but tightly) attached FAD• FADH2 transfers the electrons to electron transfer

flavoprotein (ETF)• ETF is oxidized by ETF:UQ oxidoreductase and the

electrons are delivered to coenzyme Q

28

o The double bond is in the trans form

29

2. Addition of water across the double bond• Trans-Δ2-enoyl-CoA is acted upon by enoyl-CoA

hydratase

3. Oxidation of the β –hydroxyl group • β –hydroxyacyl-CoA is oxidized by L-

hydroxyacyl-CoA dehydrogenase; NAD is the electron carrier

30

4. cleavage of the Cα-Cβ bond• β –ketoacyl-CoA cleaved by β –ketoacyl thiolase• An acetyl-CoA molecule and an acyl-CoA two

carbons shorter are produced

o Steps 2-4 of the β-oxidation of long chain fatty acids are carried out by a multienzyme complex known as trifunctional protein (TFP) individual enzymes for short and medium

chain FA

31

• A cycle of β-oxidation releases one molecule each of FADH2,NADH and acetyl-CoA

• the four steps are repeated n/2 - 1 times ( n = number of carbons) until the final acetyl-CoA is released

• n/2 acetyl-CoA and n/2 - 1 each of FADH2 and NADH are produced by the complete oxidation of a fatty acid with an even number of carbons

• taking the oxidation of palmitate (16:0):Palmitoyl-CoA+ 7 CoA+ 7 FAD+ 7 NAD++7 H2O→ 8

acetyl-CoA+ 7 FADH2+7 NADH+ 7H+

• 8 acetyl-CoA ≈ 8o ATP, 7 FADH2 ≈ 10.5 ATP and 7 NADH ≈ 17.5 ATP ⇒ total = 108 ATP

• the equivalent of two ATP is spent on activation of FA⇒ net production of 106 ATP

o The oxidation of fatty acids releases a large amount of metabolic water

32

the β-oxidation of odd-chain fatty acids• Odd-chain FA are common in plants and marine

organisms• β-oxidation proceeds in the normal way but the last

product to be released is not acetyl-CoA but propionyl-CoA

• The propionyl-CoA is first changed to D-methylmalonyl-CoA through the action of propionyl-CoA carboxylase

biotin is the coenzyme• D-methylmalonyl-CoA is epimerized• L-methylmalonyl-CoA undergoes intramolecular

rearrangement to give succinyl-CoA this is one of the two reactions in humans where

vitamin B 12 is involved• Succinyl-CoA can be used for energy production or the

synthesis of glucose

33

34

the β-oxidation of unsaturated fatty acids• Double bonds naturally occurring in fatty acids are

in the cis form• Enoyl-CoA hydratase cannot act on cis double

bonds• In order for β-oxidation to proceed, either the cis

form has to be changed to trans or the double bond should be reduced

• Two additional enzymes are needed – an isomerase and a reductase

• For monounsaturated fatty acids, the enoyl-CoA isomerase suffices

• Polyunsaturated fatty acids need the participation of both enzymes

• NADPH is used as the reductant

35

This

slid

e: t

he o

xida

tion

of

a m

onou

nsat

urat

ed f

atty

aci

d –

olea

te

Nex

t s

lide:

the

oxi

dati

on o

f a

poly

unsa

tura

ted

fatt

y ac

id–l

inol

eate

36

37

the regulation of β-oxidation• The concentration of mitochondrial CoA may be

limiting to the formation of fatty acyl-CoA• The formation of malonyl-CoA is the first step

during the synthesis of fatty acids• Malonyl-CoA inhibits CAT I making sure that fatty

acids do not get degraded at the same time they are synthesized

• High levels of FADH2 and NADH respectively inhibit acyl-CoA dehydrogenase and β-hydroxyacyl-CoA dehydrogenase; high levels of acetyl-CoA inhibit thiolase

38

Disorders of fatty acid oxidation• Inherited defects in the carnitine-assisted transport or the

enzymes of β-oxidation are manifested as serious heart disease

• CAT I/II, carnitine translocase, acyl-CoA dehydrogenases, … may be defective

• Carnitine obtained from the diet or synthesized in the body carnitine deficiency is unlikely to be seen in adults carnitine related enzymes and transporters are more

commonly deficient leading to the accumulation of long chain acyl/ acyl carnitine

weak muscles; should avoid prolonged exercise and fasting

• Acyl-CoA dehydrogenase deficiency results in the excretion of *derivatives of fatty acids in the urine and *non-ketotic hypoglycemia

39

Alternate routes of fatty acid oxidation • Minor, yet important pathways of fatty acid

oxidation 1. peroxisomal oxidation • Human diet usually contains VLCFA and

branched-chain fatty acids from chlorophyll degradation

• VLCFA are also produced in high amounts in the nervous system and incorporated into the myelin sheath

• VLCFA undergo β-oxidation but the first step is unique in that it transfers electrons from acyl-CoA to FAD and then to O2 - production of H2O2

Acyl-CoA oxidase

40

• The three remaining reactions of β-oxidation proceed in the normal way

• Acetyl groups move out of the peroxisome by themselves or carried by carnitine

• When the acyl-CoA is shortened to about 8 carbons, it is transported out of the peroxisomes (with carnitine) and its oxidation is completed in the mitochondria

41

• Another type of oxidation takes place in the peroxisomes – α-oxidation of branched-chain fatty acids• Mainly on phytanic acid and pristanic acid• phytanic acid is first changed to pristanic acid by

hydroxylation of the α carbon followed by decarboxylation • The shortening by one carbon puts methyl groups on the α

rather than the β carbon – normal β oxidation continues• Acetyl-CoA and propionyl-CoA are alternatively removed

from the acyl-CoA• When a middle-chain acyl-CoA is reached, it is transported

to the mitochondria• Refsum’s disease - deficiency of phytanic acid α

hydroxylase accumulation of phytanic acid in the body leads to serious neurological problems

42

43

• Zellweger syndrome: the absence of functional peroxisomes ; X-linked adrenoleukodystrophy (XALD): lack of tansporters for VLCFA into the peroxisomes

accumulation of VLCFA in the body, especially C26:0 and C26:1Affect mainly the liver and the brain; fatal in

the very early years of lifeω-oxidation • In the endoplasmic reticulum, the end farthest

from the carboxyl group is oxidized • first, the methyl group is changed to hydroxyl

by cytochrome p 450 enzymes• Then comes dehydrogenation which yields a

dicarboxylic acid

44

• Either end can be attached to CoA and undergo β oxidation

• β oxidation produces smaller dicarboxylic acids such as adipic and succinic acids

• Dicarboxylic acids are highly water-soluble and can be removed through the urine

• ω-oxidation is normally involved in the metabolism of xenobiotics that have structures similar with fatty acids

• ω-oxidation becomes more prominent when β oxidation is defective and the need arises to excrete the unmetabolized fatty acids

45

46

Metabolism of ketone bodies• Most of the acetyl-CoA produced from hepatic fatty acid

oxidation enters the TCA cycle• The remaining acetyl-CoA molecules undergo

ketogenesis – the production of the ketone bodies: acetone, acetoacetate and β-hydroxybutyrate

• The ketone bodies are released from the liver and provide energy for the heart, skeletal muscles, renal cortex and brain

changed back into acetyl-CoA and join the TCA cycle • Ketogenesis occurs in the mitochondrial matrix

two acetyl-CoA condense to give acetoacetyl-CoA another acetyl-CoA is added to acetoacetyl-CoA to

give β-hydroxyl-β –methyl –glutaryl –CoA (HMG-CoA)HMG-CoA is changed to acetoacetate and acetyl-CoAAcetoacetate is reduced to β-hydroxybutyrate or

decarboxylated to acetone

47

48

• The thiolase that catalyzes the first reaction of ketogenesis is the same enzyme that is involved in the last reaction of β oxidation

• Ketogenesis and *cholesterol synthesis share the reactions up to the formation of HMG-CoA

• Acetoacetate and β-hydroxybutyrate are exported to other tissues through the blood

ketone bodies are easily transportable forms of fatty acidsthe conversion of acetoacetate and β-hydroxybutyrate

back to acetyl-CoA takes place in the mitochondria two reactions are retained from ketogenesis and one

new reaction is introduced – the activation of acetoacetate by the transfer of CoA from succinyl-CoA

β-ketoacyl transferase is absent in the liver• Most of the acetone is exhaled

49

• 2 acetyl CoA = 20 ATP• changing succinyl CoA to succinate without the production of GTP ⇒ subtract 1 ATP for the activation

19 ATP• starting from β-hydroxybutyrate

⇒ 21.5 ATP (additional energy from NADH)

50

o The degradation of *ketogenic amino acids provides acetoacetyl-CoA and acetyl-CoA

• The abundance of fatty acids in the blood during the fasting state increases the level of ketone body synthesis

Oxaloacetate is diverted to gluconeogenesisMore acetyl-CoA enters ketogenesis because of the

small levels of oxaloacetate to condense with (for TCA) • In type I diabetes, the inhibitory effect of insulin on

lipolysis is relievedfatty acids released by lipolysis in turn produce excess

amounts of acetyl-CoA even though glucose is abundant in the blood

gluconeogenesis continues unabated – oxaloacetate is consumed for glucose production

51

• In addition, glucose will not be used by the liver for fatty acid synthesis

The levels of malonyl-CoA , which is the starting material for fatty acid synthesis fall

The inhibition of malonyl-CoA on CAT I is relieved β-oxidation produces excess acetyl-CoA which

feeds ketogenesis• The production of acetoacetate and β-hydroxybutyrate

brings about an associated decrease in extracellular pH• If the amount of ketone bodies is more than the amount

that can effectively be buffered by bicarbonate ( > 7mM), ketoacidosis results

the amount of ketone bodies can be measured from the urine or the blood

“Acetone breath” can serve as an indication of excess ketogenesis

52

53

FATTY ACID SYNTHESIS• Fatty acids are used for the synthesis of storage,

membrane and other important lipids • The raw material (acetyl-CoA) for the biosynthesis of fatty

acids comes from the excess intake of carbohydrates or proteins

• The main site of synthesis is the liver and the adipose also carries out some degree of synthesis

• It is a cytosolic process:the acetyl-CoA from the PDC reaction condenses with

oxaloacetate and citrate is exported from the mitochondria

citrate lyase provides cytosolic acetyl-CoA the NADPH provided by the malic enzyme reaction

(and the NADPH from PPP) is used for the biosynthesis protein degradation provides mainly cytosolic acetyl

CoA

54

• The committed step of fatty acid synthesis is the synthesis of malonyl-CoA : acetyl-CoA is acted upon by acetyl-CoA carboxylase (ACC) with the help of biotin

The first half of

the ACC reaction

55

The second half of

the ACC reaction

56

• ACC is the rate limiting enzyme of fatty acid synthesis• ACC is an octamer made up of inactive monomers• The final product of fatty acid synthesis is palmitoyl-CoA• The accumulation of palmitoyl-CoA leads to the

dissociation of the polymers• Citrate, on the other hand, favors the association • The local control exerted by citrate and palmitoyl –CoA

acts in concert with the global control of hormones dephosphorylated ACC has got a higher affinity for citrate and small amounts of citrate can activate it phosphorylated ACC has got a higher affinity for palmitoyl- CoA and small amounts of palmitoyl-CoA can inhibit it the enzyme responsible for the phosphorylation is AMP-dependent protein kinase (AMPK) – activated by AMP and inhibited by ATP

57

• Glucagon and epinephrine activate protein kinase A which phosphorylates and inactivates phosphatase 2A

• Insulin activates the phosphatase and favors fatty acid synthesis

• Adaptive control of ACC based on the diet - high carbohydrate foods induce the synthesis of ACC and fatty acid synthase

Fatty acid synthase (FAS)• During fatty acid synthesis, two carbons from malonyl-

CoA are added to a growing acyl chain that began with acetyl-CoA as a primer

• The series of reactions until the stage of palmitoyl-CoA is reached is catalyzed by FAS

• FAS is a dimeric protein with identical subunits• Each subunit has seven enzymatic activities and an

acyl carrier protein (ACP)FAS is a multifunctional protein

58

Glucagon, epinephrine

_

The regulation of ACC

59

• The subunits of FAS are arranged in a “head-to-tail” manner

• Each subunit has three domains• The first domain is responsible for the binding and

condensation of acetyl and malonyl groups: contains acetyl transferase (AT), malonyl transferase (MT) and β-ketoacyl synthase (KS)

• The second domain reduces the intermediate produced by the first domain using NADPH; contains ACP, β-ketoacyl reductase (KR), dehydratase (DH) and enoyl-CoA reductase (ER)

• The third domain contains thioesterase (TE) which releases the final product, palmitate

• Growing acyl chains are transferred between the cysteinyl sulfhydryl group of the KS of one subunit and the phosphopantetheinyl sulfhydryl group of the ACP of the other subunit

60Fatty acid synthase

61

The mechanism of fatty acid synthase • Domain 1 of one subunit interacts with domains 2

and 3 of the other subunit• Acetyl-CoA and malonyl-CoA attach to serine

residues on AT and MT, respectively (the CoA is removed)

• Acetyl is then transferred to the ACP of the other subunit and ACP takes acetyl to the KS of the previous subunit

• The now free ACP carries the malonyl and takes it to the KS

• Condensation takes place on KS with the removal of CO2

the CO2 removed is the same one that was introduced during the synthesis of malonyl-CoA decarboxylation favors nucleophilic attack of

the methylene carbon of malonyl on carbonyl of acetyl on KS; makes the process of the condensation of acyl groups exergonic

62

63

• After the condensation, the four carbon ketoacyl – acetoacetyl – would be carried by ACP

• ACP takes acetoacetyl to domain 2 where reduction, dehydration and saturation take place (step 6 on the figure)

• ACP gives the product to KS and is once again ready to accept a malonyl group from MT

• Steps 4-6 are repeated until the 16 carbon acyl, palmitate is on KS; KS then gives palmitate to ACP

• Palmitate is released from KS by thioesterase and synthesis on FAS stops

• The acetyl group added to AT in the beginning becomes the ω- carbon of palmitate

o FAS synthesizes two fatty acids simultaneously

64

β-ketoacyl

reductase (K

R)

dehydratase (DH)

enoy

l-CoA

redu

ctas

e (E

R)

65

The balance sheet of fatty acid synthesis• The activation of acetyl-CoA:7 acetyl-CoA + 7 CO2 + 7 ATP→ 7 malonyl-CoA +

7 ADP + 7Pi• Seven cycles of FAS reactions:acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14

H+→ palmitate + 7 CO2 + 14 NADP++ 8 CoA + 6 H2O

*6 H2O because one water molecule is consumed by thioesterase

• Overall reaction:8 acetyl-CoA + 7 ATP + 14 NADPH + 14 H+→

palmitate + 8 CoA + 7 ADP + Pi + 14 NADP++ 6 H2O

• Assuming all of the cytosolic malate produced by citrate lyase is changed to pyruvate, 8 NADPH would be formed for 8 cytosolic acetyl-CoA molecules

• The remaining 6 NADPH molecules would come from the pentose phosphate pathway

66

Elongation of fatty acids • Shorter chain fatty acids can be synthesized by

terminating the reaction before reaching the level of palmitate

• The synthesis of longer chain fatty acids takes place on the smooth endoplasmic reticulum and in the mitochondria

• First, palmitate is activated by CoA• In the SER, malonyl-CoA attacks the carboxyl end

of palmitoyl-CoA decarboxylation, reduction and dehydration take place in the same way as the corresponding FAS reactions

• In the mitochondria, acetyl-CoA molecules are successively added

the reactions are nearly the reverse of β-oxidation except that NADPH is used instead of FADH2 for the reduction of the double bond

67

Mitochondrial

elongation of fatty

acids

68

• The main elongation reaction in the body is the synthesis of stearate,18:0

Desaturation of fatty acids• The most common unsaturated fatty acids in the

body are palmitoleate,16:1 (△9) and oleate, 18:1 (△9)

• Desaturation takes place in the SER• O2, NADH, cytochrome b5 and the flavoprotein

cytochrome b5 reductase are involved• The reaction is catalyzed by fatty acyl-CoA

desaturase • The fatty acyl-CoA and NADH/H+ donate two

electrons and two protons each – the synthesis of two water molecules

NADH gives its electrons to cytochrome b5 reductase

cytochrome b5 reductase passes the electrons to cytochrome b5

fatty acyl-CoA desaturase accepts electrons from cyt. b5

69

• Fatty acyl-CoA desaturase donates the electrons from cytochrome b5 and fatty acyl-CoA to oxygen

a cis double bond formed; water released

o humans get trans fatty acids from butter, milk and partially-hydrogenated vegetable oils - margarine • excessive consumption of trans fatty acids is a risk factor for heart disease

70

The synthesis of polyunsaturated fatty acids• in addition to the △9 position, hepatocytes and

adipocytes can introduce double bonds at the △4 ,

△5 and △6 positions • △9 unsaturated fatty acids can be elongated to

give fatty acids with double bonds at positions beyond △9

• Fatty acids with double bonds three (ω-3) or six (ω-6) carbons away from the methyl end are required for the synthesis of important molecules known as eicosanoids : “eicosa” twenty

• Humans cannot synthesize these fatty acids de novo (even with the combination of desaturation and elongation)

• Precursors of ω-3 and ω-6 fatty acids must be provided in the diet and these precursors are known as essential fatty acids

linoleate,18:2 (△9,12) - an ω-6 fatty acidα -linolenate,18:3 (△9,12,15) - an ω-3

fatty acid

71

• Linoleate and α –linolenate are mainly obtained from plant oils

• In the body essential fatty acids are elongated and unsaturated further:

Linoleate is changed first to dihomo γ– linolenate (DGLA; eicosatrienoate), 20:3 (△8,11,14) and then to arachidonate (eicosatetraenoate) , 20:4 (△5,8,11,14)

α–linolenate is changed to eicosapentaenoate (EPA), 20:5 (△5,8,11,14,17)

Fish oils contain ω-3 and ω-6 fatty acids e.g. EPA and docosahexaenoate (DHA), 22:6 (△4,7,10,13,16,19)

DHA is found in high concentrations in the retina, cerebral cortex, testis and sperm; provided by the placenta and milk

72

Eicosanoid synthesis• Eicosatri/tetra/pentaenoate are utilized in the

synthesis of different kinds of eicosanoids – series 1, 2 and 3 eicosanoids resp.

the series number depends on the number of double bonds found outside of the ring structure of the eicosanoids

• Arachidonate obtained in the diet or synthesized in the body is found esterified in phospholipids of the membranes

• The activation of phospholipase A 2 or C (by cytokines and histamine) lyses arachidonate from phospholipids

• Arachidonate is then used for the synthesis of eicosanoids

• Properties of eicosanoids:Local hormones that act in an autocrine or

paracrine mannerExert their effects at very low concentrations

They are not stored; rapidly inactivated

73

• There are three major ways of synthesis of eicosanoids:

1. The cyclooxygenase pathway • Produces prostaglandins and thromboxanes• Prostaglandin endoperoxide synthase acts on

arachidonate to give PGH2 which is the precursor for the remaining prostaglandins and thromboxanes

74

75

•Prostaglandin endoperoxide synthase is a membrane-bound enzyme that has cyclooxygenase and gluthathione-dependent hydroperoxidase activities•Letters (E,H,…) are assigned based on ring

substituents•The numbers refer to the series of eicosanoids•Thromboxanes are structurally similar to

prostaglandins except that they have a six-membered ring containing oxygen•The functions of prostaglandins and

thromboxanes: PGD2, PGE2, PGI2 (prostacyclin) – induce

vasodilation and inhibit platelet aggregation and the action of immune cells

PGF2α - constriction of bronchi and blood vessels; smooth muscle contraction

Thromboxane A2 – favors vasoconstriction, platelet aggregation and immune action

76

• thromboxane A2 and prostacyclin have antagonistic effects•The effects of prostaglandins on smooth

muscles could have therapeutic uses: induction of labor, control of blood pressure, …• The prostaglandins and thromboxanes

synthesized from EPA (an ω-3 fatty acid) inhibit the release of arachidonate from membranes and also the synthesis of series-1 prostaglandins and thromboxanes

members of series-1 are more inflammatory → inflammation is potentially reduced

PGI3 is as potent anti-platelet aggregator as PGI2 but TXA3 is a weaker aggregator than TXA2 → longer clotting time

o Part of the reason why ω-3 fatty acids have been receiving much attention

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•Prostaglandin and thromboxane synthesis can be inhibited at two levels:

phospholipase A2 – inhibited by steroidal anti-inflammatory drugs – arachidonate cannot be released

cyclooxygenase – the site of action of aspirin and other non-steroidal anti-inflammatory drugs

• COX has two main isozymes: COX 1 - is constitutive and the

thromboxane A2 and prostacyclin it synthesizes are involved in hemostasis; prostacyclin is also involved in the reduction of proton secretion and increase of bicarbonate secretion in the stomach COX 2 - is thought to be induced in response

to inflammatory stimuli

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•Aspirin inhibits both isozymes – anti-inflammation; prevention of blood clotting and, gastric ulcer•New drugs were developed that could selectively

inhibit COX 2 thereby preventing the adverse effects on the stomach

celebrex and vioxx • But COX 2 can be constitutive in the kidneys

where PGE2 products lead to the dilation of arterioles and the excretion of sodium and water

• Vioxx was banned due to cases of hypertension associated with its use

aspirin acetylates a serine residue in the active site of COX and ibuprofen blocks the hydrophobic channel by which arachidonate enters the COX active site

the anti-clotting effect of aspirin is prominent because platelets lack a nucleus and do not make new COX (and TXA2) while blood vessels can resynthesize COX (and PGI2)

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2. The lipooxygenase pathway • 5-, 12- and 15-lipoxygenases synthesize three types

of hydroperoxyeicosatetraenoate (HPETE) • Different types of leukotrienes, lipoxins and HETE

(hydroxyeicosatetraenoate) are synthesized from the HPETE

• These are molecules without ring structures; leukotrienes and lipoxins have three conjugated double bonds

• Glutathione is used in the synthesis of LTC4 from LTA4• Slow reacting substance of anaphylaxis (SRS-

A) is a mixture of LTC4 , LTD4 and LTE4 - causes bronchoconstriction

• SRS-A , along with LTB4 , increase vascular permeability and the secretion of chemical mediators of immunity

• LXA4 and LXB4 are anti-inflammatory3. The cytochrome P 450 pathway –

monooxygenases act on arachidonate to give HETEs, diHETEs and epoxides

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THE BIOSYNTHESIS OF COMPLEX LIPIDS• Complex lipids are used for energy storage, membrane

building and the synthesis of important biological molecules

• fatty acids in the body are mainly found covalently bound to a backbone structure

• Other groups can also be found attached to the backbone structure

• The main classes of complex lipids are: glycerolipids –backbone is glycerol sphingolipids –backbone is sphingosine derivatives of cholesterol–backbone is cholesterol

• Phospholipids are a class consisting of members of both glycerolipids and sphingolipids

• Most of the reactions involved in lipid biosynthesis are carried out in the smooth endoplasmic reticulum

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Glycerolipids • Three classes; triacylglycerols,

glycerophospholipids and ether glycerolipids

• The first two classes are synthesized from a common intermediate – phosphatidate

glycerol-3-phosphate from glycerol (in the liver) or from dihydroxyacetone phosphate (in the liver and adipose) undergoes successive esterifications by two fatty acyl CoA molecules this is a different mechanism from the

one used in the intestine to resynthesize dietary triacylglycerols in the case of triacylglycerols, the

phosphate group is removed from phosphatidate to give diacylglycerol (DAG); the third fatty acid is then added

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The

synt

hesis

of T

AG• One option for the

synthesis of glycerophospholipids is changing phosphatidate to DAG and then esterifying it with an activated alcohol (head group)

• Or the phosphatidate can first be activated and then the alcohol group could be added

• Activation is through reaction with cytidine triphosphate (CTP)

• The main alcohol components of glycerophospolipids include choline, ethanolamine, serine, inositol and glycerol-3-phosphate

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• The linkage formed by the phosphate group with the glycerol backbone and the head group is known as a phosphodiester bond

• Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are produced using the first strategy

• Phosphatidylserine (PS) is synthesized by exchanging serine for the ethanolamine in PE

• PS can be decarboxylated to PE• PE can be methylated to give PC

o the methyl donor is S-adenosyl methionine (SAM)

• Phosphatidycholine is the dominant membrane lipid; most of the choline is obtained from the diet

• Dipalmitoylphosphatidylcholine is the major component of lung surfactant

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• Lipids synthesized using the second strategy include phosphatidylinositol (PI), phosphatidylglycerol (PG) and cardiolipin

• The addition of glycerol-3-phosphate to CDP-DAG gives PG

• PG can then be added to CDP-DAG to give cardiolipin

• Cardiolipin is abundant in the inner mitochondrial membrane

• PI can be phosphorylated to give phosphatidylinositiol 4,5- bisphosphate (PIP2 )

o PIP2 breaks down to the important signaling molecules inositol-1,4,5- triphosphate (IP3) and DAG

• phosphatidyl inositol is unique among phospholipids in having a nearly fixed composition of fatty acids: stearic acid at C-1 and arachidonic acid at C-2

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The synthesis of ether glycerolipids• DHAP is used as a backbone without being

changed to glycerol-3-phosphate • C-1 of DHAP is esterified with a fatty acid and then

the fatty acid is exchanged for a fatty alcohol which will be attached with DHAP by an ether linkage

the alcohol is synthesized by reducing the corresponding acyl-CoA with the help of NADPH

• The keto group at C-2 is then reduced and acylated

• Head groups are added to the 1-alkyl-2-acylglycero-3-phosphate in a manner similar to that of PC and PE

• Desaturation of the akyl group produces plasmalogens

ethanolamine plasmalogen is found in the myelin and choline plasmalogen in cardiac muscle

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• Platelet-activating factor (PAF) has a choline head group on C-3, acetyl on C-2 and a saturated (alkyl) group on C-1

The very short chain at C-2 makes PAF more water soluble than other glycerolipids

PAF is released by phagocytic cells and causes platelet aggregation, edema and hypotension

PAF synthesis takes place in the peroxisomes;

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Degradation of glycerophospholipids• Phospholipases located on the cell membrane or in

lysosomes carry out the degradation• Phospholipase A1 removes fatty acid from C-1 and

A2 from C-2; the fatty acid at C-2 is usually arachidonate

• Phospholipasse C cleaves the phosphate-glycerol bond; it is activated by hormones and is responsible for the synthesis of IP3 and DAG from PIP2

• Phospholipase D separates the head group from phosphate

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Sphingolipids• The precursors for the synthesis of the backbone

are serine and palmitoyl-CoA• The final product is ceramide , which is the

derivative of the amino alcohol sphingosine• Various head groups can be added to ceramide to

give two types of lipids: Phospholipids – sphingomyelin is

synthesized by the transfer of choline from PC to ceramide

•Sphingomyelin is a major component of the myelin sheathGlycolipids – a sugar molecule or a chain of

sugar molecules is attached to the hydroxyl at C-1 of ceramide

•Cerebrosides – a single sugar (usually glucose or galactose) is added from a UDP-activated form

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• Galactocerebrosides are characteristic of the cell membranes of neural tissue while glucocerebrosides are found in non-neural tissue

• 3’-phosphoadenosine - 5’-phosphosulfate (PAPS) donates sulfate to galactocerebroside to form sulfatides

•Globosides– are formed when additional sugars (including amino sugars) are added to ceramides•Gangliosides – globosides that contain a

sialic acid N-acetylneuraminic acid (NANA) in addition to sugars; acidic

NANA N-acetyl-galactosamine (GalNac)

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• Gangliosides on cell surfaces may play an important role as sites of recognition the oligosaccharide moieties

of glycoproteins and glycolipids are informational molecules lectins are proteins that

recognize specific oligosaccharides on cell surface and facilitate communication and adhesion between cellse.g. bacterial and viral

infection, half-life of erythrocytes and hormones, …

• the ABO blood group antigens are determined by the variation of the sugar residues present in glycolipids/glycoproteins on the surface of RBC and endothelial cells

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Sphingolipid degradation and sphingolipidoses

• Lysosomal enzymes remove members of the head group one by one in order to finally give ceramide

• Deficiency in any one of the enzymes would lead to the accumulation of partial breakdown products in the tissues leading to serious disease mainly affecting neural tissue

• Some examples: Tay-Sachs disease – a common deficiency in

hexos- aminidase which removes GalNac; retardation in development, paralysis, blindness and death before age 4

Niemann-Pick disease – a rare deficiency in sphingomyelinase which cleaves phosphocholine; mental retardation and early death

Gaucher disease – deficiency in glucosidase; accumulation of glucosyl ceramide in the liver and spleen

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Cholesterol metabolism• Cholesterol is as essential component of cell

membranes and it serves as a precursor for bile salts, steroid hormones and vitamin D

• Cholesterol is synthesized in all cells of the body but the most active tissues are the liver, adrenal cortex, the intestine and the gonads

• The entire cholesterol structure is derived from acetate

• In the first stage of cholesterol synthesis, three molecules of acetyl-CoA are changed in the SER to the six carbon molecule mevalonate

• The HMG-CoA synthase used here is a cytosolic isozyme

• the conversion of HMG-CoA to mevalonate by HMG-CoA reductase is the rate –limiting and committed step of the whole process of cholesterol synthesis

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• HMG-CoA reductase is regulated in 3 ways:

1.Phosphorylation by cAMP- dependent kinases – inactivates the enzyme

2.Degradation – HMG-CoA reductase has a half-life of 3 hrs. which could be shortened further if cholesterol levels are high

3. Repression – high levels of cholesterol reduce the synthesis of the mRNA for the enzyme

Stag

e 1

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The regulation of HMG-CoA reductase

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• In the second stage of cholesterol synthesis, mevalonate will be changed to two types of activated 5-carbon intermediates (isoprenes): isopentenyl pyrophosphate and dimethylallyl pyrophosphate

• In the third stage, the 30 carbon molecule squalene is produced from 6 units of activated isoprene

• In the fourth and final stage, squalene is changed to lanosterol, a molecule with the characteristic steroid ring

Lanosterol will be changed to cholesterol after 20 more reactions

• Some of the cholesterol synthesized in the liver is used for the synthesis of hepatocyte membranes

• Most of the cholesterol is secreted in the form of biliary cholesterol, cholesterol esters or bile salts cholesterol esters are synthesized by acyl-CoA-acyl cholesterol transferase (ACAT)

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Stag

e 2

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Stag

e 3

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Stag

e 4

4 rings (steroid nucleus) one tail 27 carbons a hydroxyl group NADPH & ATP needed

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Lipoproteins and the transport of cholesterol (and other lipids)

• The liver exports the cholesterol, cholesterol esters and TAG that it has synthesized in the form of very low density lipoproteins (VLDL )

phospholipids and apoproteins are present in VLDL, just like the case of chylomicrons

• The main difference with regards to apoproteins is that VLDL assembly begins with Apo B-100 – a non-truncated form unlike Apo B-48 of chylomicrons

• Apo C II and E play the same role that they had in chylomicrons

The TAG content of VLDL is depleted by the tissues of the adipose, muscle and (lactating) mammary gland

About half of the VLDL remnants known as intermediate density lipoproteins (IDL) are taken up by the liver

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• The remaining half of the IDL undergo further TAG depletion, gain cholesterol esters and become low density lipoproteins (LDL)

• LDL is endocytosed based on recognition of apo B-100

80 % of the LDL are internalized by the liver 20 % of the LDL travel to tissues that need

more cholesterol than they can synthesize e.g. the adrenal cortex, gonads, tissues undergoing repair if more LDL are present in the blood than

that can be taken up by the liver, adrenal cortex and gonads, non-specific uptake by macrophages near endothelial cells would increase

this would lead to atherosclerosis

111The secretion of VLDL

112The fate of VLDL

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• The lipoproteins with the highest content of proteins is called high density lipoproteins (HDL)

• HDL are synthesized as nascent HDL by the liver and the intestine

disk-shaped with a layer of phospholipids, cholesterol and many apoproteins; the interior contains little TAG and cholesterol esters

• HDL can also be assembled on apoproteins (especially A I) that bud-off or are shed by other lipoproteins

• Mature HDL (HDL3) are formed when nascent HDL acquires cholesterol and phospholipids from tissues (especially endothelial cells); HDL become globular

• The transport of cholesterol to HDL is facilitated by ATP-biniding cassette protein 1 (ABC 1)

ABC 1 brings cholesterol to the outer leaflet of the lipid bilayer

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• HDL take cholesterol from the surface; but cholesterol could still move back to the cell

• This is avoided through the action of lecithin-acyl cholesterol transferase (LCAT) which HDL acquire from the circulation LCAT transfers a fatty acid from lecithin to

cholesterol trapping it inside HDL in the form of cholesterol ester

• HDL can lose their cholesterol ester in two major ways:

1.Scavenger receptor (SR-B1) –mediated transfer to the liver and steroidogenic tissues

The transfer to the liver is known as reverse cholesterol transport The process is not endocytosis – cholesterol

esters are delivered to the tissues and what is left of the HDL reenters the circulation and keeps on picking up more cholesterol

115HDL metabolism

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2.Exchange of cholesterol ester for TAG with IDL The exchange is carried out through cholesterol

ester transfer protein (CETP)HDL depleted of cholesterol ester and rich in

TAG become HDL2 ; HDL2 can be endocytosed by the liver

The exchange of cholesterol esters and TAG

117The relative diameters of lipoproteins

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Receptor-mediated endocytosis of lipoproteins• The internalization of LDL is a representative

example • LDL receptors are found on specialized areas of the

cell membrane that are called coated pits (because they are covered with the protein clathrin)

• The receptor binds with apo B-100 • The pits are changed to vesicles that contain the

LDL and enter the cell; the vesicles are known as early endosomes

• After the clathrin and LDL receptors are returned back to the membrane late endosomes are formed

• Lysosomes that contain hydrolases are released by the Golgi complex and fuse with the late endosomes

• The main products of the actions of the enzymes are cholesterol, fatty acids and amino acids (from apo B-100)

• Cholesterol is quickly reesterified (with fatty acids different from the original ones) by ACAT

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• Excess levels of cholesterol in the cell inhibit the transcription of LDL receptor mRNA and activate the action of ACAT

excess levels of cholesterol in the cell are reflections of both synthesis and delivery by LDL

• The non-specific scavenger receptors (SR-A1/A2) on macrophages can bind different types of molecules

• These receptors are non-saturable, i.e, they will continue engulfing LDL even when the levels of cholesterol in the macrophages are high

what is the link between LDL, HDL and atherosclerosis?

• Atherosclerosis is a constriction and blockage of arteries of the brain, heart and other organs by atheromas

• The initial step in the formation of atheromas is physical damage to the endothelium caused by different risk factors

hypertension, free radicals from cigarette smoking, elevated LDL- especially modified LDL, etc

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Modification of LDL

LDL

Apo B-100

Derivatization:Aldehydes

Glucosylationeg. diabetes

Oxidation:Degradation of

B-100 by reactiveoxygen species

Derivatized LDL

Oxidized LDL

• Increased residence time of LDL in the plasma may increase the chance for modification

• The polyunsaturated fatty acids inside LDL are oxidized

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• The damage to the vessel elicits an inflammatory response

adhesiveness and permeability of the endothelium for plateletes and leukocytes increases

• The monocytes cross the endothelium and mature into macrophages inside the subintimal space

• The scavenger receptors on macrophages take in modified LDL and become foam cells

• The macrophages secrete reactive oxygen species and this leads to the production of more oxidized LDL

and cytokines secreted by vascular cells in response to oxidized LDL attract monocytes to the subintimal space and induce the proliferation of smooth muscle cells

• Through time a fatty streak of necrotic tissue and free lipid surrounded by a fibrous cap of smooth muscle cells would form

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• The fatty streak enlarges over time, deforms the overlying endothelium and protrudes into the lumen, blocking blood flow

• the eventual thinning of the fibrous cap leads to the rupture of the streak the release of the contents of the plaque into

the blood stream would lead to thrombosis; the clot would worsen the occlusion of the vessels

• HDL may be protective by picking up accumulating cholesterol from the endothelium before the advanced lesion forms

• HDL also has an enzyme that degrades oxLDL LDL - “bad cholesterol”; HDL - “good

cholesterol”the LDL:HDL ratio is thought to be a good

measure of the probability of developing atherosclerosis

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Genetic defects in lipoprotein metabolism• Rare disorders

Abetalipoproteinemia - inability to associate apo B with lipids; chylomicrons, VLDL and LDL cannot be synthesized

• accumulation of triacyglycerols in the liver; malabsorption of lipids and lipid soluble vitamins in the intestine

Tangier disease - cholesterol cannot be transported from cells to HDL due to deficiency of ABC-1 transporters• cholesterol-poor HDL is rapidly removed from

the circulation and degraded• Familial hypercholesterolemia (FH) - is a

common condition characterized by the deficiency or non-functionality of LDL receptors

• LDL cholesterol levels in the blood increase significantly

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• Heterozygotes have around half the activity of LDL receptors while homozygotes have nearly no LDL receptor activity

• Homozygotes usually die of coronary artery disease in childhood

• In addition to the blood vessels, FH leads to the deposition of lipids in the skin, eye and tendons – xanthomas

• Because LDL cholesterol is unable to adequately enter into cells, endogenous cholesterol synthesis will continue uninhibited

• The likely treatment for homozygotes is a liver transplant

• The situation in heterozygotes can be improved by stimulating cells to produce additional LDL receptors; this can be achieved through different ways:

statins – competitively inhibit HMG-CoA reductase; the decrease in intracellular cholesterol levels stimulates the synthesis of LDL receptors

127

Resins – bind and facilitate the excretion of bile salts as opposed to recirculation; the liver has to use more of the intracellular cholesterol pool for bile salt synthesis; LDL receptor synthesis activated

Ezetimibe - blocks the intestinal absorption of cholesterol; less cholesterol is sent to the liver through chylomicrons •fibers may also serve the same function

• Dietary and life style changes may supplement and/or even precede pharmacotherapy in the reduction of blood cholesterol

fibers – remove bile acids through the feces nicotinic acid – moderates the release of

fatty acids from the adipose (which then can travel to the liver and be secreted in VLDL); vitamin E prevents oxidation of LDL reduce the consumption of saturated fatty

acids, sucrose and fructose regular exercise, controlling weight, …

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The synthesis of important derivatives of cholesterol

BILE ACIDS• Present mainly as Na+ and K+ salts • The strategy of synthesis is to add more hydroxyl

groups in order to increase solubility and conjugation to increase ionization (and solubility)

• In the liver cholesterol is first changed to 7 α- hydroxy-cholesterol by a mixed-function oxidase ; rate limiting step

• After the introduction of additional hydroxyl groups, reduction of the ring double bond and shortening of the side chain, two types of primary bile acids are produced – cholate and chenocholate

• The carboxyl group of cholate and chenocolate are conjugated with glycine or taurine

• Intestinal bacterial remove glycine, taurine and the hydroxyl at C-7 producing secondary bile acids - solubility decreases

129

• The portion of the primary bile acids that has not been modified by the bacteria along with the relatively soluble type 20 bile acid- deoxycholic acid -are reabsorbed into the liver

• The least soluble of the secondary bile acids - lithocholic acid - which has a single hydroxyl group is mainly excreted

• Coprostanol , which is produced by bacterial hydrogenation of biliary cholesterol secreted into the intestine, is also excreted

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133

STEROID HORMONES• Five types of hormones are produced by the

oxidation and the removal of the side chain of cholesterol: glucocorticoids, mineralcorticoids, androgens, estrogens and progestins

• Cytochrome P-450 enzymes that require NADPH are characteristic of the synthesis pathways

• The synthesis of steroid hormones begins with the formation of pregnenolone through the action of desmolase – a mitochondrial enzyme

• Desmolase removes 6 carbons from cholesterol (27 C)

• Pregnenolone moves from the mitochondria to the SER where oxidation of hydroxyl and change in position of the double bond yields progesterone (21 C)

• The other steroid hormones are all derived from progesterone

• Glucocorticoids have 21 C, androgens 19 C and estrogens 18 C

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136

VITAMIN D• Cholecalciferol (vitamin D3) is synthesized from 7-

dehydrocholesterol present in the skin

137

• Cholecalciferol is then changed to the active form of vitamin D - 1,25–dihydrocholecalciferol (calcitriol)

138

o isopentenyl pyrophosphate (an intermediate in cholesterol biosynthesis) is a precursor to many important molecules known collectively as isoprenoids