Metabolism Flashcards
What are the histological zones of the adrenal?
Cortex: zona glomerulosa, fasciculata, reticularis
Medulla
What does each layer of the cortex produce?
Glomerulosa - mineralocorticoids
Fasciculata - glucocorticoids
Reticularis - sex steroids
What happens to the sex steroids produced by the adrenal?
Converted to more potent sex steroids by the gonads
Describe sex steroid synthesis
DHEA to delta4 androstenedione to oestrone
testosterone, 17beta oestradiol
dihydrotestosterone to ADG
What converts DHEA to delta 4 androstenedione?
3 beta hydroxysteroid dehydrogenase
What converts androstenedione to testosterone or to oestrone?
17beta hydroxysteroid dehydrogenase
p450 aromatase
What converts testosterone to DHT?
steroid 5alpha reductase
What converts DHT to ADG?
steroid 3alpha reductase
What converts oestrone to 17beta oestradiol?
17beta hydroxysteroid dehydrogenase
Describe the isoforms of steroid 5alpha reductase
Type 1: pH optimum 6-8.5, higher Km, chromosome 5p15, hair follicles, sebum glands, liver
Type 2: pH optimum 5, lower Km, chromosome 2p23, prostate, genital skin and liver
Describe girl to boy syndrome
Testosterone to DHT converted by SRD5A2 Phenotype: outwardly female and develop male characteristics at puberty Genotype: 46 XY SRD5A2 mutant SRD5A1 expression increases at puberty. Neonatal virilisation requires SRD5A2.
Describe P450 aromatase
Converts delta4 androstenedione to oestrone and testosterone to 17beta oestradiol.
Single gene, chromosome 15p21.1
Essential for generation of oestrogens.
Detrimental in cancer
What converts DHEA to DHEAS?
Steroid sulphatase
What converts DHEAS to DHEA?
SULT2A1
What does sulphation of DHEA prevent?
Makes it hydrophilic, cannot cross membranes
Which is more abundant, DHEA or DHEAS?
DHEAS
What is OATP?
A transporter that allows DHEAS into cells
Describe expression of SULTs
Different SULTs expressed in different places to control how much DHEA is available
What comes before DHEA?
Cholesterol to pregnenolone to 17alpha OH pregnenolone
What is the role of 3beta HSD?
Dual function with dehydrogenase and isomerase NAD-dependent isoforms
Type 1: placenta and skin
Type 2: adrenals and gonads
Mutations in type 2 cause congenital adrenal hyperplasia
What catalyses pregnenolone to progesterone?
3beta HSD
What is the role of 17beta HSD?
Converts delta4 androstenedione to testosterone and oestrone to 17beta oestradiol
Referred to as a sex steroid activating/inactivating switch
11 known isoforms. Not all understood.
Mutations in 17betaHSD3 feminises 46XY babies
What is congenital adrenal hyperplasia?
21-hydroxylase deficiency
Large adrenal glands and shortage of cortisol
Hypothalamus stimulates pituitary, produces ACTH, signals to adrenals to produce cortisol
Deficiency in CYP21 prevents production of cortisol. No negative feedback to hypothalamus, constant production of ACTH.
Results in androgen excess
Virilisation of females.
Degree of virilisation = degree of enzyme function loss
What enzymes can cause CAH?
21 hydroxylase
11 beta hydroxylase
3 beta HSD
17 alpha hydroxylase
Where are glucocorticoids synthesised?
Zona fasciculata and zona reticularis
Name some effects of glucocorticoids
Brain: depression, psychosis Eyes: glaucoma Carbohydrate and lipid metabolism Adipose tissue distribution Bone and calcium metabolism Growth and development Immune system
What effects the release of CRH from the hypothalamus?
Stress
Diurnal rhythm
Cytokines
What are mineralocorticoids?
Synthesised in the zona glomerulosa
Aldosterone is produced by the adrenals
Salt and water homeostasis
Mineralocorticoid receptor activation
Describe mineralocorticoid receptor specificity
The same for mineralocorticoids and cortisol
Both exert the same effect
What is apparent mineralocorticoid excess?
Severe hypertension, hypokalaemia, low renin and aldosterone levels.
Caused by a block in cortisol to cortisone conversion. Plasma cortisone levels are undetectable. Normal circulating cortisol levels.
Increased urinary THF/THE ratio and cortisol/cortisone
11betaHSD2 eliminated and cortisol freely binds MR
(also mimicked in liquorice excess)
What is the role of 11beta hydroxysteroid dehydrogenase?
Conversion of cortisol to cortisone and back
11betaHSD1: predominantly cortisone to cortisol, liver, adipose and bone
11betaHSD2: only cortisol to cortisone, kidney, colon and salivary gland
What happens if cortisol levels are lowered?
Aldosterone activates the mineralocorticoid receptor
Describe pre-receptor regulation by 11betaHSD
High levels of 11betaHSD2 present in the kidney
All cortisol is converted to cortisone
Only mineralocorticoid receptor activation is by aldosterone
What is obesity-metabolic syndrome?
Prevalent
25% of UK BMI of 30+
Premature mortality
Hypertension, insulin resistance, diabetes mellitus type 2, hyperlipidaemia, CVD, central obesity
What is the link between 11betaHSD1 and adipogenesis?
Cortisol causes adipogenesis (Cushing’s disease)
Adipose cells in vitro grow most in the presence of cortisol
Cortisone causes slight increase in growth (11betaHSD1)
11betaHSD1 inhibitor LJ2 prevents this
Overexpression = obesity
KO = poor glucose clearance
What clinical drugs inhibit 11betaHSD1?
Amgen
Biovitum
Carbonexalone
