Cholesterol metabolism
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Transcript of Cholesterol metabolism
Cholesterol MetabolismCholesterol Metabolism
Dr. V. Siva Prabodh Dr. V. Siva Prabodh MDMD
ProfessorProfessor
Dept. of BiochemistryDept. of Biochemistry
NRI Medical CollegeNRI Medical College
CHOLESTEROLCHOLESTEROL
→→ Cholesterol is a Cholesterol is a light yellow crystalline solidlight yellow crystalline solid
→ → It is a It is a 2727 Carbon compound Carbon compound
→ → contains contains cyclopentano perhydro phenanthrenecyclopentano perhydro phenanthrene
ringring
→ → One hydroxyl group One hydroxyl group (OH) at 3(OH) at 3rdrd position position
→ → Double bondDouble bond between between 5 & 65 & 6 Carbons Carbons
→ → 8 Carbon side chain8 Carbon side chain at 17 at 17thth Carbon Carbon
Significance of CholesterolSignificance of Cholesterol1)1) Normal level Normal level 150 – 200 mg/dl150 – 200 mg/dl . Increased levels . Increased levels
increases the risk for increases the risk for AtherosclerosisAtherosclerosis
2)2) Important Important component of cell membranescomponent of cell membranes which which affects fluid state of membraneaffects fluid state of membrane
3)3) It is used to It is used to Insulate Nerve fibersInsulate Nerve fibers..
4)4) Bile acidsBile acids (24 Carbon) are derived from (24 Carbon) are derived from CholesterolCholesterol
5)5) Steroid hormonesSteroid hormones (21 ‘C’ glucocorticoids, 19 ‘C’ (21 ‘C’ glucocorticoids, 19 ‘C’ androgens and 18 ‘C’ estrogens) are produced androgens and 18 ‘C’ estrogens) are produced from cholesterolfrom cholesterol
6)6) Vitamin DVitamin D formed from Cholesterol formed from Cholesterol
Biosynthesis of CholesterolBiosynthesis of Cholesterol
Major sites – Major sites – Liver, Adrenal Cortex, testis, ovariesLiver, Adrenal Cortex, testis, ovaries and and IntestineIntestine
80% by Liver80% by Liver
The enzymes involved in synthesis are located partly in The enzymes involved in synthesis are located partly in cytoplasmcytoplasm and and endoplasmic reticulumendoplasmic reticulum..
Requirements:Requirements:
1) Acetate of 1) Acetate of acetyl CoAacetyl CoA provides all the carbon atoms of provides all the carbon atoms of cholesterolcholesterol
2) Reducing equivalents by 2) Reducing equivalents by NADPH NADPH
3) Energy from 3) Energy from ATPATP..
De novo Synthesis of De novo Synthesis of CholesterolCholesterol
Primary site: liver (~1g/d)Primary site: liver (~1g/d) Secondary sites: adrenal cortex, ovaries, Secondary sites: adrenal cortex, ovaries,
testestestes
Overall equation:Overall equation:
Cholesterol Synthesis in Cholesterol Synthesis in 5 stages5 stages
1)1) Synthesis of Synthesis of HMG CoA (6 HMG CoA (6 cc))
2)2) Formation of Formation of mevalonate mevalonate (6 C)(6 C)
3)3) Production of Production of Isoprenoid UnitsIsoprenoid Units (5 C)(5 C)
4)4) Synthesis of Synthesis of squalenesqualene (30 C)(30 C)
5)5) Conversion of Conversion of Squalene to cholesterolSqualene to cholesterol (27 C)(27 C)
2C►6C►►6C6C ►►5C5C ► ►10C10C ► ►15C15C ► ►30C30C ► ►27C 27C
Step I : Step I : CondensationCondensation
Two molecules of Acetyl CoA condense to form Two molecules of Acetyl CoA condense to form Acetoacetyl CoAAcetoacetyl CoA
Enzyme: Enzyme: Acetoacetyl CoA SynthaseAcetoacetyl CoA Synthase
Step II : Step II : Production of HMG CoAProduction of HMG CoA
One acetyl CoA condenses with Acetoacetyl CoA to form One acetyl CoA condenses with Acetoacetyl CoA to form ββ-hydroxy -hydroxy ββ-methyl glutaryl CoA-methyl glutaryl CoA (HMG CoA) (HMG CoA)
Enzyme: Enzyme: HMG CoA SynthaseHMG CoA Synthase
Cytosol Mitochondria
Cholesterol Synthesis Ketone bodies synthesis
Step III – Regulating StepStep III – Regulating Step
Formation of Formation of MevalonateMevalonate
Reduction of HMG CoA to MevalonateReduction of HMG CoA to Mevalonate
Enzyme: Enzyme: HMG CoA reductaseHMG CoA reductase
requires 2 NADPHrequires 2 NADPH
Step 4 : Step 4 : Formation of Isoprenoid UnitFormation of Isoprenoid Unit (5 C) (5 C)
Mevalonate is Mevalonate is phorphorylatedphorphorylated three times three times
to form to form 3” phospho 5” pyrophospho 3” phospho 5” pyrophospho
mevalonatemevalonate, requires 3 ATP. , requires 3 ATP.
This undergoes This undergoes decarboxylationdecarboxylation to form to form
Isopentanyl PyrophosphateIsopentanyl Pyrophosphate (5 C) (5 C)
Step 5: Step 5: Synthesis of Squalence (30 C)Synthesis of Squalence (30 C)
Isopentanyl pyrophosphateIsopentanyl pyrophosphate Isomerizes to form Isomerizes to form
Di methyl allyl pyrophosphateDi methyl allyl pyrophosphate
One molecule of One molecule of IPPIPP (5 C) condenses with (5 C) condenses with DMPDMP
(5 C) to form (5 C) to form Geranyl pyrophosphateGeranyl pyrophosphate (10 C) (10 C)
One molecule of One molecule of IPPIPP (5 C) condenses with (5 C) condenses with GPGP
(10 C) to form (10 C) to form Farnesyl pyrophosphateFarnesyl pyrophosphate (15 C) (15 C)
Two molecules of Two molecules of Farnesyl pyrophosphate (15 C)Farnesyl pyrophosphate (15 C)
condenses to form condenses to form Squalene (30 CSqualene (30 C))
Step 6 : Step 6 : CyclizationCyclization
SqualeneSqualene undergoes oxidation and cyclization to undergoes oxidation and cyclization to form form Lanosterol Lanosterol
Lanosterol first formed steroid compound.Lanosterol first formed steroid compound.
2C►6C►►6C6C ►►5C5C ► ►10C10C ► ►15C15C ► ►30C30C ► ►27C 27C
Regulation of Cholesterol Regulation of Cholesterol SynthesisSynthesis
HMG CoA reductaseHMG CoA reductase is the regulating Enzyme is the regulating Enzyme
1.1. Feed back Inhibition:Feed back Inhibition:The end product cholesterol in excess inhibits The end product cholesterol in excess inhibits
the gene which is responsible for production of the gene which is responsible for production of HMG CoA reductaseHMG CoA reductase
2. 2. Hormonal regulationHormonal regulation::Glucogon & GlucocorticoidsGlucogon & Glucocorticoids favor the favor the
formation of Inactive HMG CoA reductase, thus formation of Inactive HMG CoA reductase, thus decreasesdecreases the cholesterol synthesis the cholesterol synthesis
Insulin increasesInsulin increases cholesterol synthesis by cholesterol synthesis by enhancing the formation of active HMG CoA enhancing the formation of active HMG CoA reductase.reductase.
3. 3. Inhibition by drugs:Inhibition by drugs:
Compactive Compactive
LovastatinLovastatin
Competitive Inhibitors for HMG CoA reductase.Competitive Inhibitors for HMG CoA reductase.
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Inhibition of Cholesterol BiosynthesisInhibition of Cholesterol Biosynthesis
COSCoA
HOCO2
-CH3
C -S -CoA
HOCO2
-CH3
H
OH
][HO
CO2-
CH3
OH
HOCO2
-H
OH
CH2CH2
NF
C6H5NHCO Atorvastatin (Lipitor):resembles intermediate
HMG CoA MevalonateIntermediate
HMGCoAreductase
Degradation of cholesterolDegradation of cholesterol
Cholesterol is not completely degraded to Cholesterol is not completely degraded to
CoCo22 & H & H22o.o.
It is converted to It is converted to Bile acidsBile acids
Steroid hormonesSteroid hormones
Vitamin DVitamin D
Bile acids:Bile acids:
24 Carbon compounds with steroid ring.24 Carbon compounds with steroid ring.
Helps in digestion & absorption of lipids.Helps in digestion & absorption of lipids.
Synthesis takes place in Synthesis takes place in LiverLiver
7-hydroxylase is the regulating Enzyme7-hydroxylase is the regulating Enzyme
Primary Bile acids – Primary Bile acids –
cholic acid, chenodeoxy cholic acid cholic acid, chenodeoxy cholic acid
Secondary Bile acids – Secondary Bile acids –
deoxycholic acid, Lithocholic acid deoxycholic acid, Lithocholic acid
Enterohepatic circulationEnterohepatic circulationThe bile salts which are secreted into the intestine are The bile salts which are secreted into the intestine are reabsorbed and returned to the liver. This is known as reabsorbed and returned to the liver. This is known as entero hepatic circulation.entero hepatic circulation.
Bile sequestering agentsBile sequestering agents
Lowering CholesterolLowering Cholesterol
Bileacids
liver
Bile acids
95 % reabsorbed
5% in feces
NH3+
NH3+
1. Bind bile acid2. Utilize more cholesterol to make bile acids
>10% in feces
Cholelithiasis:Cholelithiasis: Bile salts and phospholipids are Bile salts and phospholipids are responsible to keep cholesterol in bile in a responsible to keep cholesterol in bile in a soluble state.soluble state.Deficiency of Bile salts, leads to Deficiency of Bile salts, leads to precipitation of cholesterol into crystals in precipitation of cholesterol into crystals in gall bladder resulting in Gall stones or gall bladder resulting in Gall stones or cholelithiasischolelithiasis
Causes:Causes: ►►Impairment in LiverImpairment in Liver ►► Obstruction of biliary tractObstruction of biliary tract
►► Defect in Enterohepatic Defect in Enterohepatic circulation of bile saltscirculation of bile salts
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Transformations of Cholesterol:Transformations of Cholesterol: Steroid HormonesSteroid Hormones
O
O
O
OH
OHHO
O
CH3
HO
CH3
Cholesterol
Estradiol
Progesterone
Cortisol
O
OH
TestosteroneHO
OH
CH2
HO
OH
OH Vitamin D
HYPER CHOLESTEROLEMIAHYPER CHOLESTEROLEMIA
Serum cholesterol level is more than Serum cholesterol level is more than 200mg/dl 200mg/dl it is it is considered as Hypercholesterolemiaconsidered as Hypercholesterolemia
Causes- Causes- 1) Diabetes mellitus1) Diabetes mellitus2) Hypothyroidism2) Hypothyroidism3) Obstructive jaundice3) Obstructive jaundice4) Nephrotic syndrome4) Nephrotic syndrome
Atherosclerosis :Atherosclerosis : Deposition of cholesterol esters and Deposition of cholesterol esters and other lipids in the internal layers of arterial walls, other lipids in the internal layers of arterial walls, leading to hardening and closure of coronary & cerebral leading to hardening and closure of coronary & cerebral arteries arteries
Treatment for HypercholesterolemiaTreatment for Hypercholesterolemia
1)1) Consumption of PUFAConsumption of PUFA
2)2) Dietary fiberDietary fiber
3)3) Avoiding high carbohydrate dietAvoiding high carbohydrate diet
4)4) Drugs like Lovastatin Drugs like Lovastatin
AtorvastatinAtorvastatin
CholestyramineCholestyramine
CholestipolCholestipol
Inhibit HMG CoA reductase
bind with bile acid decreases Entero hepatic circulation