cholesterol metabolism nr 2010

8/8/2019 Cholesterol Metabolism NR 2010

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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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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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CPP

nucleus

Side

chain

C3-OH

Double bond between

C5 & C6

Methyl groups

Structure


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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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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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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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- Sources of Acetyl CoA

Like Fatty Acid synthesis

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Synthesis


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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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Acetyl CoA HMG CoA Mevalo

Synthesis


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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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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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Synthesis

ATP-dependent decarboxylation isopentenylpyrophosphate, IPP, an activated isoprenoid molecule.

Mevalonate IPP

CO2

ATP ADP+ Pi


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IPP Squalene

Synthesis

IPP Geranyl PP Farnesyl PP Squalene


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Synthesis

Squalene Lanosterol CHOLESTEROLNADPH,H+ NADP

O2 H2O

Squalene monooxygenase


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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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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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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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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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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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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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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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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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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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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



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Enterohepatic circulation


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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



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Synthesis ofBile acids and Bile salts:

Regulation


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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


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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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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Investigation : Ultrasound

Treatment:

Laparoscopic cholecystectomy Chenodeoxycholic acid supplements

Cholelithiasis:

cholesterol metabolism nr 2010

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