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CASE FILES: BIOCHEMISTRY
ACTH, which then moves into the blood and down to the adrenal glands. Once
in the zona fasciculata of the adrenal cortex, ACTH binds membrane receptors
stimulating transfer of cholesterol to the mitochondria for cleavage events
leading to synthesis and release of cortisol. After diffusing out of the cell into
the blood stream, cortisol binds corticosteroid-binding globulin (CBG), also
known as transcortin. Cortisol then moves to receptors back in the pituitary to
signal reduction of ACTH and CRH production, thus regulating cortisol syn-
thesis by a negative feedback mechanism.
As the major stress hormone, cortisol has many functions. For example, in
trabecular bone, cortisol inhibits synthesis of new bone by osteoblasts and
decreases absorption of Ca2+ in the GI tract, leading to osteopenia. However, the
two principal influences of cortisol are on metabolism and the immune system.
Metabolism:
Cortisol is catabolic and carries out lipolysis and muscle tis-
sue degradation. Muscle catabolism provides a source of amino acids used by
the liver to fuel gluconeogenesis and increases blood glucose levels. Proteolysis
of collagen can lead to skin fragility, easy bruising, and striae. Lipolysis, or
lipid degradation, generates free fatty acids in the blood, which when degraded
by P-oxidation in the liver provide an alternative energy source, decreasing the
demand for glucose. Increased lipolysis in Cushing syndrome is also thought
to cause the redirection of fat deposition away from the limbs toward the trunk,
leading to symptoms, such as “buffalo hump” and “moon face.” In addition to
increasing blood glucose levels, too much cortisol can inhibit insulin activity
and exacerbate diabetic complications. Cortisol and cAMP induce two enzymes
phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase
(G6Pase), both of which lead to increased glucose levels. The effect of corti-
sol is to induce PEPCK and G6Pase gene expression through a glucocorticoid
response element (GRE) upstream of each gene. PEPCK and G6Pase both
increase the rate of gluconeogenesis and antagonize insulin response activity,
leading to increased blood glucose.
Immune System:
Cortisol also has immunosuppressive effects and can
reduce inflammation. For example, other synthetic forms of cortisol, such as
hydrocortisone, are used medicinally to reduce inflammation. Cortisol’s
immunosuppressive effects are partly a result of its ability to sequester lym-
phocytes in the spleen, thymus, and bone marrow. Most other immunosuppres-
sive effects come from cortisol’s ability to modulate gene transcription. Cortisol
diffuses into the cell and binds glucocorticoid receptors, which disaggregate
into single, or monomer, proteins. Now that the activated receptor, or transcrip-
tion factor, has a free DNA binding domain it will translocate to the nucleus to
alter gene expression. This activity induces transcription of several immuno-
suppressive genes that inhibit expression of target genes, such as IL-2.
Cushing syndrome is a rare condition in which elevated levels of cortisol are
present in the patient for an extended period of time (hypercortisolism). Typically,
it affects those between the ages of 20 and 50 years. On rare occasions, this dis-
ease may result from an inherited condition, which leads to growth of adenomas
in endocrine glands, such as the adrenal, parathyroid, pancreas or pituitary glands.
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