cholesterol Flashcards
3 important lipid components of biological membrane;
— , — and —
- Occurs as – component —%
- least – soluble
- More– than other membrane lipids
-Inserts itself between— chains prevents their –
phospholipids, sphingolipids and cholesterol
minor
10% ???
h20
rigid
fatty acid
crystallisation
-Cholesterol is synthesised from — in– stages
-The complex regulation of cholesterol biosynthesis takes place at several levels
-Cholesterol is transported in the — by — and is taken up in cells by specific cell surface receptors
-Important derivatives of cholesterol include — and—
acetyl coenzyme A
3 stages
blood
low density lipoproteins
bile salts ad steroid hormones
cholesterol structure:
-an essential —
-Condensed – structure
- — H2O solubility
- — & — Esterified - long chain —
cholesterol sythesis:
-All 27 carbon atoms of cholesterol are derived from — in a three stage synthetic process
1. Stage one is the synthesis of — (key building block of cholesterol)
2. Stage two is the — of – molecules of isopentenyl pyrophosphate to form –
3. Stage three, squalene – and the — product is converted to –
biomolecule
4 ring
low
storage and transport
fatty chain
( the structure of it basically has a methyl and hydroxy group m steroid nucleas and a branched group )
acetyl CoA
isopentenyl pyrophsophate
condensation
6
squalene
cyclists
tetracyclic
cholestole
( check slide 7 and 8 )
- synthesis of isopentenyl pyrophsophate II:
Mevalonate is converted to— in three consecutive reactions requiring –
basically its from 5 phosphor-mevolate –> 5 pyrophosphate mevolate –> 3 isopentenyl pyrophosphate - Condensation of isopentenyl pyrophosphate to form squalene - Squalene is synthesised from six molecules of isopentenyl pyrophsophate by the reaction sequence is —
isopentenyl pyrophosphate
ATP
c5 –> c10 —> c15 —> c30
( Acetyl-CoA → HMG-CoA → Mevalonate → Squalene → Lanosterol → Cholesterol)
Squalene cyclizes to form — :
-Squalene is first – to squalene 2,3-epoxide
- which undergoes — to form —
Cyclization: A series of concerted — group and — shifts along the chain of the squalene molecule to bring about the formation of the – rings.
Lanosterol is converted to – by – reactions
cholesterol
oxidised
crytsalization
lanosterol
1,2 methyl group
hydride
4
cholesterol
multiple
- cholesterol levels :
- – Cholesterol in adult human (mainly in — )
-Serum Levels (3.7 - 5.2 mmol/L)
-Bound to — (Chylomicrons, VLDL, LDL, HDL) 2/3 in an — form. Mainly cholesterol oleate or linoleate
-Essential to life BUT deposition in arteries associated with Cardiovascular Disease and stroke
-Healthy balance: biosynthesis, utilisation and transport - regulation of cholesterol biosynthesis:
- Cholesterol can be obtained from the– or can be synthesised –
- — (1g/day)
-Meat and animal produce (eggs) - rich sources - (≈1g/day) - — (0.5 - 1.0g/day synthesised in the body)
- All – cells are capable of synthesis. But Major sites are: — , — , — tissues, — glands
140g
cell membranes
lipoproteins
esterfied
diet or de novo
exogenous
endogenous
nucleated
liver
intestine
reproductive
adrenal
- The rate of cholesterol formation in the body is highly responsive to— levels of cholesterol
It is controlled by a — feedback mechanism mediated primarily by changes in the — and — of 3-hydroxy-3-methylglutaryl CoA reductase ( – CoA — ) (inhibited by — ) - control of HMG CoA reductase:
1- Rate of synthesis of reductase mRNA is controlled by the — , When cholesterol levels are low this — factor induces — of HMG CoA reductase
2- Rate of translation of reductase mRNA is inhibited by — derived from — and dietery —
3- Degradation of the reductase. In response to — levels of cholesterol the enzyme can undergo —
4- — decreases the activity of the reductase in response to – levels of ATP
cellular
-ve
amount and activity
HMG reductase
statins
regulatory element binding protein (SREBP).
transcription
transcription
non sterol metabolite
mevaolnate
cholesterol
increasing
protolysis
phospholration
low
cholesterol transport:
- Cholesterol and triacylglycerols are transported in the form of — particles
- — is the major site of cholesterol synthesis, cholesterol in excess of the liver’s own needs is exported in the — in the form of —
VLDL is converted to — which carries — primarily —
-The role of LDL is to transport cholesterol to – and regulate — cholesterol synthesis at these sites
- High density lipoproteins (HDL) picks up cholesterol released back into the — from — cells.
- Acyltransferase in HDL — the cholesterol and then shuttles it back to — or returns it to the —
lipoprotein
liver
blood
very low density lipoproteins (VLDL)
low density lipoprotein
cholesterol esters
linoleate
peripheral tissues
de novo
plasma
dying
esterfies
LDLP
liver
pharmacological regulation of cholesterol:
1- Inhibition of de novo synthesis of cholesterol in the liver – —- . HMG- CoA inhibitors (e.g. — ).
2- Sequestering bile acids in the intestine – (Cholestyramine/Colestipol.) Reduces the — of exogenous cholesterol and — the metabolism of endogenous cholesterol into bile acids (e.g. cholestyramine, colestipol).
3-Altering the relative levels of different lipoproteins:— . Decreasing — production, increasing the activity of — and enhancing the — of LDL by the liver (e.g. — ).
4-Reducing circulating LDL: — . — is ubiquitously expressed across tissues. Blocking PCSK9 enhances the number of – receptors on target tissue. Blocking PCSK9 can — circulating LDLs. FDA approved in 2015 for patients unresponsive/intolerant of statins.
5- GLP-1 — work by — theGLP-1 receptor to — gastric emptying, inhibit the release of — , and stimulate — production, thereby reducing — . In addition these drugs reduce food intake, A similar class of drugs,DPP-4 inhibitors, work by reducing the breakdown of endogenous GLP-1, bur are less potent than GLP-1 agonists. Metabolic effects of GLP-1 agonists in pre-clinical models demonstrated increased synthesis of fibroblast growth factor 21 (FGF21).
statins
statins
absorption
increases
vibrates
lipoprotein lipase
clearance
fibrates
PCSK9 inhibitors
PCSK9
LDL
lower
activating
slow
glucagon
insulin
hypergalcemia
read:
Long Term Safety and Efficacy of Lowering LDL Cholesterol With Statin Therapy: 20-Year Follow-Up of West of Scotland Coronary Prevention Study
check slides 18,19
The West of Scotland Coronary Prevention Study was a primary prevention trial in 45-64 year old men with high LDL cholesterol.
6595 men were randomized to receive pravastatin 40mg once daily or placebo for an average of 4.9 years.
Linkage to electronic health records permitted analysis of major incident events over 20 years.
RESULTS:
Men allocated to pravastatin had reduced all-cause mortality; hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.80-0.94, p=0.0007, mainly attributable to a 21% decrease in cardiovascular death; HR 0.79 (CI 0.69-0.90), p=0.0004. There was no difference in non-cardiovascular or cancer death rates between
groups.
Cumulative hospitalisation event rates were lower in the statin treated arm: by 18% for any coronary event (p=0.002), 24% for myocardial infarction (p=0.01) and 35% for heart failure (p=0.002). There were no significant differences between groups in hospitalization for non-cardiovascular causes.
Statin treatment for five years was associated with a legacy benefit with improved survival and a substantial reduction in cardiovascular disease outcomes over a 20-year period, supporting the wider adoption of primary prevention strategies.
- deratives of cholesterol:
Cholesterol is a precursor for other important — molecules as: —- - bile acid and bile salt production:
-Role: Elimination of — from the body
-Humans cannot metabolise Cholesterol to – +—
-Instead we eliminate the sterol nucleus by:
[a] conversion to — and—
[b] secretion of cholesterol into the – (excreted in the – ) - Bile is a – mixture of – & — compounds including— and –
-Following synthesis (liver), bile is either excreted via the common — or stored in the —
steroids
as: Bile salts
Steroid Hormones
Vitamin D
cholesterol
c02 + h20
bile salts and bile acids
bile
feaces
watery
organic and inorganic
bile salts and lecithin
bile duct
gall bladder
bile acids :
-Contain — carbons, – OH groups and a — group
-PKa of the COOH group is ~ –; therefore it is not fully — at physiologic pH (hence ‘bile acid’)
- — molecules, having a — and a — face; as a result, they can act as — agents in the — [bile acids help to break down dietary —]
24
2-3
COOH
6
ionised
amiphleitic
hydrophilic and hydrophobic
emulsifying
intestine
tgs
bile salts:
-Produced in the — by conjugating — with either — or—
eg:
Glycocholic acid
Taurocholic acid
Glycochenodeoxycholic acid Taurochenodeoxycholic acid
- — ionised ( — charge) at physiologic pH
-More effective —
-Bile salts are exposed to — of the –
This can result in:
[a] the — of bile acids by — of the glycine or taurine
[b] the production of ‘—bile salts’ by the removal of an – group
eg: Cholic acid –> –
Chenodeoxycholic acid —> –
liver
bile salts
glycerin or taurine
fully
negative
detergents
bacterial flora
intestine
regeneration
removal
secondary
oH
deoxycholic acid
lithocholic acids
-Bile salts are synthesised in the — , stored and concentrated in the — and released into the —
-Bile salts the major constituent of bile solubilises —
-Bile salts are the major break down products of —
liver
gall bladder
small intestine
dietary lipids
cholesterol
Cholesterol gall-stone disease [Cholelithiasis] :
Problem:
not enough — being secreted to handle the amount of — being secreted
Causes:
- — of bile acids (intest.)
- biliary tract —
- — dysfunction
- reduced bile synthesis due to accelerated— of bile acids
-Lack of —
Result:
Cholesterol precipitates in the —
Tx: Cholecystectomy
bile salts
cholesterol
malabsorption
obstruction
hepatit
recycling
melatonin
gall bladder
- Cholesterol is the precursor of the five major classes of — which are Progestagens, glucocorticoids, mineralocorticoids, androgens and estrogens
1- Progesterone, a progestagen, prepares the – of the uterus for implantation of an–. Progesterone is also essential for the maintenance of —
2- Androgens (e.g. — ) are responsible for the development of —
3- Estrogens are responsible for the development of — . Along with progesterone participate in the —
4-Glucocorticoids (e.g.—) promote—- and breakdown of —, enhance — of fat and protein and inhibits the — response
5-Mineralocorticoids (aldosterone) act on the — of the – to increase the — of Na+ and the — of K+ and H+
steroid hormones
lining
ovum
pregnancy
testastorn
male 2ndary sex characteristics
female 2ndary sex characteristics
ovarian cycle
cortisol
glucogenesis
glycogen
degradation
inflammatory
distal tubules
kidney
reabsorption
excretion
- Cholesterol is the precursor of —
- 7-dehydrocholesterol is — by the — of the– to — which is spontaneously — to —
-Vitamin D3 (cholecalciferol) is converted to — , the active hormone by — reactions in the – and— - vitamin d binds to — receptor proteins (similar to — receptors)
-Selectively stimulates —
-Regulate plasma levels of — and —
vitamin d
pholysed
uv light of the sun
pre vitamin d3
isomerises
vitamin d3
calcitriol
hydroxylation
liver anf kidney
intracellular
steroid
gene trancpriton
calcium and phosphprous
-Vitamin D deficiency in children produces — , a disease characterised by inadequate calcification of cartilage and bone
-Occurs when the 7-hydrocholesterol in the skin is not — to pre-vitamin D3 and dietary intake of vitamin D is –
-In adults vitamin D deficiency leads to softening and weakening of bones, a condition called —
-The recommended daily intake of vitamin D is — international units, irrespective of age
rickets
pholysed
low
osteomalcia
400
