LECTURE 14LECTURE 14Metabolism of CholesterolMetabolism of Cholesterol

V.SrideviV.Sridevi07.02.201407.02.2014

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Cholesterol MetabolismCholesterol Metabolism

The The objectivesobjectives of this lecture are to of this lecture are to Discuss the biosynthesis of cholesterol.Discuss the biosynthesis of cholesterol. Regulation of cholesterol synthesis, the Regulation of cholesterol synthesis, the

catabolism and excretion of cholesterol.catabolism and excretion of cholesterol.

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IntroductionIntroduction CholesterolCholesterol is a waxy steroid metabolite found is a waxy steroid metabolite found

in the cell membranesin the cell membranes It is an essential structural component of It is an essential structural component of

mammalian cell membranes, where it is required mammalian cell membranes, where it is required to establish proper membrane permeability and to establish proper membrane permeability and fluidity. fluidity.

The most publicized lipid, notorious because of The most publicized lipid, notorious because of the strong correlation between high levels of the strong correlation between high levels of cholesterol in the blood and the incidence of cholesterol in the blood and the incidence of human cardiovascular diseases.human cardiovascular diseases.

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Introduction…Introduction…

Cholesterol and other fats can't dissolve Cholesterol and other fats can't dissolve in the blood. They have to be transported in the blood. They have to be transported to and from the cells by special carriers to and from the cells by special carriers called lipoproteins. called lipoproteins.

There are several kinds, mainly low-There are several kinds, mainly low-density lipoprotein (LDL) and high-density density lipoprotein (LDL) and high-density lipoprotein (HDL).lipoprotein (HDL).

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Cholesterol FunctionsCholesterol Functions

Membrane componentMembrane component Precursor toPrecursor to

– Bile acidsBile acids– Vitamin DVitamin D– Steroid hormones:Steroid hormones: progesterone,oestrogens, progesterone,oestrogens,

androgens, androgens, glucocorticoids, and glucocorticoids, and mineralocorticoidsmineralocorticoids

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Sources of cholesterolSources of cholesterol

- Can be Can be obtained from the obtained from the dietdiet or be or be synthesized endogenously.synthesized endogenously.

- Regulatory mechanismsRegulatory mechanisms exist to balance the exist to balance the amount of cholesterol made by the body-daily amount of cholesterol made by the body-daily with both the dietary intake and the amount with both the dietary intake and the amount excreted (either in bile or as bile salts) excreted (either in bile or as bile salts)

- Failure leads to high plasma cholesterolFailure leads to high plasma cholesterol levels levels and an increased risk of cardiovascular diseasesand an increased risk of cardiovascular diseases

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Dietary cholesterolDietary cholesterol Liver produces about 1,000 milligrams per day. Total Liver produces about 1,000 milligrams per day. Total

body content is about 35g. body content is about 35g. Diet- animal products- egg yolks, meat, poultry, Diet- animal products- egg yolks, meat, poultry,

shellfish ,milk and dairy products(200-300mg/day)shellfish ,milk and dairy products(200-300mg/day) Plants- Don’t contain cholesterolPlants- Don’t contain cholesterol Cholesterol is recycled. It is excreted by the liver via Cholesterol is recycled. It is excreted by the liver via

the bile into the digestive tract. Typically about 50% of the bile into the digestive tract. Typically about 50% of the excreted cholesterol is reabsorbed by the small the excreted cholesterol is reabsorbed by the small bowel back into the bloodstream bowel back into the bloodstream

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Sources of CholesterolSources of Cholesterol

Diet De novo synthesisCholesterol synthesized in extrahepatic tissues

Liver cholesterolpool

Free cholesterolIn bile

Conversion to bile salts/acidsSecretion of HDLand VLDL

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De novo Synthesis of De novo Synthesis of CholesterolCholesterol

Primary site: liver (~1g/d)Primary site: liver (~1g/d)– Secondary sites: Intestine, adrenal cortex, Secondary sites: Intestine, adrenal cortex,

ovaries, testesovaries, testes Overall equation:Overall equation:

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Cholesterol SynthesisCholesterol SynthesisSimilar to ketogenic pathwaySimilar to ketogenic pathway

Occurs in cytosolOccurs in cytosol

Requires NADPH and ATPRequires NADPH and ATP

Highly regulatedHighly regulated

80 % in liver, ~10% intestine, ~5% skin80 % in liver, ~10% intestine, ~5% skin

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De novo Synthesis of Cholesterol:four stagesDe novo Synthesis of Cholesterol:four stages Formation of HMG CoA (cyto)Formation of HMG CoA (cyto)

– Analogous to KB synthesis (mito)Analogous to KB synthesis (mito)

Conversion of HMG CoA to activated isoprenoidsConversion of HMG CoA to activated isoprenoids

*

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De novo Synthesis of Cholesterol:four stagesDe novo Synthesis of Cholesterol:four stages

Condensation of Condensation of isoprenoids to isoprenoids to squalenesqualene

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De novo Synthesis of Cholesterol:four stagesDe novo Synthesis of Cholesterol:four stages

Conversion of Squalene to Conversion of Squalene to CholesterolCholesterol

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Biosynthesis of CholesterolBiosynthesis of Cholesterol

3CH3

+ Pi

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De novo Synthesis of Cholesterol:De novo Synthesis of Cholesterol:What do you need to know?What do you need to know?

All carbons from acetyl-CoAAll carbons from acetyl-CoA Requires NADPH, ATP, & ORequires NADPH, ATP, & O22

StagesStages– One: formation of HMG CoAOne: formation of HMG CoA– Two: HMG coA forms activated 5 carbon intermediates Two: HMG coA forms activated 5 carbon intermediates

(isoprenoids)(isoprenoids)– Three: Isoprenoids form squaleneThree: Isoprenoids form squalene– Four: Squalene + OFour: Squalene + O22 form cholesterol form cholesterol

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Regulation of cholesterol synthesisRegulation of cholesterol synthesis1.1. HMG CoA reductaseHMG CoA reductase is the rate-limiting enzyme in cholesterol is the rate-limiting enzyme in cholesterol

synthesis. synthesis. Feed back regulation Feed back regulation by cholesterol. The amount of dietary by cholesterol. The amount of dietary cholesterol determines cholesterol syncholesterol determines cholesterol synthesis.thesis.

2.2. Hormonal regulationHormonal regulation: Short term regulation is by covalent : Short term regulation is by covalent modification of the enzyme. modification of the enzyme. GlucagonGlucagon via cyclic AMP cascade via cyclic AMP cascade favours formation of inactive (phosphorylated) form of favours formation of inactive (phosphorylated) form of HMG CoA HMG CoA reductase. reductase. Hence, synthesis of cholesterol Hence, synthesis of cholesterol decreases.decreases.

In contrast, insulin promotes formation of active form of enzyme In contrast, insulin promotes formation of active form of enzyme → → increases synthesis of cholesterol.increases synthesis of cholesterol.

3. Long term regulation involves 3. Long term regulation involves suppression of transcriptionsuppression of transcription of the gene of the gene for for HMG CoA reductaseHMG CoA reductase synthesis synthesis by cholesterolby cholesterol..

4.4. Inhibition by drugsInhibition by drugs: Cholesterol lowering drugs (Statin drugs) like: Cholesterol lowering drugs (Statin drugs) like Zocor, LipitorZocor, Lipitor are reversible, competitive inhibitors of HMG CoA are reversible, competitive inhibitors of HMG CoA reductase.reductase.

5.5. Policosanol, extract from sugar cane wax, acts like the statin drugs Policosanol, extract from sugar cane wax, acts like the statin drugs

i.e. inhibit HMG CoA reductasei.e. inhibit HMG CoA reductase

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Abbreviations: ER, endoplasmic reticulum; Abbreviations: ER, endoplasmic reticulum; INSIG, insulin-induced gene; SCAP, INSIG, insulin-induced gene; SCAP, SREBP cleavage-activating protein; SRE, SREBP cleavage-activating protein; SRE, sterol regulatory element; SREBP, sterol sterol regulatory element; SREBP, sterol regulatory element-binding protein.regulatory element-binding protein.

When cellular cholesterol is high, the When cellular cholesterol is high, the SREBP–SCAP complex is retained in the SREBP–SCAP complex is retained in the ER membrane by the INSIG proteins, ER membrane by the INSIG proteins, leading to inhibition of sterol synthesis.leading to inhibition of sterol synthesis.

Under low-cholesterol conditions, INSIG Under low-cholesterol conditions, INSIG dissociates from the SREBP–SCAP dissociates from the SREBP–SCAP complex, which is then transported to the complex, which is then transported to the Golgi membrane. Golgi membrane.

The active form of SREBP is cleaved and The active form of SREBP is cleaved and translocates into the nucleus, where it translocates into the nucleus, where it activates the expression of genes activates the expression of genes containing the SRE in their promoter containing the SRE in their promoter region, including genes involved in region, including genes involved in cholesterol synthesis.cholesterol synthesis.

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Cholesterol and Bile Acid/Salt MetabolismCholesterol and Bile Acid/Salt Metabolism

Synthesis of bile acids is the predominant Synthesis of bile acids is the predominant mechanism by which excess cholesterol is mechanism by which excess cholesterol is eliminated from the bodyeliminated from the body

Major excretory form of cholesterolMajor excretory form of cholesterolOccurs in liverOccurs in liver

Bile acid/salts involved in dietary lipid digestion Bile acid/salts involved in dietary lipid digestion as emulsifiersas emulsifiers

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Bile Acids and Salts (Biological detergents)

• Bile acids are synthesized from cholesterol and is major metabolic fate of cholesterol.

• Bile acids are synthesized and secreted by the liver and conjugated with glycine or taurine to form bile salts before leaving the liver.

• Bile salts are stored in gallbladder and passed through the bile duct into the intestine.

Most of bile salts secreted in upper intestine is absorbed in the lower small intestine and returned to liver for reuse via the portal blood – called enterohepatic circulation.

Cholestyramine, a non-absorbable ionic resin binds bile salts increase the conversion of →cholesterol to bile acids and excreted →treatment to lower cholesterol

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Synthesis of bile acidSynthesis of bile acid

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Types of Bile Acids/SaltsTypes of Bile Acids/Salts Primary bile acidsPrimary bile acids::

End product of cholesterol catabolism in liver.End product of cholesterol catabolism in liver. chenodeoxycholic acidchenodeoxycholic acid (45%) and (45%) and cholic cholic

acidacid (31%). (31%).

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Bile saltsBile salts The carboxyl group of primary bile acids is The carboxyl group of primary bile acids is

conjugated with glycine or taurine to yield conjugated with glycine or taurine to yield glycocholic acid and taurocholic acid glycocholic acid and taurocholic acid which are called as which are called as bile saltsbile salts..

Lithocholic acid and deoxycholic acid are Lithocholic acid and deoxycholic acid are the the secondary bile acidssecondary bile acids formed by the formed by the action of intestinal bacterial enzyme 7-action of intestinal bacterial enzyme 7-alpha dehydroxylase.alpha dehydroxylase.

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Role of Bile Salts in Fat Digestion

• Bile salt molecule has both hydrophobic and hydrophilic surfaces (amphipathic).

• Bile salts able to orient at an oil-water interface, with the hydrophobic surface in contact with the apolar phase and the hydrophilic surface in contact with the aqueous phase.

• Detergent action emulsifies lipids and yields micelles hence allowing attack by water-soluble enzymes.

• Most of the digestion carried out by pancreatic lipase which acts at the water-oil interface.

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Learning outcomesLearning outcomesAt the end of the lecture, students should be able At the end of the lecture, students should be able

to:to: Describe the steps involved in Describe the steps involved in de novode novo

synthesis of cholesterol and explain how synthesis of cholesterol and explain how it is regulated.it is regulated.

Discuss the role of statin drugs in Discuss the role of statin drugs in inhibiting cholesterol synthesis.inhibiting cholesterol synthesis.

Explain how cholesterol is degraded and Explain how cholesterol is degraded and excreted in bile.excreted in bile.

The The objectivesobjectives of this lecture are to of this lecture are to Discuss the biosynthesis of cholesterolDiscuss the biosynthesis of cholesterol Regulation of cholesterol synthesis.Regulation of cholesterol synthesis. Catabolism and excretion of cholesterol.Catabolism and excretion of cholesterol.

At the end of the lecture, students should be At the end of the lecture, students should be able to:able to:

Describe the steps involved in de novo Describe the steps involved in de novo synthesis of cholesterol and how it is synthesis of cholesterol and how it is regulated.regulated.

Discuss the role of statin drugs that help in Discuss the role of statin drugs that help in inhibiting cholesterol synthesisinhibiting cholesterol synthesis

Explain how cholesterol is degraded and Explain how cholesterol is degraded and excreted in bile.excreted in bile.