Corticosteroid production and regulation Flashcards
How are steroid hormones derived?
enzymatic modifcation of cholesterol
Where are enzymes involved in steroid production found?
in the mitochondria and smooth ER
What do all steroids share?
a typical (not identical) ring structure
What are the properties of steroid hormones?
- lipid soluble
- freely permeable to membranes
- not stored
- synthesised and immediately released
- not water soluble
- carried in blood complexed to specific binding globulins
What carries cortisol in the blood?
corticosteroid binding globulin
Where is the adrenal gland?
- abdomen, above kidneys
What are the adrenal glands?
endocrine glands
What gives adrenal glands their colour?
- yellow
- due to high cholesterol
Which area of the adrenal gland has a rich nerve and blood supply?
`medulla
Describe the adrenal glands
- outer cortex composed of zones with characteristic histology
- inner medulla - embryologically and histologically distinct
What arteries supply the adrenal glands?
Each gland is supplied by the superior, middle and inferior suprarenal arteries
Describe the blood flow in the adrenal glands
The blood reaches the outer surface of the gland before entering and supplying each layer (centrepetal blood flow).
Which vein in the adrenal gland does blood flow into
medullary vein
Describe the course of the medullary veins
emerge from the hilum of each gland before forming
the suprarenal veins, which join the inferior vena cava on the right side and the left renal vein on the left
Describe the nerve supply of the adrenal glands
derived from
the coeliac plexus and the thoracic splanchnic nerves. The nerves supply
the chromaffin cells of the adrenal medulla.
Describe the histology of the adrenal gland
- fibrous capsule
- cortex:
- zona glomerulosa
- zona fasciculata
- zona reticularis - medulla
Describe the zona glomerulosa
clusters of small cells. Fewer lipids than other layers
Describe the zona fasciculata
large cells arranged in cords
Describe the zona reticularis
smaller cells - haphazard arrangement
Describe the medulla
Contains:
- chromaffin cells
- medullary veins
- numerous capillaries
- splanchnic nerves
Where are adrenal androgens produced?
zona reticularis
What regulates the production of adrenal androgens?
ACTH
Name adrenal androgens
DHEA
Androstenedione
Name glucocorticoids
- cortisol
- corticosterone
Where are ghlucocorticoids produced?
zona fasciculata
What regulates the production of glucocorticoids?
ACTH
What is the importance of glucocorticoids?
Carbohydrate regulation
What is the importance of adrenal androgens?
- important source of androgens in women
How is cholesterol taken up for steroid synthesis?
from circulation or synthesised de novo from acetyl CoA
also taken up by the cell in the form of low density
lipoprotein (LDL).
What is the rate limiting enzyme in cholesterol biosynthesis?
HMG-CoA reductase
What is LDL?
complex composed of cholesterol, phospholipids, triglycerides, and proteins (proteins and phospholipids make LDL soluble in blood).
How is LDL taken into cells?
via LDL receptors, and broken down into
esterified cholesterol, and then free cholesterol
What is the first enzymatic step in steroid hormone synthesis?
the conversion of cholesterol to pregnenolone.
Which enzyme catalyses the conversion of cholesterol to
pregnenolone.
Cytochrome P450 which requires co-factor.
Where is cytochrome P450 found?
in the inner mitochondria
What is the rate-limiting step in transport of free cholesterol
the transport of free cholesterol from cytoplasm into mitochondria carried out by Steroidogenic Acute Regulatory Protein (StAR)
Describe the mechanism of action of steroids
- steroid diffuses through plasma membrane
- binds to intracellular receptor
- receptor-hormone complex enters nucles
- binds to glucocorticoid response element (DNA sequence)
- binding initiates gene transcription to produce mRNA
- mRNA translated into a protein, which mediates the effects-target cell response
Where are glucocorticoid receptors found?
widespread
Where are mineralcorticoid receptors found?
- Distal Nephron
- Salivary glands
- Sweat glands
- Large intestine
- Brain
- Vascular tissue
- Heart
Describe the mineralcorticoid receptor affinity
Aldo>DOC>corticosterone>
cortisol>Dexamethasone
Describe the glucocorticoid receptor affinity
Dexamethasone>corticosterone>
cortisol=aldosterone
How is the mineralcorticoid receptor protected from glucocorticoid binding?
11b-HSDII catalyses the conversion of Cortisol (active) to Cortisone (inactive) in selective tissues (e.g kidney) allowing aldosterone to function normally.
What are the effects of cortisol?
- Stimulates gluconeogenesis in liver
- Permissive effect on glucagon
- stimulation of lipolysis in adipose tissue
- insulin antagonist
- breakdown skeletal muscle protein
- memory, learning, mood
- immune suppression
What is the result of cortisols effect on lipolysis?
fatty acids released are used for production of energy
in tissues like muscle and the released glycerol
provides another substrate for gluconeogenesis.
What are the actions of Aldosterone?
sodium reabsorption and concomitant K+ and H+ secretion
How does aldosetrone effect sodium levels?
Acts on mineralocorticoid receptors (MR) in the principal
cells of the distal tubule and the collecting duct
of the nephron-upregulates/activates basolateral Na/K pumps.
Aldosterone upregulates epithelial sodium channel (ENaC)
increasing apical membrane permeability for Na+
Aldosterone stimulates Na+ and water reabsorption
from the gut, salivary and sweat glands in exchange for K+
How does aldosetrone effect K+/H+ levels?
Aldosterone stimulates the secretion of K+
into the lumen.
Aldosterone stimulates secretion of H+ via the H+/ATPase
in the intercalated cells of the cortical collecting tubules
Aldosterone stimulates Na+ and water reabsorption
from the gut, salivary and sweat glands in exchange for K+
Describe the action of aldosterone in the kidney
Aldosterone binds to mineralocorticoid receptor (MR)
Translocated into the nucleus,
Acts as transcription factor-
Binds to HREs
Repression or induction of
aldosterone responsive genes
mRNA transcripts (SGK-1, ENaC, NaK-ATPase)
Aldosterone Action in Kidney.
= Sodium Reabsorption
= Potassium Excretion
What process regulates cortisol and androgen production?
hormones produced by hypothalamus and anterior pituitary gland (HPA Axis)
What process regulates aldosterone production?
renin-angiotensin system
(RAS) and plasma potassium
How is ACTH formed?
- cleavage of proopiomelanocortin (POMC)
What other peptides are formed along with ACTH?
- lipotropin
- beta-endorphin
- met-enkephalin
- melanocyte-stimulating hormone (MSH)
What is the action of ACTH?
ACTH has rapid and long-term actions:
Stimulation of cholesterol delivery to the
mitochondria (rapid).
Increased transcription of genes coding for steroidogenic
enzymes e.g. 11B-hydroxylase (long-term).
= increased cortisol (androgen production)
Describe ACTH binding
ACTH binds to 7TMD G-protein receptors
Conformation changes in receptor stimulate adenyl cyclase , causing an increase in cAMP, activation of PKA and calcium influx
When is RAS activated?
in response to low
blood pressure, plasma
sodium
What is the result of RAS activation?
Leads to production of Ang II
which causes direct
(vasoconstriction) and indirect (aldosterone, thirst) methods
of BP elevation,
Describe angiotensin II binding
AngII binds to 7TMD G-protein coupled receptor
Activates phospholipase C
What is the function of phospholipase C (as a consequence of angiontensin II)
Hydrolyses phosphatidylinositol bisphosphate (PIP2) to form 2nd messengers inositol triphosphate (IP3) and diacyl glycerol (DAG).
What is the function of IP3 (as a consequence of angiontensin II)?
causes stored Ca2+ to be released
What is the result of a rise in intracellular calcium (as a consequence of angiontensin II)?
activates Ca2+-calmodulin
dependent protein kinases (CaMKs) which stimulate the
transcription of StAR and cholesterol uptake into mitochondria
How does potassium regulate aldosterone?
Extracellular potassium tightly controlled
Increases in potassium = increases aldosterone
> Sodium reabsorption
Potassium excretion
= Normalises potassium concentration
