•Function •Biosynthesis •Transport in theorganism ...

[Pages:16]Cholesterol metabolism

? Function ? Biosynthesis ? Transport in the organism ? Hypercholesterolemia

Cholesterol

- component of all cell membranes - precursor of bile acids

steroid hormones vitamin D

Sources: dietary cholesterol (~ 25% of a daily turnover)

- 0,3g/day

synthesis in tissues (~ 75 %)

- 1 g/day

liver (reproductive tissues -adrenal cortex, ovaries, testes, placenta)

enzymes of biosynthesis present in virtually all tissues

Transport:

as a component of lipoproteins, most as cholesteryl esters

chylomicrons: VLDL: LDL: HDL:

intestine liver

plasma plasma

(extrahepatic tissues)

liver plasma extrahepatic tissues liver

Overview of cholesterol metabolism in liver

Dietary cholesterol

De novo synthesis of cholesterol in liver

Chylomicron remnants

Cholesterol from extrahepatic tissues

HDL

Secretion in HDL and VLDL Free cholesterol secreted in bile

Conversion to Bile acids/salts

Cholesterol excretion

! Steroid ring can not be cleaved in humans

1. cholesterol liver bile acids/salts

bile intestine

feces

cholestanol

2. cholesterol bile

intestine

koprostanol

feces

Cholesterol availability in diets widely varies

balance the rate: cholesterol synthesis

regulatory mechanisms

cholesterol excretion

Imbalance:

elevation of circulating cholesterol excessive cholesterol excretion into bile

coronary artery disease

precipitation in the gallblader

and bile duct

gallstones

Cholesterol biosynthesis

Initial substrate: acetyl-CoA Tissue localization: predominantly liver

mitochondria

acetyl-CoA

farnesyl pyrophosphate

endoplasmic reticulum

citrate

isopentenyl pyrophosphate

translokase for citrate

citrate

oxaloacetate

acetyl-CoA

mevalonate

cytosol

HMG-CoA

squalene lanosterol cholesterol

Cholesterol biosynthesis: acetyl-CoA mevalonate

O

O

CH3-C-S-CoA + CH3-C-S-CoA 2 x acetyl-CoA

OO

O

acetoacetyl-CoA CH3-C-CH2-C-S-CoA + CH3-C-S-CoA

HMG-CoA

O

CH3 O

CoASH

HMG-CoA synthase

-O-C-CH2-C-CH2-C-S-CoA OH

CoASH

HMG-CoA reductase

O

CH3

-O-C-CH2-C-CH2-CH2-OH

OH

mevalonate

Cholesterol biosynthesis: mevalonate

cholesterol

Control of cholesterol synthesis

Regulation of HMG CoA reductase, rate-limiting enzyme of cholesterol synthesis

SRE = sterol regulatory element SREBP = sterol regulatory binding protein ? transcription factor associated with ER membrane

proteolytic release binding to DNA at SRE transcription of HMG CoA reductase

blocked by cholesterol

1. Regulation of transcription (HMG CoA reductase ? short biological half-time ~ 2 h): feed-back repression of HMG-CoA synthesis: cholesterol LDL-CH - liver, periferal cells CHR-CH ? liver

2. Hormonal regulation: insulin - enzyme dephosphorylation = activation, enzyme expression glukagon - enzyme phosphorylation - inactivation

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