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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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De novo Synthesis of Cholesterol
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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De novo Synthesis of Cholesterol
Stage 1: Synthesis of meva onate rom acety CoA
Formation of HMG CoA (cyto)
Analogous to KB synthesis (mito)
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De novo Synthesis of Cholesterol
Conversion of mevalonate to isoprenoids.
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De novo Synthesis of Cholesterol
Conversion of mevalonate to isoprenoids.
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De novo Synthesis of Cholesterol
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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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De novo Synthesis of 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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Synthesis of Bile Acids
Hydroxylation
function oxidase system
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Synthesis of Bile Acids
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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