Glucocorticoids Flashcards
What are the major functions of glucocorticoids?
metabolism and differentiation of adipose
embryonic development
immune suppression (anti-inflammatory and T cell death)
gluconeogenesis, protein turnover, and lipolysis
stress resposne and memory consolidation
bone formation and calcium metabolism
salt/water flux and blood pressure
HPA axis and gonadal axis of the endocrine system
Why did cholesterol evolve?
response to O2 stress
synthesis requires O2
cholesterol limits O2 diffusion and maintains membrane microfluidity
sterols appeared shortly after the Great Oxygenation Event
last common ancestor able to make sterols was probably a eukaryote
What is the action of glucocorticoids?
diffuses across the cell membrane, enters the cytosol, binds the glucocorticoid receptor, and displaces the receptor’s chaperone proteins, and triggers dimerization of the receptor, which then diffuses through a nuclear pore and into the nucleus to inhibit or promote transcription
Where are glucocorticoids formed?
cortisone, aldosterone, and dehydroepiandrosterone are adrenocortical steroid hormones synthesized in the cortex of the adrenal gland
What is the advantage of synthetic dexamethasone?
extra double bond int he A-ring, a 9-alpha-fluoro moeity, in the B ring, and a 16-alpha-methyl moiety in the C ring
the result is that this drug is more potent as a glucocorit
What are the targets and receptors of glucocorticoids?
genomic effects occur over hours to days
nongenomic effects occur over minutes
fourtargets - two on the genome (pGREs and nGREs)
all nuclear glucocorticoid receptors derivefrom a signel gene, but multiple isoforms exist
What is the mechanism of glucocorticoids?
molecule diffuses through the cell membrane, enter the cytosol, and binds the glucocorticoid receptor, displaces the receptor’s chaperone proteins, and triggers dimerization of the glucocorticoid receptor
the receptor diffuses through a nuclear pore and into the nucleus where some of the dimer separate
dimerized glucocorticoid receptors bind to pGREs and monomeric activated glucocorticoid receptors bind to nGREs
What is a positive glucocorticoid response element? (pGRE)
a genetic palindrome - a short DNA sequence followed by an inverted repeat of the same short DNA
pGRE are located within the promoter region of a target gene
a dimer of activated glucocorticoid receptors will bind to a pGRE causing transactivation of the corresponding gene with increased expression of mRNA and (often), increased translation of the expressed peptide
What are negative glucocorticoid response elements (pGREs)?
similar to a pGRE but with the difference that two monomeric activated receptors will bind to a nGRE causing transrepression of the corresponding gene with decreased expression of mRNA and (often), decreased translation of the expressed peptide
Describe the cortisol-cortisone shuttle.
cortisol is a much more potent glucocorticoid than is cortisone
in glucocorticoid-responsive cells, cortisone is activated to cortisol by 11-beta-hydroxysteroid dehydrogenase isozyme 1 (11-ß HSD1)
in mineralocorticoid cells, cortisol is deactivated to cortisone by 11-ß HSD2
What does glycyrrhizic acid do?
inhibits 11-ß HSD2 and has potent mineralocorticoid activity
under physiologic stress of dehydration and salt restriction, aldosteron acts to signal renal retention of salt and water
What is the role of corticotropin releaseing hormone?
secretion is influenced by cicadian inputs and physiologic stress
the paraventricular nucleus of the hypothalamus causes secretion of corticotropin releasing hormone from the median eminence into the capillary plexus of the hypothalamo-hypophyseal portal system
carried to the anterior lobe of the pituitary and stimulates the release of ACTH
What is the role of adrenocorticotropic hormone (ACTH)
released from the anterior pituitary in response to increased CRH levels
inhibits CRH release
stimulates production and release of cortisol and cortisone from the adrenal cortex
Why do quadraplegics often lose the circadian rhythm for melatonin but usually retain their circadian rhythm for cortisol?
melatonin synthesis in the pineal gland requires input from peripheral sympathetic nerves but CRH production by the anterior pituitary does not
What are the adverse effects on the kideny of prolonged administration of exogenous glucocorticoids?
may result in adrenal cortical atrophy and inability to synthesize endogenous cortisol
withdrawal of exogenous glucocorticoid may then precipitate acute adrenal insufficiency, which can be life-threatening
Cushing Syndrome
increased synthesis of crotisol, inducing gluconeogenesis and causing hypoglycemia
Weight gain and fatty tissue deposits, particularly around the midsection and upper back, in the face (moon face)
between the shoulders (buffalo hump)
Pink or purple stretch marks (striae) on the skin of the abdomen, thighs, breasts and arms
Thinning, fragile skin that bruises easily
Slow healing of cuts, insect bites and infections
Acne
What is the role of eicosanoids?
products of the arachidonic acid cascade
phospholipase A2 catalyzes the production of arachidonic acid from triglyceride
arachadonic acid then serves as a feedstock for synthesis of prostacyclin, the prostaglandins, and the thromboxanes
arachidonic acid is used to synthesize the leukotrienes via 5-lipoxygenase
What is the effect of glucocorticoids on inflammation and immunity?
rapid nongenomic effects on eicosanoid-mediated inflammation
slow genomic effects
What are the rapid nongenomic effects of glucocorticoids on ecosanoid-mediated inflammation?
- cytosolic steroid receptor coactivation (c-Src) is an accessory protein of the glucocorticoid receptor
- binding of glucocorticoid releases c-Src, which induces the phsophorylation of annexin 1, inhibiting cytosolic phospholipase A2 activity, reducing production of arachidonic acid, and thereby inhibiting synthesis of the eiconasoids
- occurs in minutes to hours
What are the slow genomic effects of glucocorticoids on inflammation?
ligand-bound glucocorticoid receptor in the nucleus transprepresses expression of activator protein 1 (AP1) and NF-kappaB (proinflammatory transcription factors)
transactivates expression of annexin 1 (pivotal inhibitor of inflammation and modulator of innate and adaptive immunity)
glucocorticoids induce lymphocyte apoptosis in part through modulation of miRNA expression and processing
What are the effects of glucocorticoids on bone and muscle?
inhibit formation of new bone by attenuating osteoblast differentiation via the monomeric glucocorticoid receptor inhibitor
this leads to osteopenia and also to reduced production of osteocalcin by osteoblasts
the reduction in osteocalcin production induces hepatic insulin resistance, inhibits adiponectin production in the adipose tissue, and causes metabolic syndrome
What may cause glucocorticoid resistance?
may occur due to phosphorylation or nitrosylation of glucocorticoid receptor driven by cytokines or microbial superantigens
ubiquination of glucocorticoid receptor may increase degradation of glucocorticoid receptor by the proteasome or glucocorticoid receptor may be sequestered by NF-kappaB or AP-1 or be blocked from binding to pGREs by presence of the GRbeta isoform
theophyline increases cAMP and may reverse glucocorticoid resistance in many patients
