cholesterol metabolism 2012

7/30/2019 Cholesterol Metabolism 2012

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C o estero Meta o ism

Dr. Atif Hassan Khirelsied

Faculty of Medicine

,


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Cholesterol structure and functions

Membrane component Precursor of :

Bile acids Vitamin D Steroid hormones


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Cholesterol

Animal roducts e s, meat, brain tissues

Transported in the circulation in lipoproteins

storage form is cholesterol ester found in most tissues.

Increase intake = decreased absorption

Excrete 1 g/day (bile acids)


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Central Role of the Liver in Cholesterol Balance:Sources of hepatic cholesterol

Dietar cholesterol From chylomicron remnants

Cholesterol from extra hepatic tissues

Reverse c o estero transport via HDL Chylomicron remnants IDL

De novo synthesis


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Central Role of the Liver in Cholesterol Balance:Sources of hepatic cholesterol

VLDL> LDL Transport to extra hepatic tissues

Direct excretion into bile a s ones common y are prec p a es o c o es ero

Bile acid synthesis and excretion into bile


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De novo Synthesis of Cholesterol

r mary s e: ver g Secondary sites: intestine, adrenal cortex,

ovaries, testes, skin

Overall equation:


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ynt es ze rom acety o an e m nate as e

acids m ar to etogen c pat way

Occurs in cytosol

Requires NADPH and ATP

Highly regulated

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


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Stage 1: Synthesis of meva onate rom acety CoA

Formation of HMG CoA (cyto)

Analogous to KB synthesis (mito)


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Conversion of mevalonate to isoprenoids.


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Conversion of mevalonate to isoprenoids.


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De novo Synthesis of

Stage 4 :

Conversion of squalene to anos ero e our r ng steroid nucleus)

Stage 5:

lanosterol to cholesterol


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Regulation of Cellular Cholesterol Content

Cellular cholesterol content exerts transcriptional control of HMGCoA reductase

Half life = 2 hours LDLreceptor synthesis


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Regulation of Cholesterol Synthesis

Covalent Modification

of

HMG

CoA Reductase

Insulin induces protein phosphatase

Activates HMGCoA reductase


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Regulation of Cholesterol Synthesis


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Bile Acid/Salt Metabolism

Ma or excretor form of cholesterol

degraded in humans

Bile acid/salts involved in e ary p ges on as

emulsifiers


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Bile Acid/Salt Metabolism

Primary bile acids Good emulsifying agents

All OH rou s on same side pKa = 6 (partially ionized)

Conjugated bile salts Amide bonds with glycine or

taurine Very good emulsifier

pKa lower than bile acids


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Synthesis of Bile Acids

Hydroxylation

Side chain cleavage

Conjugation

Secondary bile acids Intestinal bacterial modification

Deconjugation Dehydroxylation

Deoxycholic acid

Lithocholic acid


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Hydroxylation

function oxidase system


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Conjugation of Bile Acid


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Recycling of Bile Acids

Enterohepatic circulation 98% recycling of bile acids

Cholestyramine Treatment

Resin binds bile acids Prevents recycling Increased uptake of LDLC for bile acid synthesis


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Recycling of Bile Acids

cholesterol metabolism 2012

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