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CHOLESTEROL ANDSTEROID METABOLISM
I
Structure, Function,
Biosynthesis and Elimination
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Cholesterol is a lipid
Review:
Definition of lipid
Examples of lipid molecules
Amphipathic
Hydrophobic
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Structure of free cholesterol
an amphipathic lipid
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Ester bond formation
alcohol + acid = ester + watercan be organic or mineral acid
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Structure of cholesteryl ester
a hydrophobic lipid
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Enzymology of cholesterol esterification
In plasma lecithin: cholesterol acyltransferase(LCAT) forms CE (dienoic) (LCAT deficiency/fisheye disease)
In cells acylcoenzyme A: cholesterolacyltransferase (ACAT) forms CE (monenoic)
In pancreas, intestine, liver and kidneycholesterol esterase hydrolyzes CE
In all cells CE from LDL hydrolyzed by lysosomalacid lipase deficiency + Wolman disease (CE
storage disease)
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Distribution
In plasma, 70 72 % of total cholesterolis CE
In cells, nearly all cholesterol is freecholesterol
CE is the transport or storage form of cholesterol
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Lipids in the body
In cells Amphipathic lipids in
membranes
Hydrophobic lipids in oildroplets
In extracellular fluid Amphipathic lipids inlipoprotein surface coat
Hydrophobic lipids inlipoprotein core
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Essential cholesterol!
Despite its bad press, cholesterol is absolutelyessential for human life
Obtained in diet and synthesized endogenously Cholesterol synthesis requires molecular O2 -
ancient organisms like Tetrahymena lackcholesterol synthetic pathway use
tetrahymenol in membranes but usecholesterol if available in culture medium
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Tetrahymenol looks like cholesterol
and
..its synthesis is blocked by cholesterol
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Biomembrane structure
Membranes contain amphipathic lipids and proteinswith some carbohydrate (from glycoproteins andglycolipids)
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Cholesterol intercalates between fatty acylchains in cell membranes and reduces
membrane fluidity
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Free cholesterol in membranes
Often measured as C/PL molar ratio - C/PL is veryvariable erythrocyte = 0.8,Hepatocyte = 0.2
Most FC is in plasma membrane very little in
mitochondrial inner membrane In plasma membrane FC is evenly distributed
between the 2 leaflets contrast PL and glycolipids
Within a single leaflet, FC may be concentrated in lipid rafts with low fluidity/permeability leavingFC-free areas of high fluidity/permeability
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Free cholesterol in membranes
FC is not covalently bound in membrane
Free to exchange with FC of lp particles
Important for removal of excess cellularcholesterol
Also provides a receptor-free pathway for
cholesterol uptake by cells In disease, low LCAT activity leads to
increase in membrane FC (RBC C/PL >1 )
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Biosynthesis of cholesterol
From 2 carbons to 27 carbons a medicalstudents worst nightmare!
Even biochemists dont understand all that it entails!
Breakdown into sections for easier generalunderstanding
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Overview
Acetyl CoA (C2) Mevalonate (C6)
(Isoprenyl pyrophosphates) (C5, C10, C15)
Squalene (C30) Lanosterol (C30)
Cholesterol (C27)
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Biosynthesis of mevalonate
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HMGCoA reductase is the rate-
limiting enzyme
Metabolic regulation of any pathway is usually
achieved by modulation of the activity of onekey enzyme:
The rate-limiting enzyme
Catalyzes the committed step
For cholesterol biosynthesis, control occurs earlyin the pathway at HMGCoA reductase
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...of cholesterol biosynthesis
Fasting (+)
Increased dietary intake of cholesterol (-)
HMGCoA reductase is controlled by
covalent modification induced bycholesterol feedback and by varioushormones
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. and the target for statins
Rings
Partially reduced naphthalene lovastatin, simvastatin, pravastatinIndole fluvostatin Pyrrole atorvastatin
Pyrimidinine rosuvastatin Pyridine glenvastatin
Quinoline - pitavastatin
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Statins
Competitive inhibitors of HMGCoAreductase
Natural products from Penicillium citrinum(mevastatin), Aspergillus, Monascus oranalogues
Effective at lowering cholesterol, but mayhave other effects as well impotence bone-building etc.
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Biosynthesis of farnesyl pyrophosphate
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Transmethylglutaconate shunt
Until recently, it was thought that mevalonateonce formed was destined to become farnesyl
pyrophosphate and hence cholesterol
Now known that dimethylallyl pyrophosphatecan escape this fate and can be
dephosphorylated and converted back toacetoacetate and acetyl CoA
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Biosynthesis of squalene
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From squalene to sterols
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Regulation of cholesterol
biosynthesisSophisticated process because synthesisrepresents a large investment of energy
Diet inverse relationship between dietaryintake and cholesterol synthesis liver
Daily cholesterol availability is fairly constant dietary intake has only weak effect on plasmacholesterol
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Intracellular cholesterol pools
In liver FC used for: Bile acid synthesis
Bile cholesterol
VLDL cholesterol
HDL cholesterol
In adrenals & gonads Steroid hormones
In other tissues Repair & growth
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HMGCoA reductase
If intracellular FC rises, regulation occurs by:
reduction in activity of HMGCoA reductase
reduction of synthesis of HMGCoA reductase
downregulation of LDL receptors
increase in esterification of FC by ACAT increase in FC removal from plasma
membrane by HDL promoted by LCAT
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Factors influencing HMGCoA
reductase activity Intracellular [HMGCoA]
Intracellular [cholesterol]
Hormones
Insulin (+)
Tri-iodothyronine (+)
Glucagon (-)
Cortisol (-)
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Factors influencing cholesterol
regulationIncrease [FC] Decrease
All cells
de novo synthesis inhibition of synthesishydrolysis of stored CE esterification by ACAT
receptor-mediated LDL uptake downregulation of receptors
direct uptake of FC from lipoproteins release of FC to lipoproteins
Liver and gonads only
receptor-mediated HDL uptake synthesis of bile acids/steroidsLiver only
uptake of chylomicron remnants secretion in bile
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Circadian rhythm
Hepatic cholesterol synthesis peaks 6hours after dark
At a minimum, 6 hours after light
Changes in HMGCoA reductase activity mechanism unclear
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BBRREE A AKKTTIIMMEE
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Cholesterol is not broken down
in the human body
Once formed cholesterol is hard to degrade
Only micro-organisms can break down steroidring for energy
Instead in humans, cholesterol is converted intoother compounds bile salts, hormones, VitaminD
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Bile acids are quantitativelythe most important
cholesterol-derived products
Bile acids - C24 compounds differ by position and numberof E-OH groups
Methyl groups are in F-configuration
Amphipathic in that one face of the nucleus is polar andthe other non-polar good emulsifiers
However, pK a of carboxyl group is about 6 not fullyionized at physiological pH
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Primary bile acids
Synthesis in liver
Multi-step, multi-organelleprocess
OH groups are inserted at specific positions of ring
Double bond in B ring isreduced
Chain shortened by 3 carbonsand ends in a carboxyl group
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Cholesterol 7-E-hydroxylase
Rate-limiting step inbile acid synthesis
Cytochrome P450enzyme
Only in ER of liver
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Bile salts enhanced
amphipathic compounds Before leaving liver
bile acids are
conjugated witheither glycine ortaurine by amidebond formation
New acidic groups arefully ionized at physiological pH
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Bile salt function
Act as detergents
Emulsify dietary lipids toenable enzymic digestion.Products form into smallmicelles
Micelles transport fatty
acids, cholesterol, M AGs,Lysolipids to mucosal cellsurface for absorption
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Effect of intestinal flora onEffect of intestinal flora on
bile saltsbile salts Bacteria remove
glycine or taurine to
regenerate primarybile salts
May also remove one
hydroxyl group toyield secondary bileacids
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Enterohepatic circulation of
bile acids and salts
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Cholestyramine interruptseneterohepatic circulation of bile salts
and lowers plasma cholesterol
Cholestyramine is a positively chargedresin
In the gut, it binds negatively charged bileacids
The bile acids are excreted rather thanreturned to liver
Liver uses cholesterol to make updeficiency of bile acids
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Cholelithiasis cholesterol
gallstone disease Bile contains cholesterol
which is solubilized bybile salts and
phospholipids
If balance is disturbed,then cholesterol may
precipitate out to formgallstones
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Cholesterol solubility dependsupon phospholipids and bile
salts
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Causes of gallstones
Decrease in bile salt content of bile from:
Gross malabsorption of bile acids as in ileal disease
Bile duct obstruction Severe hepatic dysfunction leading to decreased
synthesis
Excessive feedback suppression of de novo bile salt
synthesis Increased bile acid excretion with fibrates orcholestyramine
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Steroid hormones
Cholesterol is precursor of all steroid hormones glucocorticoids, mineralocorticoids(corticosteroid hormones) and sex hormones
Groups of different hormones differ in carbonNo. C-21, C-19 and C-18
Within each group, individual hormones maydiffer by a C=C double bond or orientation of an
OH group
Systematic nomenclature necessary
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Steroid hormone groups
C-21 (pregnane ring)
C-19 (androstane ring)
C-18 (estrane ring)
Only 2-C left in side chain
Side chain completely lost
Loss of methyl C-19 as ring A is aromatized
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Steroidogenic tissues
Adrenal cortex cortisol, aldosterone andandrogens
Ovaries (and placenta) estrogens andprogestins
Testes - testosterone
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Steroid transport
Steroid hormones are hydrophobic
Complexed to protein for transport
Albumin non-specific carrier transports
aldosterone. Specific transporters transcortin for corticosteroids and sex-hormone-binding protein
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Steroidogenesis
Formation of Pregnenolone
Progesterone
Cortisol Aldosterone Testosterone
Estradiol
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Formation of progesterone
Rate-limiting stepcatalyzed by desmolase
(Cytochrome P450 mixed
function oxidase in innermitochondrial membrane usesO2 and N ADPH) followed byisomerization - pregnenolone
Oxidation catalyzed by3- F-hydroxysteroiddehydrogenase
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3- F-hydroxysteroid
dehydrogenase deficiency A congenital adrenal hyperplasia (CAH)
No formation of glucocorticoids,mineralocorticoids or sex hormones
Marked salt excretion in urine
All patients have female genitalia
i f
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Conversion ofprogesterone to
active hormones
Other CAHs involveother mixed functionoxidases on thesepathways
Enzyme deficiencieslead to deficiency of product hormone andexcess of substratehormone/metabolite
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Cholesterol (C27)
Pregnenolone (C21)
Progesterone (C21)
17-a-Hydroxyprogesterone
11-Deoxycorticosterone (C21) 11-Deoxycortisol (C19) Androstenedione (C19)
Corticosterone Testosterone (C19)
Aldosterone Cortisol (C21) Estradiol (C18)
ENZYME BLOCKSLEADING TO CAH
X
X
X
X
X
X
X
3 F-hydroxysteroiddehydrogenase
17-E-hydroxylase
21-a-hydroxylase
11-E-hydroxylase
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17-E-hydroxylase deficiency
Lack of enzyme blocks conversion of
progesterone to 17--hydroxyprogesterone onpathway to sex hormones and cortisol
Increased production of mineralocorticoids leads
to sodium and fluid retention and hypertension
All patients have female genitalia
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Cholesterol (C27)
Pregnenolone (C21)
Progesterone (C21)
17-a-Hydroxyprogesterone
11-Deoxycorticosterone (C21) 11-Deoxycortisol (C19) Androstenedione (C19)
Corticosterone Testosterone (C19)
Aldosterone Cortisol (C21) Estradiol (C18)
ENZYME BLOCKSLEADING TO CAH
X
X
X
X
X
X
X
3 F-hydroxysteroiddehydrogenase
17-E-hydroxylase
21-a-hydroxylase
11-E-hydroxylase
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21-E-hydroxylase deficiency
Conversion of both progesterone to 11-deoxycorticosterone and 17-E-hydroxyprogesterone to 11-deoxycortisol
Commonest CAH - total or partial absence of corticosteroids
Androgen overproduction masculinization of external genitalia in females and precociousvirilization in males
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Cholesterol (C27)
Pregnenolone (C21)
Progesterone (C21)
17-a-Hydroxyprogesterone
11-Deoxycorticosterone (C21) 11-Deoxycortisol (C19) Androstenedione (C19)
Corticosterone Testosterone (C19)
Aldosterone Cortisol (C21) Estradiol (C18)
ENZYME BLOCKSLEADING TO CAH
X
X
X
X
X
X
X
3 F-hydroxysteroiddehydrogenase
17-E-hydroxylase
21-a-hydroxylase
11-E-hydroxylase
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11- F-hydroxylase deficiency
Conversion of both 11-deoxycorticosterone tocorticosterone and 11-deoxycortisol to cortisol isblocked
Increased 11-deoxycorticosterone causes fluidretention and supresses the renin/angiotensinsystem hypertension
Masculinization and virilization
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Secretion of steroid hormones
Steroid Tissue Control
Cortisol Middle layer of adrenal cortex
Hypothalmus via Cortictropin RH which stimulates
Adrenocorticotropic H secretionin pituitary via cAMP
Aldosterone Outer layer of adrenal cortex
Decrease in plasma Na+/K+ andby Angiotensin II - via PIP2
Androgens -
androstenedioneetc.
Both layers Weak androgens converted in
peripheral tissues totestosterone and estradiol
Sex hormones Gonads Hypothalmus via gonadotropin-releasing hormone stimulates LH and FSH secretion by pituitary
via cAMP
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Steroid hormone action
Diffuse into cells in cytosol or nucleus, bind to specificsteroid receptor
Receptor-ligand complex accumulate in nucleus and
dimerize Bind to hormone response elements (specific regulatory
DN A sequences) in conjunction with co-activator proteins
Increase transcription by promotor activation
HRE are found in enhancer elements near genes that respond to steroid hormones co-ordinated regulation
Hormone-receptor complexes can also inhibit transcription in association with co-repressor proteins
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Vitamin D3
Vitamin D3 or Cholecalciferolis derived fromcholesterol
Dietary sources include (fishliver oil, egg yolk) orergocalciferol invegetables
Majority is made in theMalpighian layer of theepidermis of skin byphotolysis of 7-dehydrocholesterol
Cholecalciferol is biologically inactive but is
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Cholecalciferol is biologically inactive, but isconverted into the active form 1,25 dihydroxycholecalciferol by sequential
hydoxylationsCholecalciferolCholecalciferol
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Regulation Transport of cholecalciferol from skin to liver and of 25-
hydroxycholecalciferol from liver to kidney requires aspecific Vit D-binding protein
Formation of 25-hydroxycholecalciferol is unregulated
Formation of 1,25-dihydroxycholecalciferol by 1-E-hydroxylase enzyme is the rate-limiting step
Low calcium diets and hypocalcaemia markedly increaseactivity effect requires parathyroid hormone (PTH) low phosphorus diets and hypophosphatemia weaklystimulate
1,25-dihydroxycholecalciferol also regulates its ownproduction inhibiting the 1-E-hydroxylase and causing
inactive 24,25-dihydroxycholecalciferol to accumulate
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1,25 dihydroxycholecalciferol orcalcitriol is an important calciotropic
hormone It diffuses into its target cell and binds to a
nuclear receptor
Intestine increased transcription of proteinsincluding calcium-binding protein effect is toincrease transfer of calcium and phosphate ionsfrom intestinal lumen across the mucosal cell
and into the circulation Bone in presence of PTH, stimulates
mobilization of calcium and phosphate ions
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Vitamin D deficiency
Demineralization of bone:
Rickets in infants
Osteomalacia in
adults
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Signs of RicketsSigns of Rickets
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Vitamin D - summary
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Summary I
Hydrophobic and amphipathic lipids
Cholesteryl ester and free cholesterol
Enzymology of cholesteryl esters
Lipids in cells and extracellular fliud
Functions of cholesterol
Cholesterol in biomembranes
Cholesterol biosynthesis
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Summary II Bile acids
Primary bile acids bile salts function
Secondary bile acids enterohepatic circulation Questran
Cholesterol gallstones Steroid hormones
Steroidogenic tissues and steroidogenesis
Different hormones action and control
Congenital adrenal hyperplasias -21-E-hydroxylasedeficiency etc.
Vitamin D Dietary sources sunlight formation of calcitriol
mode of action - deficiency