Cholesterol metabolism

• Metabolis transformations of cholesterol

• Bile acids

• Steroid hormones

• Vitamin D

cholesteryl esters

kalciolsvitamins D

bile acids(24 C)

steroidhormones

adrenal corticalsteroid hormones

(21 C)

glucocorticoids mineralocorticoids

sexhormones

androgens(19 C)

estrogens(18 C)

18

HO 3

19

21 20

17

24

Metabolic transformation of cholesterol

HO

CH2-O-C

O

C-O-CH

CH2-O-

O

P -cholin

-R

CH2-O-C

O

HO-CH

CH2-O- P -cholin

-RC~CoA

O

O

C

O

1 - ACAT (intracellular e.)(acyl-CoA:cholesterol acyltransferase)

2 - Cholesterolesterase

3 - LCAT (plasma e.)(lecithin:cholesterol acyltransferase)

lecithin

lysolecithin

Cholesteryl ester (CE)

CoA-SH

1

23

cholesterol

Cholesteryl esters

Bile acids

24 carbon steroid compounds – degradation products of cholesterol(50-75% of daily cholesterol turnover)

Provide cholesterol excretion as:• metabolic products• solubilizer of cholesterol in bile

Bile salts- products of conjugation of bile acids with glycin or taurin

COOH + H2N-CH2-COO-

COOH + H2N-CH2-SO3 -

pKa = 2,2

pKa = 1,2

more polar sidechain

more effective detergents

pKa = 6polar and apolar face emulsifying agents

(bile, intestine)

- H2ORatio glycine- to taurine-conjugated acids ~ 3: 1

Metabolism of bile acids

Synthesis: liver

cholesterol primary bile acids primary bile salts

bile

intestine secondary bile acids/salts+ primary bile acids/salts

feces

enterohepatic circulation

bound to albumin

Cholelithiasis: cholesterol gallstones – precipitation of cholesterolin bile due to decreased amount of bile acids/salts in bile

malabsorption of bile acids, obstruction of biliary tract, decreased synthesis, increased cholesterol excretion into bile

Biosynthesis of primary bile acidscholesterol

7-α-hydroxycholesterol

choloyl-CoA

chenodeoxycholoyl-CoA

cholic acid = cholate

chenodeoxycholic acid= chenodeoxycholate

glycocholatetaurocholate

Cytochrome P450NADPH + H+ O2

CoASH

CoASH

glycin

taurin

7-α-hydroxylase (+ vitamin C, - BA)

conjugated bile acids = bile salts

HO

primary bileacids - liver

secondary bileacids - intestine

7-oxolithocholate lithocholate

ursodeoxycholate

cholate 30 % chenodeoxycholate 44 %

deoxycholate24 %

cholesterol

O

OH

derived by 7-dehydroxylation through action of bacterial enzymes primarily in large intestine

Metabolism of bile acids

Increase in bile acids fecal excretion increased conversion of cholesterol to bile acids, (for example pectins from fruit) incresed number of LDL- receptors on hepatocytes

decreased cholesterol plasma level

Treatment of hypercholesterolema – cholestyramin, colestipol – hydrophilic, water-insoluble,nondigestable and nonabsorbable synthetic resins– bind bile acids, increase their loss in fecesand interrupt their enterohepatic circulation

Steroid hormones

Synthesis: from cholesterol via pregnenolone

• Adrenal cortex - aldosterone

cortisol

• Corpus luteum - progesterone

• Ovaries - estradiol

• Testes - testosterone

Transport by blood to target tissues:

• Albumin - nonspecific carrier

• Transcortin - cortisol, corticosterone

• Sex hormone-binding protein – sex hormones

Conversion of cholesterol to adrenal cortical hormones

1. Side chain cleavage 21 C

pregnenolone

2. Dehydrogenation of 3-OH, moving of double bond from B ringtothe ring A

progesterone

3. Hydroxylations in several positions

aldosterone cortisol

21, 11, 18 17, 21, 11

211811

21

17

11Hydroxylases – cytochrome P450-linkedenzymes, require O2, NADPH

Conversion of cholesterol to sex hormones

1. Side chain cleavage 21 C

pregnenolone

2. Dehydrogenation of 3-OH, moving of double bond from B ringtothe ring A

progesterone

3. Hydroxylations in position 17, side chain removal 18 C testosterone

4. Aromatisation of the ring A, removal of C18 methyl group 17 C

estradiol

Estrogens – only steroids containing aromatic ring

Disorders in steroid hormone synthesis

Secretion of steroid hormones

Synthesis and secretion - elicited by other hormones (peptide hormones placed higher in hierarchyof hormonal regulation of the organism)

Peptide hormone – binds to cell membrane receptor –

activation of adenylate cyclase opening of Ca2+ channels

(mediated by G-protein

cAMP elevation of cytosolic Ca2+

protein kinase A activation

phosphorylation of several enzymes

hydrolysis of stored cholesterol esters, increased transport ofcholesterol into mitochondria, side chain cleavage, hormonesynthesis

Control of secretion of adrenal steroid hormones - glucocorticoids

stress , low level of circulating cortisol

hypothalamus

CRF (=corticotropin-releasing factor)

pituitary

ACTH(= adrenocorticotropic hormone)

adrenal cortex

cortisol (synthesis and secretion)

muscle liver

↑ protein degradation ↑ gluconeogenesis

StAR = steroidogenic acute phase regulatoryprotein – facilitates translocation of cholesterol From outer ro inner mitochondrial membrane –start of hormone biosyntheis

Control of secretion of adrenal steroid hormones - mineralocorticoids

↓ Na+/K+

renin-angiotensin system

angiotensin II, III

adrenal cortex

aldosterone(synthesis and secretion)

kidney tubules

retention of Na+

Control secretion of sex hormones secretion

circulating levels of sex hormones, LH, FSH

GSH (gonadotropin-releasing factor)

Metabolic transformation of steroid hormones= inactivation

Liver - reduction of unsaturated bonds- (hydroxylation) conjugation with glucuronic

or sulfuric acid soluble comounds

excretion

bile kidney

feces urine20-30 % 70-80 %

Mechanism of steroid hormone action

Hormone diffusion across plasma membrane

binding to intracellular receptor hormone-receptor complex

binding to HRE (hormone-response element)= specific regulatory sequence of DNA

initiation of transcription of target gene

translation (synthesis of a protein)

provide a response to a specific steroid hormone

Vitamin D

transformation to active forms = hydroxylation at C25, C1

1,25-dihydroxycholecalciferol =calcitriol = D-hormone

Function:↑↑↑↑ resorption of Ca 2+ in kidney

and intestine↓↓↓↓

induction of the synthesis ofcalcium-binding protein –

transport of Ca 2+ in enterocyte

Precursors: 7-dehydrocholesterol (D3),ergosterol (D2)

skinsun light (UV)

cleavage of B-ring calciferols