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CHOLESTEROL
METABOLISM
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CHOLESTEROL METABOLISM
Steroid alcohol (sterol) Characteristic of animal tissues
Derived from diet and synthesized denovo
Functions Component ofplasma and intracellular membranes
especially abundant in myelinated structures
Precursor of bile acids
Precursor of various steroid hormones
Precursor of various Vitamin D
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CHOLESTEROL METABOLISM
Structure Cyclopentanoperhydrophenanthrene nucleus
or steroid nucleus 4 fused rings
Single hydroxyl group at C-3 Double bond at C5-C6
8 membered hydrocarbon side chain
attached to D ring at C-17
2 methyl groups
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CHOLESTEROL METABOLISM
CPP
nucleus
Side
chain
C3-OH
Double bond between
C5 & C6
Methyl groups
Structure
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CHOLESTEROL METABOLISM
Sterols also present in plant tissues -sitosterol
Not absorbed from GIT
When absorbed they are activelytransported back to lumen along with
cholesterol dietary treatment of
Hypercholesterolemia
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CHOLESTEROL METABOLISM
Most plasma cholesterol is in an esterified
form with its 3-OH esterified to fatty acid
cholesterol ester (cholesteryl ester)
More hydrophobic Cholesterol and its ester carried by
lipoproteins
From liver to tissues LDL
From tissues to Liver -HDL
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CHOLESTEROL METABOLISM
Accounts for > half of total body cholesterol
in all tissues
liver and intestines with adrenal cortex andreproductive tissues make large contributions
occurs in the cytoplasm and endoplasmicreticulum
Enzymes in cytoplasm and membrane ofendoplasmic reticulum
All 27 carbon atoms of cholesterol arederived from acetyl CoA
NADPH provides the reducing equivalents
Synthesis
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CHOLESTEROL METABOLISM
- Sources of Acetyl CoA
Like Fatty Acid synthesis
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Synthesis
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CHOLESTEROL METABOLISM
The process has five major steps:
3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)synthesis
Mevalonate synthesis
isopentenyl pyrophosphate (IPP) formation
Synthesis of squalene
Cholesterol formation
Synthesis
Acetyl CoA HMG CoA Mevalonate IPP Squalene Cholestero
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CHOLESTEROL METABOLISM
Acetyl CoA HMG CoA Mevalo
Synthesis
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CHOLESTEROL METABOLISM
Synthesis of HMG CoA
takes place in the cytosol
Two moles of acetyl-CoA are condensedforming acetoacetyl-CoA.
Acetoacetyl-CoA and a third mole of acetyl-CoA are converted to HMG-CoA
by the action ofHMG-CoA synthase.
Q: differentiate from ketone body synthesis
Synthesis
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CHOLESTEROL METABOLISM
HMG-CoA is converted to Mevalonate
committedstep
irreversible step,
3-hydroxy-3-methylglutaryl CoA reductase(HMG-CoA reductase),
important control site
an integral membrane protein in the
endoplasmic reticulum.
Synthesis
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CHOLESTEROL METABOLISM
Synthesis
ATP-dependent decarboxylation isopentenylpyrophosphate, IPP, an activated isoprenoid molecule.
Mevalonate IPP
CO2
ATP ADP+ Pi
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CHOLESTEROL METABOLISM
IPP Squalene
Synthesis
IPP Geranyl PP Farnesyl PP Squalene
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CHOLESTEROL METABOLISM
Synthesis
Squalene Lanosterol CHOLESTEROLNADPH,H+ NADP
O2 H2O
Squalene monooxygenase
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CHOLESTEROL METABOLISM
Regulation
1. At the DNA level
- SREBP-SCAP (SREBP-SCAP-insig)
- Hormone
2. At the Protein level
- Degradation-Covalent modification
HMG-CoA Reductase rate-limiting step is a major control point
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CHOLESTEROL METABOLISM
Sterol dependent regulation of geneexpression.
Low sterol
SREBP + SCAP migrates to golgi protease action
release of soluble SREBP
migrates to nucleus
activates transcription
High sterol SREBP + SCAP associated withanother integral protein (insigs) preventsmigration to Golgi no activation
Regulation
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CHOLESTEROL METABOLISM
Regulation
Sterol-accelerated enzyme degradation High cholesterol HMG CoA reductase + insig
protein ubiquitinated and degraded
Phosphorylation/dephosphorylation Phosphorylated protein is inactive AMP activated protein kinase (AMPK) &
phosphoprotein phosphatase
Hormonal regulation : Insulin & glucagon Through phosphorylation /dephosphorylation
Regulation of gene expression insulinupregulates and glucagon down regulates
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CHOLESTEROL METABOLISM
Drugs competitive inhibitors of HMG-CoAReductase.
Examples include various statin drugs such as
lovastatin and derivatives A portion of each statin is analogous in structure to
mevalonate or to the postulated mevaldehydeintermediate.
Regulation
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CHOLESTEROL METABOLISM
Degradation
Humans cannot degrade the ring structure of
cholesterol
Excreted in the form of
bile acids and Bile saltsmajor form Some into bile intestine eliminated
Some cholesterol acted on by bacteria coprostanol and
cholestanol
coprostanol and cholestanol along with cholesterol
called neutral fecal sterols
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CHOLESTEROL METABOLISM
Bile acids and Bile salts
synthesized in the liver stored and concentrated in the gall bladder,
and
released into the small intestine.
24 carbons + 2 or 3 hydroxyl groups + sidechain with COO-
- Amphipathic (emulsifying)
solubilize dietary lipids more surface area is exposed to the digestive
action of lipases and
lipids are more readily absorbed by the intestine
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CHOLESTEROL METABOLISM
Synthesis ofBile Acids and Bile salts
from cholesterol in multiple steps First step is 7 hydroxylation
Rate limiting step
Occurs in Microsomes
Enzyme is 7 hydroxylase (ER-associated cytochromeP450 (CYP)
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CHOLESTEROL METABOLISM
Conversion of 7a-hydroxycholesterol to thebile acids requires several steps
By mono oxygenases
Leads to formation ofcholic acid andchenodeoxy cholic acid primary Bile Acids
Synthesis ofBile Acids and Bile salts
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CHOLESTEROL METABOLISM
in liver carboxyl group of primary and secondary bile acids
conjugated to glycine or taurine
yield glycoconjugates and tauroconjugates, respectively
Synthesis ofBile acids and Bile salts
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CHOLESTEROL METABOLISM
Due to the negative charge on the carboxyl on aminoacids the bile salts are more amphipathic Increased efficiency of detergent action
Glycine : Taurine 3:1
Secondary bile acids Intestinal bacterial modification
Deconjugation
Dehydroxylation
Deoxy cholic acid
Lithocholic acid
Synthesis ofBile acids and Bile salts
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CHOLESTEROL METABOLISM
Synthesis ofBile acids and Bile salts
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CHOLESTEROL METABOLISM
Enterohepatic circulation
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CHOLESTEROL METABOLISM
Enterohepatic circulation
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CHOLESTEROL METABOLISM
Bile salts and bile acids secreted into intestine
the primary and secondary bile acids arereabsorbed almost exclusively in the ileum
returning to the liver by way of the portalcirculation (98 to 99%)
this is known as the Enterohepatic circulation
less than 500 mg a day escapes reabsorption andis excreted in the feces
Enterohepatic circulation
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CHOLESTEROL METABOLISM
Synthesis ofBile acids and Bile salts:
Regulation
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CHOLESTEROL METABOLISM
Cholestyramine Treatment
Resin binds bile acids
Prevents recycling Increased uptake of LDL-C for bile acid
synthesis
In treatment of Hypercholesterolemia
Dietary fiberbinds and increases excretion
Enterohepatic circulation
The role of Bile salts in the metabolism of cholesterol is 2-fold
-Formation
-Solubilisation
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Clinical Significance:
Cholelithiasis: Movement of cholesterol from liver to gall bladderaccompanied by Phospholipids and Bile Salts.
If there is an imbalance and more cholesterol
reaches the Gall bladder cholesterol gall stones
or Cholelithiasis
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CHOLESTEROL METABOLISM
Causes
Conditions where Bile acids are absorption ileal disease
Obstruction of biliary tract interrupts Enterohepaticcirculation
Hepatic disorders
Excessive suppression of synthesis of bile acids due to recycling
biliary cholesterol excretion Use of fibrates
Cholelithiasis:
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CHOLESTEROL METABOLISM
Investigation : Ultrasound
Treatment:
Laparoscopic cholecystectomy Chenodeoxycholic acid supplements
Cholelithiasis:
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