Week 4 L3 Functions of Adrenal Cortex

Question 1

What is the order of the layers of the adrenal cortex?

Answer 1

Remember GFR: glomerulosa, fasciculata, reticularis (from outer to inner)

Question 2

What does the zona glomerulosa produce?

Answer 2

Aldosterone

Question 3

What does the zona fasciculata produce?

Answer 3

Cortisol

Question 4

What does the zona reticularis produce?

Answer 4

Androgens: DHEA, androstenedione

Question 5

What is the relationship between cortisol and epinephrine in the adrenal gland?

Answer 5

Blood washes first through the zona fasciculata and becomes saturated with cortisol. That blood then reaches the adrenal medulla, where high cortisol concentration is necessary for stimulation of the PNMT enzyme that produces epinephrine from norepinephrine

Question 6

What is cholesterol synthesized to as the rate-limiting step of steroid biosynthesis? What is the enzyme?

Answer 6

Makes pregnenolone, by cholesterol side chain cleavage enzyme (CYP11A1)

Question 7

In the zona glomerulosa, what steroid biosynthesis enzyme is present and what enzyme is missing, and because of this it is able to produce its particular hormone?

Answer 7

It has CYP11B2 (aka aldosterone synthase), but is missing CYP17 (17 alpha hydroxylase). So it follows down its pathway to produce aldosterone

Question 8

In the zona fasciculata, what steroid biosynthesis enzyme is present and what enzyme is missing, and because of this it is able to produce its particular hormone?

Answer 8

It has CYP17 (17 alpha hydroxylase) and CYP11B1, but no CYP11B2. Also, activity of 17,20 lyase is low so it falls down the cortisol pathway and doesnt produce sex steroids.

Question 9

In the zona reticularis, what steroid biosynthesis enzyme is present and what enzyme is missing, and because of this it is able to produce its particular hormone?

Answer 9

It has CYP17 (17 alpha hydroxylase) and the 17,20 lyase activity is higher than in the fasciculata, so it produces DHEA and androstenedione

Question 10

What enzyme converts pregnenolone to progesterone? (also converts 17-OH pregnenolone and DHEA)

Answer 10

3-Beta Hydrogenase (or 3β-HSD for hydroxysteroid dehydrogenase)

Question 11

What enzyme converts pregnenolone or progesterone into 17-OH pregnenolone or 17-OH progesterone?

Answer 11

CYP17, activity of 17 alpha hydroxylase

Question 12

What enzyme converts 17-OH pregnenolone and 17-OH progesterone into sex steroids, and what are their products?

Answer 12

17,20 Lyase. Converts 17-OH pregnenolone -> DHEA, while 17-OH progesterone -> androstenedione

Question 13

What enzyme is used to convert progesterone to DOC (deoxycorticosterone? It also converts 17-OH progesterone into 11-deoxycortisol

Answer 13

21 Hydroxylase (CYP21A2)

Question 14

What enzyme converts deoxycorticosterone (DOC), and into what product?

Answer 14

CYP11B2 (a 11β-Hydroxylase function) converts DOC -> corticosterone

Question 15

What enzyme converts 11-deoxycortisol, and into what product?

Answer 15

CYP11B1 (a 11β-Hydroxylase), converts it into cortisol

Question 16

What enzyme converts corticosterone, and into what product?

Answer 16

Again, CYP11B2 (but the 18-Hydroxylase function) converts it into 18-OH corticosterone

Question 17

What enzyme converts 18-OH corticosterone, and into what product?

Answer 17

Again, CYP11B2 (but the 18-Oxydase function), converts it into Aldosterone

Question 18

What happens to androstenedione after it is produced in the zona reticularis?

Answer 18

It is converted to other steroids in the periphery (testis, ovary)

Question 19

What protein helps cholesterol to be transported into the mitochondria of cells that synthesize steroid hormones?

Answer 19

StAR (Steroidogenic Acute Regulatory Protein)

Question 20

Is there storage of steroid hormones?

Answer 20

No, they are produced and secreted on-demand. However, there is storage of cholesterol esters in lipid droplets that are converted back to cholesterol (by cholesterol esterase) then made into steroids

Question 21

What is the main regulatory hormone of steroid synthesis? What is its mechanism?

Answer 21

ACTH. Activates ACTH MC2 receptor -> cAMP increase -> PKA -> StAR phosphorylated -> cholesterol transport into mitochondria increased. ACTH also leads to proliferation of zona fasciculata

Question 22

What are the effects of Angiotensin II on hormone synthesis?

Answer 22

Angiotensin II -> AT1 receptor -> calcium signal -> PKC -> StAR phosphorylated -> cholesterol transport into mitochondria increased

Question 23

When a person is given glucocorticoids for a long time and then taken off of them, what may occur as a result of negative feedback?

Answer 23

While taking the glucocorticoids, negative feedback caused the adenohypophysis to produce less ACTH, and in its absence the zona fasciculata may become atrophied. Thus, when glucocorticoid supplementation ends, the body may not have the ability to produce enough cortisol to maintain normal levels.

Question 24

What protein does cortisol bind to most of the time for transport? What percentage of cortisol is bound to this protein? What is the significance of this binding?

Answer 24

Transcortin (CBG) - 90% of cortisol is bound to it. Has high binding affinity, and increases the half-life of cortisol to about 70 minutes

Question 25

What percentage of cortisol is bound to albumin?

Answer 25

5-7%

Question 26

What protein does aldosterone bind to, and how is the affinity? What is the significance of this?

Answer 26

Aldosterone binds to albumin with low affinity-binding. Leads to a shorter half-life than cortisol (about 20 minutes)

Question 27

What is the difference in secretion rate between cortisol and aldosterone? What is the difference between their concentrations?

Answer 27

Cortisol has 100 x more secretion, but 1000 times difference in concentration

Question 28

How much cortisol is secreted in a day?

Answer 28

20 mg / day

Question 29

How much aldosterone is secreted in a day?

Answer 29

0.15 mg / day

Question 30

What is the plasma concentration of cortisol?

Answer 30

0.1-0.5 micromolar

Question 31

What is the plasma concentration of aldosterone?

Answer 31

0.1-0.3 nanomolar

Question 32

In humans, what is the main glucocorticoid? What is the main mineralocorticoid?

Answer 32

GC = cortisol, MC = aldosterone

Question 33

What 2 types of receptors (broadly) can be targeted by corticosteroids?

Answer 33

Cytosolic and membrane receptors

Question 34

What is an example mentioned in lecture where the corticosteroid receptor is a transcription factor?

Answer 34

For the glucocorticoid receptor (GR), which is a dimer with heat shock protein 90. It binds to its ligand and then dissociates from HSP90, and then it can upregulate or downregulate expression of proteins

Question 35

What is the effect of glucocorticoids on the NF-κB pathway?

Answer 35

The NF-κB is a transcription factor which regulates cytokines involved in inflammation. Without stimulus, NF-κB is inhibited by its IκB subunit, which breaks free and degrades if there is inflammatory stimuli. Glucocorticoids are anti-inflammatory in that they stimulate transcription of IκB and bind to NF-κB to prevent it from transcribing inflammatory factors

Question 36

What are the two GPCRs (7 transmembrane receptors) of membrane receptors by glucocorticoids?

Answer 36

Gs (activating cAMP) and Gq (calcium signal)

Question 37

Regarding the glucocorticoid receptor type I (mineralocorticoid receptor, MR), what is the effect of its “preceptor specificity?”

(yes the naming for these receptors is confusing)

Answer 37

The cytosolic type I receptors bind to cortisol and aldosterone with equal affinity (so can still be called glucocorticoid receptors). However, these cells also contains 11-β-HSD2, which inactivates cortisol into cortisone. This enzyme has no effect on aldosterone, and so more aldosterone can target the MR type I receptor than cortisol, despite the 1000 x larger cortisol concentration.

Question 38

What are the main effects of aldosterone?

Answer 38

Reabsorption of sodium in the collecting duct, potassium excretion, Na+/K+ ATP-ase activity increase, and activation of proton pump in intercalated cells (Summary: increases body’s Na+; decreases body’s K+ and H+)

Question 39

What effect does aldosterone have on the citric cycle enzymes?

Answer 39

It increases their expression, matches an increased ATP demand

Question 40

What is the effect of ANP on aldosterone? Of ACTH?

Answer 40

ANP -> inhibition of aldosterone production. ACTH -> increased responsiveness of cells to aldosterone

Question 41

What is the effect of angiotensin II on aldosterone? Why does this occur?

Answer 41

Stimulates its production (via AT1 receptor, Gq). Occurs due to blood volume decrease, arterial pressure decrease, sympathetic tone increase, and low sodium intake.