Glucocorticoid degradation

This cytoplasmic protein is phosphorylated by an IKK complex which is activated by cytokines, reactive oxygen species, and mitogens. Phosphorylated IkB can be ubiquitinylated and degraded, thus releasing its hold on NF-kB. Glucocorticoids affect many steps in this process, as described in the text. 

A second example is the colon-specific delivery of glucocorticoids linked to dextran via a succinic acid or glutaric acid spacer [256a]. Such conjugates resist hydrolysis in the upper gastrointestinal tract, but are rapidly degraded by bacteria in the colon and caecum where little drug absorption occurs. 

Estrogen receptor-dependent protea-somal degradation of the glucocorticoid receptor is coupled to an increase in mdm2 protein expression. Mol Cdl Biol, 2003, 23(16), 5867-81. 

Sengupta, S. and B. Wasylyk, Ligand-dependent interaction of the glucocorticoid receptor with p53 enhances their degradation by Hdm2. 

Loss of muscle protein in trauma is caused by increased degradation rather than decreased synthesis. The degradation is controlled by changes in the levels of glucocorticoids, insulin and the proinflammatory cytokines TNFa and IL-1. The proteolytic enzyme complex that degrades the protein is the proteasome (Chapter 8). The mechanism by which the enzyme is activated is not known, but increased activities of the enzymes involved in ubiquitina-tion of proteins and an increase concentration of ubiquitin may play a role (Chapter 8). 

Increased plasma concentrations of glucocorticoids and proinflammatory cytokines (tumour necrosis factor and some interleukins) produced by both tumour cells and macrophages within the tumour stimulate hpolysis and protein degradation. This is accompanied by low levels of insuhn which also encourage hpolysis and proteolysis. 

Glucocorticoids—mainly cortisol (see p. 374)—induce all of the key enzymes involved in gluconeogenesis [4, 6, 8, 9]. At the same time, they also induce enzymes involved in amino acid degradation and thereby provide precursors for gluconeogenesis. Regulation of the expression of PEP carbo>Q -kinase, a key enzyme in gluconeogenesis, is discussed in detail on p. 244. 

Cortisol, the most important g/ucocorticoid, is synthesized by the adrenal cortex, it is involved in regulating protein and carbohydrate metabolism by promoting protein degradation and the conversion of amino acids into glucose. As a result, the blood glucose level rises (see p. 152). Synthetic glucocorticoids (e.g., dexamethasone) are used in drugs due to their anti-inflammatory and immunosuppressant effects. 

Hepatic degradation of glucocorticoids reduces plasma concentrations fairly rapidly. After 8 hours, only 25% of the peak concentration value remains, and the active drug disappears completely in about 12 hours. 

In some species (eg, the rat), corticosterone is the major glucocorticoid. It is less firmly bound to protein and therefore metabolized more rapidly. The pathways of its degradation are similar to those of cortisol. 

Glucocorticoids Adrenal cortex Cortisol Promotes gluconeogenesis and glycogen formation enhances fat and protein degradation... 

Stimulation of HA synthesis also occurs following phorbol ester (PMA) and PDGF treatment, although a direct effect on HAS has not been demonstrated. Glucocorticoids induce a nearly total inhibiton of HAS mRNA in dermal fibroblasts and osteoblasts.183 Extracts of dermal fibroblasts indicate that HAS-2 is the predominant HA synthase therein. This may be the molecular basis of the decreased HA in glucocortcoid-treated skin. However, an additional effect on rates of HA degradation has not been examined. 

Protein degradation and amino acid metabolism are highly elevated in the diabetic, because the stimulatory effect of insulin on protein synthesis is nonexistent and the relative excess of glucagon and glucocorticoids causes protein breakdown to continue. Indeed, muscle wasting is a cardinal symptom of the untreated diabetic. Insulin also inhibits amino add release into the bloodstream, and this may be a reason a moderate rise in plasma amino add levels is observed in the diabetic. Such increased amino adds are largely of the branched-chain type, and alanine levels are in fact lower than normal. Nevertheless, alanine uptake by the liver is twice that of the normal individual, and it continues to be a major actor in the gluconeogenesis process. 

Thioredoxin was shown to reduce the two interchain disulfides of insulin very efficiently around neutral pH and in the presence of either thioredoxin reductase and NADPH or lipoamide, lipoamide dehydrogenase and NADH [277,278], This reduction may be important in hormone action since the reduction of insulin disulfides is a prerequisite of proteolytic degradation of insulin. Thioredoxin has also been identified as the endogenous activator of the rat glucocorticoid receptor to a steroid-binding state [279]. Finally, recent data suggest that thioredoxin is secreted by immunocompetent cells and then behaves as an autocrine growth factor [280]. 

Insulin and tri-iodothyronine (T3) increase the binding of LDLs to liver cells, whereas glucocorticoids (e.g. dexamethasone) have the opposite effect. The precise mechanism for these effects is unclear, but it may be mediated through the regulation of apo-B degradation. The effects of insulin and T3 on hepatic LDL binding may explain the hypercholesterolaemia and increased risk of atherosclerosis that have been shown to be associated with uncontrolled diabetes and hypothyroidism. 

Glucocorticoids released during stress or starvation, oppose the effects of insulin and result in protein degradation (metabolism). 

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