Metabolism of steroids Pavla Balínová. Cholesterol is a maternal molecule of all steroids in human...

Metabolism of steroids

Pavla Balínová

Cholesterol

• is a maternal molecule of all steroids in human body

• is a starting molecule for synthesis of bile acids and steroid hormones (sex hormones, gluco- and mineralocorticoids)

• is a component of plasma membranes

Cholesterol structure

Figures were assumed from a book T. M. Devlin et al.: Textbook of Biochemistry With Clinical

Correlations, 4th ed., Wiley‑Liss, Inc., New York, 1997.

„free“ cholesterol cholesterol ester

Cholesterol biosynthesis

• organ location: liver, intestine, skin, adrenal cortex• subcellular location: smooth endoplasmic reticulum• amount: about 1 g daily = endogenous cholesterol, about 0,3 g of cholesterol is taken up from food per day (exogenous cholesterol)● regulatory enzyme: HMG CoA reductase

Sections of cholesterol biosynthesis

• formation of mevalonate from acetyl-CoA• formation of isopentenyl diphosphate („active

isoprene“) from mevalonate• formation of squalene from 6 units of

isopentenyl diphosphate• formation of cholesterol

Synthesis of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA)

2x acetyl-CoA → acetoacetyl-CoA

+ acetyl-CoA HMG-CoA

Figure was byl assumed from book T. M. Devlin et al.: Textbook of Biochemistry

With Clinical Correlations, 4th ed., Wiley‑Liss, Inc., New York, 1997.

Formation of mevalonate

• reduction of HMG-CoA with the help of NADPH + H+ to mevalonate

• key regulatory enzyme: HMG-CoA reductase

Figure was assumed from book T. M. Devlin et al.: Textbook of Biochemistry

With Clinical Correlations, 4th ed., Wiley‑Liss, Inc., New York, 1997.

Formation of isopentenyl diphosphate

• phosphorylation of mevalonate (2 ATP) → mevalonyl diphosphate → decarboxylation with consumption of ATP → isopentenyl diphosphate („ active isoprene“)

Figure was assumed from book T. M. Devlin et al.: Textbook of Biochemistry

With Clinical Correlations, 4th ed., Wiley‑Liss, Inc., New York, 1997.

Formation of squalene

• squalene is synthesized by series of reactions (intermediates are geranyl diphosphate and farnesyl diphosphate

• reducting agent is NADPH + H+

• squalene contains 30 C atoms

Figure was assumed from book T. M. Devlin et al.: Textbook of Biochemistry With Clinical

Correlations, 4th ed., Wiley‑Liss, Inc., New York, 1997.

Formation of cholesterol

• squalene is cyclized with consumption of O2 and NADPH + H+ → lanosterol → 3 methyl groups are cleaved → cholesterol

Figure was assumed from http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/cholesterol.htm

Regulation of cholesterol biosynthesis

Regulatory enzyme HMG CoA reductase• hormonal stimulation by insulin and

triiodotyronine, glucagon inhibits the enzyme• glucagon → ↑ cAMP → phosphorylation of

enzyme → inhibition• insulin → ↓ cAMP → dephosphorylation of

enzyme → activation● cholesterol acts as a repressor of transcription● exogenous cholesterol (from food) inhibits the

enzyme• competitive inhibitors – drugs e.g. lovastatin

(structure similar to mevalonate)

Metabolic fates of cholesterol

What happens with synthesized cholesterol??

Esterification with help of lecithine:cholesterol acyltransferase (LCAT) → transfer of acyl of FA on –OH group of cholesterol in position 3

Cholesterol synthesized in liver:-half-life (days) → about 75% is converted into bile acids

Cholesterol synthesized in skin:→ conversion into 7-dehydrocholesterol → vitamin D (calcitriol)

Transport of cholesterol into adrenal cortex and gonads →steroid hormones

Bile acids

• a way to get off cholesterol• are formed from cholesterol in the liver and they are excreted into a bile• primary bile acids:cholic and chenodeoxycholic

bacteriain intestine● secondary bile acids:deoxycholic and lithocholicfunction: emulsification of lipids in intestine → digestion and absorptionFigure was assumed from book T. M. Devlin et al.: Textbook of Biochemistry With Clinical

Correlations, 4th ed., Wiley‑Liss, Inc., New York, 1997.

Cholesterol as a source of steroid hormones

• cholesterol is a metabolic precursor of all steroid hormones in human body

• number of C atoms is changing during synthesis of hormones: from 27 to 21, 19 or 18

• adrenal cortex and gonads

Hormonal stimulation of biosynthesis of steroid hormones

Figure was assumed from book T. M. Devlin et al.: Textbook of Biochemistry With Clinical

Correlations, 4th ed., Wiley‑Liss, Inc., New York, 1997.

Adrenal steroid hormones

Figure was assumed from book T. M. Devlin et al.: Textbook of Biochemistry With Clinical Correlations, 4th ed., Wiley‑Liss, Inc., New York, 1997.

Adrenal steroid hormones

• Cholesterol → removal of 6 C atoms from side chain → pregnenolone (21 C)

progesterone (21 C)hydroxylation hydroxylation in positions 21 and 11 in positions 17, 21

and 11

aldosterone (21 C) cortisol (21 C) mineralocorticoids glucocorticoids

Male sex hormones produced in adrenal cortex

• in zona reticularis: cholesterol → pregnenolone → DHEA (dehydroepiandrosterone) → androstenedione

Figure was assumed from book T. M. Devlin et al.: Textbook of Biochemistry With Clinical

Correlations, 4th ed., Wiley‑Liss, Inc., New York, 1997.

Male sex hormones produced in testes

cholesterol

pregnenolone

progesterone DHEA

androstenedione

hydrogenation at position 17 Leydig cells (testes)

testosterone

dihydrotestosterone

Testosterone

Figure was assumed from book T. M. Devlin et al.: Textbook of Biochemistry With Clinical

Correlations, 4th ed., Wiley‑Liss, Inc., New York, 1997.

Female sex hormones

• Progesterone• Testosterone → removal of 18th C atom and aromatisation → estradiol (18 C)Aromatase is located in ovaries and adipose tissue:androgens → estrogens

Figure was assumed from book T. M. Devlin et al.: Textbook of Biochemistry With Clinical

Correlations, 4th ed., Wiley‑Liss, Inc., New York, 1997.

Degradation of steroid hormones

• sterane skeleton is very stable and it is unable to destroy it

• reduction is included in inactivation of steroids (hydrogenation of double bond) in ring A

• inactivation reactions occur in liver• conjugation with glucuronic acid or

sulphuric acid• formed conjugates are excreted with urine

Lipoproteins = carriers of lipids and cholesterol

Figure was assumed from http://www.lce.hut.fi/research/sysbio/biospectroscopy/lipoprotein/

cholesterol ester

cholesterol

TAG

apolipoprotein

phospholipid

type source most component

importantapolipoprote

ins

they transport mainly

chylomicrons

intestine

TAG B-48, C-II, E TAG from food intoextrahepatal tissues

VLDL liver TAG C-II, B-100 recently synthesized TAG into tissues

IDL VLDL cholesterol esters,TAG, phospholipids

B-100 remnants of VLDL into tissues

LDL VLDL cholesterol esters

B-100 cholesterol into tissues

HDL liver cholesterol esters, phospholipids

A-I, E, C-II cholesterol from tissues into liver

Lipoproteins

Concentration of lipoproteins in serum

• HDL up to 2.6 mmol/L („good“ cholesterol)• LDL up to 3.9 mmol/L („bad“ cholesterol)• Total cholesterol up to 5.0 mmol/L

Reference values depend on an age, sex and diet.

Values were assumed from Department of biochemistry and pathobiochemstry 3. LF UK and FNKV

Is it possible to influence the LDL level in blood?

• decrease of LDL: diet with higher content of unsaturated FA, estrogens, intake of a small amount of an alcohol, drugs (statins)

• increase of LDL: surfeit (mainly diet with higher content of animal fats), deficit or mutation of LDL receptors, diabetes, intake of a high amount of alcohol, smoking

• prevention of atherosclerosis: antioxidants (vit. C and E), fiber