CHOLESTEROL AND BILE ACIDS CHOLESTEROL 1 2 HO

CHOLESTEROL AND BILE ACIDS

CHOLESTEROL 1 2 HO 3 A 4 CH 3 10 5 CH 3 H H H CH 3 H C C CH 3 12 17 H 11 13 16 C C C H H H C 9 B 6 8 7 D 14 15 CH 3

SIGNIFICANCE OF CHOLESTEROL COMPONENT OF BIOLOGICAL MEMBRANES PRECURSOR OF BILE ACIDS PRECURSOR OF ALL STEROID HORMONES PRECURSOR OF VITAMIN D COMPONENT OF PLASMA LIPOPROTEINS

CHOLESTEROL l total content in the body: 140 g l content in the nervous tissue: 40 g l total amount in plasma: 5 g l half-life in plasma: 75 days l most of body cholesterol exists in the form of unesterified cholesterol (free cholesterol) l cholesteryl esters predominate in plasma

SOURCES OF CHOLESTEROL IN THE LIVER l CHYLOMICRON REMNANTS (DIETARY CHOLESTEROL) l HDL (CHOLESTEROL SYNTHESIZED IN EXTRAHEPATIC TISSUES - ENDOGENOUS CHOLESTEROL) l CHOLESTEROL SYNTHESIZED IN THE LIVER

CHOLESTEROL ELIMINATION FROM THE LIVER l AS CHOLESTEROL IN BILE l AS CHOLESTEROL AND CHOLESTERYL ESTERS IN VLDL l AS BILE ACIDS IN BILE

TISSUE LOCALIZATION OF CHOLESTEROL SYNTHESIS l LIVER l INTESTINE l ADRENAL CORTEX l GONADS (OVARIES, TESTES) l PLACENTA

SYNTHESIS OF CHOLESTEROL (1) acetate (activation) 2 acetyl-Co. A thiolase acetoacetyl-Co. A + Co. A acetyl-Co. A HMG-Co. A synthase HMG-Co. A

SYNTHESIS OF CHOLESTEROL (2) HMG-Co. A + 2 NADPH + 2 H+ HMG-Co. A reductase mevalonate + Co. A + 2 NADP+ 2 ATP kinases 5 -pyrophosphomevalonate + 2 ADP ATP pyrophosphomevalonate decarboxylase isopentenyl pyrophosphate + ADP + Pi + CO 2

SYNTHESIS OF CHOLESTEROL (3) isopentenylpyrophosphate isomerase isopentenyl pyrophosphate 3, 3 -dimethylallyl pyrophosphate dimethylallyl transferase geranyl pyrophosphate (10 C) geranyl pyrophosphate isopentenyl pyrophosphate geranyl transferase farnesyl pyrophosphate (15 C)

SYNTHESIS OF CHOLESTEROL (4) farnesyl pyrophosphate squalene synthase NADPH + H+ squalene (30 C) + NADP+ + PPi NADPH + H+ + O 2 squalene monoxygenase lanosterol (30 C) + NADP+ + H 2 O cholesterol (27 C)

SYNTHESIS OF BILE ACIDS (1) cholesterol inhibition 7α-hydroxylase 7α-hydroxycholesterol cholic acid chenodeoxycholic acid taurochenodeoxycholic acid glycochenodeoksycholic acid (primary bile acids)

SYNTHESIS OF BILE ACIDS (2) PRIMARY BILE ACIDS deconjugation 7α-dehydroxylation SECONDARY BILE ACIDS deoxycholic acid lithocholic acid