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, „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 O 2 and NADPH + H + → lanosterol → 3 methyl groups are cleaved → cholesterol Figure was assumed from 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 bacteria in intestine ● secondary bile acids: deoxycholic and lithocholic function: emulsification of lipids in intestine → digestion and absorption Figure 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 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 18 th 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 cholesterol ester cholesterol TAG apolipoprotein phospholipid

typesource most component important apolipoproteins they transport mainly chylomicronsintestineTAGB-48, C-II, E TAG from food into extrahepatal tissues VLDLliverTAGC-II, B-100 recently synthesized TAG into tissues IDLVLDL cholesterol esters, TAG, phospholipids B-100 remnants of VLDL into tissues LDLVLDL cholesterol esters B-100 cholesterol into tissues HDLlivercholesterol esters, phospholipids A-I, E, C-IIcholesterol 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