09-03-23 - Steroid hormone biosynthesis Flashcards
Learning outcomes
- Describe the mechanisms of synthesis, dietary uptake, transport and major physiological functions of cholesterol
- Summarise the lipid particles used to transport cholesterol and describe the exogenous and endogenous pathways of metabolism
- Describe the roles of the LDL receptor and receptor mediated uptake of cholesterol
- Explain the regions of the adrenal cortex and the steroids produced
- Describe the enzymatic processing of intracellular cholesterol esters into the major steroid hormones
- Compare the structural differences between cortisol, aldosterone, testosterone, progesterone and estradiol
- Summarise the roles of Leydig, Sertoli, Theca and Granulosa cells in the processing of sex steroids
What is the pre-cursor if all steroids?
Describe the structure of cholesterol
What compounds can the centre sterol nucleus of cholesterol be found in?
What are 3 distributions of cholesterol?
- Cholesterol is the pre-cursor of all steroids
- Cholesterol is a 27-carbon compound with a unique structure with a hydrocarbon tail, a central sterol nucleus made of four hydrocarbon rings, and a hydroxyl group.
- The center sterol nucleus or ring is a feature of all steroid hormones.
- 3 distributions of cholesterol:
1) Membrane lipid (regulates membrane fluidity)
2) In plasma, associated with proteins (apolipoproteins), triacylglycerols, phospholipids in various types of micellular structures called lipoproteins
3) Cytosolic lipid droplets as cholesterol esters (steroid secreting endocrine cells)
When might cholesterol be synthesised?
Where does this process take place?
What is the rate-limiting step of this process?
What is the role of statins when it comes to cholesterol?
- If dietary intake of cholesterol is not sufficient, the liver synthesizes cholesterol from acetyl CoA in a multi-step process in the SER (smooth endoplasmic reticulum) and cytosol.
- The rate-limiting step is conversion of 3-hydroxymethylglutaryl CoA (HMGCoA) to mevalonate by HMG-CoA reductase.
- Statins help to reduce cholesterol levels to reduce risk of coronary events
Describe the following terms:
* HDL
* IDL
* LDL
* VLDL
- HDL - high-density lipoprotein (good cholesterol)
- IDL - intermediate-density lipoprotein
- LDL - low-density lipoprotein (bad cholesterol)
- VLDL - very-low-density lipoprotein.
Describe the 9 steps of the exogenous pathway for cholesterol metabolism
- 9 steps of the exogenous pathway for cholesterol metabolism :
1) The exogenous pathway starts with the intestinal absorption of triglycerides and cholesterol from dietary sources.
2) Its end result is the transfer of triglycerides to adipose and muscle tissue and of cholesterol to the liver.
3) After absorption, triglycerides and cholesterol are re-esterified in the intestinal mucosal cells and then coupled with various apoproteins, phospholipids, and unesterified cholesterol into lipoprotein particles called chylomicrons.
4) The chylomicrons in turn are secreted into intestinal lymph, enter the bloodstream through the thoracic: duct, and bind to the wall of capillaries in adipose and skeletal muscle tissue.
5) At these binding sites the chylomicrons interact with the enzyme lipoprotein lipase, which causes hydrolysis of the triglyceride core and liberation of free fatty acids.
6) These fatty acids then pass through the capillary endothelial cells and reach the adipocytes and skeletal muscle cells for storage or oxidation, respectively.
7) After removal of the triglyceride core, remnant chylomicron particles are formed.
8) These are high in cholesterol esters and characterized by the presence of apoproteins B, CIII, and E.
9) These remnants are cleared from the circulation by binding of their E apoprotein to a receptor present only on the surface of hepatic cells.
Describe the 8 steps in the endogenous pathway for cholesterol metabolism
- 9 steps in the endogenous pathway for cholesterol metabolism
1) The liver constantly synthesizes triglycerides by utilizing as substrates free fatty acids and carbohydrates; these endogenous triglycerides are secreted into the circulation in the core of very-low-density lipoprotein particles (VLDL).
2) The synthesis and secretion of VLDL at cellular level occur in a process similar to that of chylomicrons, except that a different B apoprotein (B-100 instead of B-48) together with apoproteins C and E intervene in their secretion.
3) Subsequent interaction of the VLDL particles with lipoprotein lipase in tissue capillaries leads to hydrolysis of the core triglycerides and production of smaller remnant VLDL particles rich in cholesterol esters (intermediate-density lipoproteins, IDL) and liberation of free fatty acids.
4) Around half of these remnant particles are removed from the circulation in 2 to 6 hours as they bind tightly to hepatic cells.
5) The rest undergo modifications with detachment of the remaining triglycerides and its substitution by cholesterol esters and removal of all the apoproteins except apoprotein B.
6) This process results in transformation of the remnant VLDL particles into low-density lipoprotein particles (LDL) rich in cholesterol.
7) Their predominant function is to supply cholesterol to cells with LDL receptors, like those in the adrenal glands, skeletal muscle, lymphocytes, gonads, and kidneys.
8) The quantity of cholesterol freed from LDL is said to control cholesterol metabolism in the cell through the following mechanisms:
1) Increased LDL cholesterol in the cell decreases synthesis of the enzyme 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase, which modulates the intracellular synthesis of cholesterol;
2) Increased LDL cholesterol may enhance the storage of cholesterol within the cell by activation of another enzyme;
3) Increased cholesterol within the cell diminishes the synthesis of LDL receptors through a negative feedback process.
Describe the uptake of LDL by receptor-mediated endocytosis and steroid hormone synthesis.
What can liberated cholesterol then be used for?
- Uptake of LDL by receptor-mediated endocytosis and steroid hormone synthesis:
- On hepatocytes, bound remnants of LDL cholesterol are taken to the inside of hepatic cells by endocytosis mediated LDL receptors (involves protein clathrin) and then catabolized by lysosomes.
- This process liberates cholesterol, which is then either converted into bile acids, excreted in bile, incorporated into lipoproteins originated in the liver (VLDL), or used to create steroid hormones
What are the 3 main physiological roles of cholesterol?
- 3 main physiological roles of cholesterol:
1) Major component of cell (plasma) membranes
* Decreases membrane fluidity
* Decreases physical permeability to charged/polar compounds
* Associated with the formation of lipid rafts
2) Precursor for the production of bile salts
* Uptake of fats and fat-soluble vitamins in GI tract
3) Precursor for all steroid hormones
* Glucocorticoids, mineralocorticoids, sex steroids
Describe the 4 steps in the biosynthesis of steroid hormones
- 4 steps in the biosynthesis of steroid hormones:
1) Cholesterol esters are converted into free cholesterol (from which all steroids are derived) by cholesterol ester hydrolase
2) Steroidogenic acute regulatory protein (STAR) moves cholesterol into the mitochondria and SER ofr enszymatic processing
3) Free cholesterol is converted to pregnenolone by desmolase (Side chain cleavage)
4) Pregnanolone can be used to form several steroid hormones:
* Progesterone
* Oestradiol
* Testosterone (can be converted to oestradiol with aromatase)
* Cortisol
* Aldosterone
Which enzymes are involved in steroidogenesis?
How many genes are there encoding for P450 enzymes?
Which enzyme catalyses a reaction in the production of oestrogens?
- P450 enzymes are involved in steroidogenesis, with their being 57 different genes encoding P-450 enzymes identified in the human genome
- P-450arom catalyses a reaction essential for the production of oestrogens
Describe the biosynthesis of adrenal steroids flowchart
Describe the anatomy of the adrenal gland, and which steroids are produced in each part
Describe the flowchart for biosynthesis of sex steroids in the testes (in picture).
What are hormones needed for?
What are androgens?
What is the major androgen in men?
- Flowchart for biosynthesis of sex steroids in the testes (in picture)
- Hormones are needed for different processes like growth, reproduction and well-being.
- Androgens are the group of sex hormones that give men their ‘male’ characteristics (collectively called virilisation).
- The major sex hormone in men is testosterone, which is produced mainly in the testes
What do the testes synthesise?
What is the production of these regulated by?
Describe the 5 steps in testosterone and sperm production in males
- The testes synthesize two essential products: testosterone, needed for the development and maintenance of many physiological functions including normal testis function; and sperm, needed for male fertility.
- The synthesis of both products is regulated by endocrine hormones produced in the hypothalamus and pituitary, as well as locally within the testis.
- 5 steps in testosterone and sperm production in males
1) The secretion of hypothalamic gonadotropin-releasing hormone (GnRH) stimulates production of luteinizing hormone (LH) and follicle stimulating hormone (FSH) by the pituitary.
2) LH is transported in the blood stream to the testes, where it stimulates Leydig cells to produce testosterone: this can act as an androgen (via interaction with androgen receptors) but can also be aromatized to produce estrogens.
3) The testes, in turn, feedback on the hypothalamus and the pituitary via testosterone and inhibin secretion, in a negative feedback loop to limit GnRH and gonodotropin production.
4) Both androgens and FSH act on receptors within the supporting somatic cells, the Sertoli cells, to stimulate various functions needed for optimal sperm production. Spermatogenesis is the process by which immature male germ cells divide, undergo meiosis and differentiate into highly specialized haploid spermatozoa.
5) Optimal spermatogenesis requires the action of both testosterone (via androgen receptors) and FSH.
Describe the flowchart for biosynthesis of sex steroids in the ovaries (in picture)
What is produced by theca and granulosa cells in the ovaries?
