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    Cholesterol and Lipoprotein Metabolism

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    Benjamin Prabhu
    Cholesterol is an important component of cell membranes and lipoproteins. It exists in two forms - free cholesterol and cholesterol ester. Cholesterol is synthesized in the liver, intestine, and other tissues from acetyl-CoA through a multi-step process involving mevalonate and isoprenoid intermediates. The rate-limiting step is the conversion of HMG-CoA to mevalonate by HMG-CoA reductase, which is regulated by feedback inhibition by cholesterol and other mechanisms. Cholesterol synthesis proceeds through the formation of lanosterol and its reduction to cholesterol through either a major or alternative pathway in the endoplasmic reticulum. Excess cholesterol is stored as cholesterol esters

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    Cholesterol and Lipoprotein Metabolism

    Uploaded by

    Benjamin Prabhu
    111 views32 pages
    Cholesterol is an important component of cell membranes and lipoproteins. It exists in two forms - free cholesterol and cholesterol ester. Cholesterol is synthesized in the liver, intestine, and other tissues from acetyl-CoA through a multi-step process involving mevalonate and isoprenoid intermediates. The rate-limiting step is the conversion of HMG-CoA to mevalonate by HMG-CoA reductase, which is regulated by feedback inhibition by cholesterol and other mechanisms. Cholesterol synthesis proceeds through the formation of lanosterol and its reduction to cholesterol through either a major or alternative pathway in the endoplasmic reticulum. Excess cholesterol is stored as cholesterol esters

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    Cholesterol is an important component of cell membranes and lipoproteins. It exists in two forms - free cholesterol and cholesterol ester. Cholesterol is synthesized in the liver, intestine, and other tissues from acetyl-CoA through a multi-step process involving mevalonate and isoprenoid intermediates. The rate-limiting step is the conversion of HMG-CoA to mevalonate by HMG-CoA reductase, which is regulated by feedback inhibition by cholesterol and other mechanisms. Cholesterol synthesis proceeds through the formation of lanosterol and its reduction to cholesterol through either a major or alternative pathway in the endoplasmic reticulum. Excess cholesterol is stored as cholesterol esters

    Copyright:

    Attribution Non-Commercial (BY-NC)
    Download as PPT, PDF, TXT or read online from Scribd
    Download as ppt, pdf, or txt
    111 views32 pages

    Cholesterol and Lipoprotein Metabolism

    Uploaded by

    Benjamin Prabhu
    Cholesterol is an important component of cell membranes and lipoproteins. It exists in two forms - free cholesterol and cholesterol ester. Cholesterol is synthesized in the liver, intestine, and other tissues from acetyl-CoA through a multi-step process involving mevalonate and isoprenoid intermediates. The rate-limiting step is the conversion of HMG-CoA to mevalonate by HMG-CoA reductase, which is regulated by feedback inhibition by cholesterol and other mechanisms. Cholesterol synthesis proceeds through the formation of lanosterol and its reduction to cholesterol through either a major or alternative pathway in the endoplasmic reticulum. Excess cholesterol is stored as cholesterol esters

    Copyright:

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    Download as PPT, PDF, TXT or read online from Scribd
    Download as ppt, pdf, or txt
    of 32

    Cholesterol and Lipoprotein

    Metabolism

    Ricardo R. Santos, MD
    Structure of Cholesterol
    An alicyclic compound whose structure
    include:

    • Cyclopentanoperhydrophenanthrene nucleus
    • Single hydroxyl group at C-3
    • Double bond between C-5 and C-6

    • Eight-membered branched hydrocarbon chain


    attached to ring D at C-17

    • Two angular methyl groups: a) one designated C-18


    attached to C-13; b) second designated C-19
    attached to C-10
    Two forms of cholesterol
    1. Free cholesterol
    - unesterified to fatty acid; amphipathic
    - found in membranes and outer layer
    of lipoproteins
    - 30% of total cholesterol in the blood
    - biologically active form

    2. Cholesterol ester
    - fatty acid is esterifed to OH grp at C-3
    - found in lipid core of lipoproteins
    - 70% of total cholesterol in the blood
    - storage form of cholesterol in the tissue
    Cholesterol Values

    • Plasma: 150 – 200 mg/100 ml


    (mostly as cholesterol ester)

    • Bile: 390 mg/100 ml


    (mostly as free cholesterol; 96% of total)

    • Total cholesterol is estimated by


    Liebermann-Burchard reaction
    Importance of Cholesterol
    • Important component of membranes and
    outer layer of lipoproteins

    • Precursor of:
    - vitamin D3 (skin)
    - bile acids (liver)
    - steroid hormones (adrenals and gonads)

    • Protects gallbladder membrane from


    irritating and harmful effects of bile salts
    Foods rich in cholesterol

    • Cholesterol is primarily of animal origin


    - skin, liver, intestines, adrenal gland,
    gonads, brain

    • Egg yolk, meat


    Medical importance of cholesterol

    • Atherosclerosis
    • Gallstones
    • Hyperlipoproteinemias
    Biosynthesis of Cholesterol
    General considerations
    - Liver, intestine, adrenal cortex, gonads, placenta
    have the greatest capacity to synthesize chol.

    - All carbon atoms of cholesterol are derived from


    acetyl CoA.

    - Cholesterol synthesis takes place in the cytosol


    and endoplasmic reticulum; 700 mg/day

    - Synthesis is expensive (18 ATPs/cholesterol)

    - Reducing power in the form of NADPH is


    provided by HMP shunt
    Five Steps in the Synthesis of Cholesterol

    1. Biosynthesis of mevalonate

    2. Formation of isoprenoid units

    3. Formation of squalene

    4. Cyclization of squalene to lanosterol

    5. Conversion of lanosterol to cholesterol


    Step 1 – Formation of Mevalonate
    (Rate-limiting Step)

    Acetyl CoA
    Thiolase
    CoA

    Acetoacetyl CoA
    HMG-CoA synthase Acetyl CoA
    (cytosolic)
    CoA

    3-Hydroxy-3-methylglutaryl CoA
    (HMG-CoA)
    From HMG-CoA to Mevalonic Acid

    HMG-CoA

    HMG-CoA reductase NADPH


    (committed enzyme)

    NADP

    Mevalonate
    Regulation of HMG-CoA Reductase
    HMG-CoA reductase is an intrinsic membrane protein
    of the endoplasmic reticulum and its active site
    extends into the cytosol.

    1. Feedback inhibition by cholesterol


    2. Hormonal regulation
    * Insulin stimulates (favor dephosphorylated
    active form of enzyme)
    * Glucagon inhibits (favor phosphorylated
    inactive form of enzyme)
    3. Cholesterol-mediated inhibition of gene
    transcription
    4. Inhibition by drugs: “statins” – e.g., simvastatin,
    lovastatin, pravastatin, atorvastatin, etc.
    Regulation of Cholesterol Synthesis
    Step 2. Formation of isopentenyl
    pyrophosphate
    • Sequential phosphorylation of mevalonate
    by kinases utilizing ATP

    • Take place several times


    • Need six isoprenoid units to form one
    cholesterol

    • Most expensive stage


    • 1 mevalonate to 1 isoprenoid unit = 3 ATPs
    • 6 isoprenoid units to 1 cholesterol = 18 ATPs
    Step 3. Formation of Squalene

    • Involves initial isomerization of isopentenyl


    pyrophosphate.
    • Followed by a series of condensation reactions
    forming geranyl pyrophosphate and
    farnesylpyrophosphate.
    • Condensation of two farnesylpyrophosphates
    forming the 30-carbon atom squalene.
    • Pyrophosphate is released in each
    condensation step.
    • Isopentenyl-PP is a precursor of important
    compounds like ubiquinone and dolichol.
    Synthesis of Cholesterol
    Step 4. Formation of Lanosterol

    • Involves cyclization of squalene to form


    lanosterol by endoplasmic reticulum-bound
    squalene oxidocyclase

    • Squalene oxidocyclase has two enzymatic


    activities: epoxidase (monooxygenase) and
    cyclase (oxidosqualene:lanosterol cyclase)

    • Lanosterol has also 30 carbon atoms


    Synthesis of Cholesterol
    Step 5. From Lanosterol to Cholesterol
    • Takes place in the membrane of endoplasmic
    reticulum

    • The major pathway in mammals proceeds


    through 7-dehydrocholesterol involving a
    series of double bond reductions and
    demethylations.

    • Alternative pathway involves:


    1. three demethylations to give zymosterol
    2. isomerization of double bond to form desmosterol
    3. reduction of double bond to form cholesterol
    Major and alternative routes from lanosterol
    to cholesterol
    Lanosterol

    Major route Alternative route

    7-dehydrocholesterol Zymosterol

    Desmosterol

    Cholesterol
    Metabolism of Cholesterol
    Mutations on LDL Receptor
    Fate of Endogenous Cholesterol
    Plaque Formation in Atherosclerosis
    Oxidized LDL and plaque formation
    Fatty Streak of Atherosclerosis
    Fibrofatty plaque of Atherosclerosis
    Intraluminal Thrombus

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