Liver Corticosterone Research Articles

Interplay between H6PDH and 11β-HSD1 implicated in the pathogenesis of type 2 diabetes mellitus

Extensive studies have been performed on the role of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) in metabolic diseases. Our previous study reported glucose could directly regulate hexose-6-phosphate dehydrogenase (H6PDH) and 11β-HSD1. Recently, we further investigated the interplay of H6PDH and 11β-HSD1 and their roles in hepatic gluconeogenesis and insulin resistance to elucidate the importance of H6PDH and 11β-HSD1 in pathogenesis of type 2 diabetes mellitus (T2DM). T2DM rats model and H6PDH or 11β-HSD1 siRNA transfected in CBRH-7919 cells were used to explore the effect of H6PDH and 11β-HSD1 in T2DM. The results showed that the expression and activity of H6PDH and 11β-HSD1 in livers of diabetic rats were increased, with the expressions of PEPCK and G6Pase or liver corticosterone increased apparently. It also showed that H6PDH siRNA and 11β-HSD1 siRNA could inhibit the protein expression and enzyme activity by each other. With H6PDH siRNA, the enhancement of gluconeogenesis was blocked and insulin resistance stimulated by corticosterone was reduced. H6PDH and 11β-HSD1 might be the effective and prospective targets for T2DM and metabolic syndromes, based on the interplay between these two enzymes.

Testosterone and melatonin effects on adrenal cortex of orchiectomized and pinealectomized rats.

The study aimed to examine the effects of pinealectomy (PX) and melatonin on adrenal cortex of orchiectomized rats and to explain whether the testosterone action on adrenal cortex is modified by the pineal gland. Neither PX (53 days) nor melatonin administration (10 days) had an effect on the structure as well as on the studied functional parameters of the adrenal gland--corticosterone output by homogenates, 11 beta-hydroxylase and 5 alpha-reductase activities, liver corticosterone metabolism and serum corticosterone level. On the contrary, PX of 14 months duration resulted in an increase in 5 alpha-reductase activity. Testosterone administration into orchiectomized rats lowered corticosterone output and liver corticosterone metabolism and these effects were unaffected by PX or melatonin. Testosterone lowered 5 alpha-reductase and 11 beta-hydroxylase activities, the effects not modified by PX, however, after melatonin administration activities of these enzymes were similar as in orchiectomized rats. Obtained results cast doubts on a physiological role of the pineal gland and its principal hormone--melatonin--in regulation of adrenocortical structure and secretory activity and suggest that testosterone action on the rat adrenal cortex is not modified by the pineal gland.

Perhydroquinolylbenzamides as Novel Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1

High-throughput screening identified 5 as a weak inhibitor of 11beta-HSD1. Optimization of the structure led to a series of perhydroquinolylbenzamides, some with low nanomolar inhibitory potency. A tertiary benzamide is required for biological activity and substitution of the terminal benzamide with either electron-donating or -withdrawing groups is tolerated. The majority of the compounds show selectivity of >20 to >700-fold over 11beta-HSD2. Analogues which showed >50% inhibition of 11beta-HSD1 at 1 muM in an cellular assay were screened in an ADX mouse model. A maximal response of >70% reduction of liver corticosterone levels was observed for three compounds; 9m, 25 and 49.

Effect of High-fat Diet on KKAyandob/obMouse Liver and Adipose Tissue Corticosterone and 11-dehydrocorticosterone Concentrations

The present study was performed to compare glucocorticoid levels in obese KKA (y) and ob/ob mice with those in normal C57BL/6J mice, and the effect of high-fat diet on glucocorticoids in KKA (y) and ob/ob mice. Liver, mesenteric and epididymal adipose tissue corticosterone and 11-dehydrocorticosterone concentrations as well as circulating corticosterone concentrations were measured. The KKA (y) and ob/ob mice displayed elevated serum corticosterone levels compared to normal mice, 2.0 to 2.8-fold in KKA (y), and 11 to 16-fold in ob/ob mice. Liver corticosterone levels were 3.0 to 5.1 and 6.2 to 8.1-fold, and 11-dehydrocorticosterone levels were 3.4 to 3.6 and 6.7 to 8.2-fold higher in KKA (y) and ob/ob mice compared to normal mice. Mesenteric adipose tissue corticosterone levels were 2.7 to 4.2-fold higher, and 11-dehydrocorticosterone levels were 2 to 4-fold higher in ob/ob than in KKA (y) mice. Epididymal adipose tissue corticosterone levels were 3.0 to 6.2-fold higher, and 11-dehydrocorticosterone levels were 1.8 to 2.0-fold higher in ob/ob than in KKA (y) mice. Circulating, hepatic, and mesenteric and epididymal adipose tissue glucocorticoid concentrations were low in the normal C57BL/6J mouse, high in the ob/ob mouse, and intermediate in the KKA (y) mouse. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mRNA levels were doubled in ob/ ob compared to KKA (y) mice in all three tissues. Glucocorticoid concentrations correlated with 11beta-HSD1 mRNA levels. High-fat diet had no effect on the tissue glucocorticoid concentrations.

Perinatal changes in liver corticosterone, serum insulin and plasma glucagon and corticosterone in the rat.

This report describes some hormonal changes occuring in the rat during the last 3 days of gestation and the first 6 h after surgical deliversy on days 20–22uu ofgestation. In the foetus, the concentration of glucagon increased 2‐fold and that of insulin decreaed from 4.7 to 3.5 ng/ml between days 21 and 22. Consequently the insulin/glucagon molar ratio decreased from 15.6 on day 21 to 5.9 on day 22. After delivery on dasys 21 and 22 of gestation plama glucagon concentration increased 2‐fold and reeached a maximim at 30 min after birth. In addition, the concentration of serum insulin decreased to about 50% of the foetal values by 30 min post partum. Consequentaly the insulin/glucagon ratio decreased to a minimum 30 min after delivery. There was no sinificant change in the concentration of total, that bound to corticosteroid‐binding globulin and free corticosterone in the plasma nor in the concentration of liver corticosterone for 6 h after delivery on day 22 of gestation. Only free plasma corticosterone concentration increased after delivery on day 21 and peaked one hour after birth. The concentration of both pancreatic hommones and corticosterone showed a different development pattern after premauature delivery on day 20 of gestatin. Plasma glucagon increased and plasma insulin decreased for 2 h. Consequentaly the insulin/glucagon ratio decreased from 8.8 at birth to 2.4 at 2 h post partum. The concentration liver corticosterone as well as total, bound and free corticosterone in the plsma incrreased to maximal levels within 1–2 h ofdelivery. The results support the proposal that the relative concentration of insulin and glucagon in the blood regulate the adenosine 3′:5′‐monophosphate concentration and thus enzyme induction in the liver of the perinatal rat. However, the changes in corticosterone concentration wer not consistent with the view that steroids are a primary signal for tyrosine sminotransferase induciton in the newborn rat.

Levels and subcellular distribution of endogenous corticosterone in rat liver during development

The concentration of corticosterone in liver homogenates, liver cytosol and purified nuclear fractions, and in plasma of fetal, newborn, immature and adult rats has been measured by radioimmunoassay. Highest plasma corticosterone levels were found in fetal rats, decreasing close to the levels observed in the adrenalectomized rat by the 6th day of postnatal life followed by a rise in the adult rat. The concentration of corticosterone in liver during development paralleled the plasma levels, the liver to plasma corticosterone ratio ranging between 0.09 and 0.17 suggesting that the corticosterone retained by the tissue is related to the unbound fraction of the hormone in plasma.Both plasma and tissue corticosterone levels declined after adrenalectomy and they were elevated after ether stress. Fractionation of liver homogenates showed that the major fraction of liver corticosterone is localized in the cytosol. Purified liver nuclei contained between 9 and 16% of the total liver corticosterone. The amount of corticosterone in the nuclei seems to be related to the plasma and tissue hormone levels rather than the concentration of cytoplasmic glucocorticoid receptors. Since most of the nuclear corticosterone appears to be bound to receptors, it has been calculated that close to 60% of the cellular receptors in fetal liver are localized in the nucleus. In adult rat liver, only about 10% of the cellular receptors appear to be associated with nuclei. Changes in the concentration of glucocorticoid receptors in liver during development and after adrenalectomy are inversely related to changes in plasma corticosterone levels. It is suggested that corticosterone may regulate the levels of its own receptors in liver.

Influence of stress and phenobarbital on corticosterone metabolism during early postnatal life of rat

Postnatal changes in liver corticosterone metabolism in vitro were investigated in male rats pretreated for three days twice daily by physiological saline i.p./stress/ or by phenobarbital /20 mg/kg/. Perinatally, both stress and phenobarbital decrease corticosterone side chain metabolism while no change was observed in A ring reduction rate. In older animals no effect of the stress on corticosterone metabolism was observed. The inhibitory influence of phenobarbital on the side chain metabolism was still apparent at age of 14 days, but not in adult animals. The A ring reduction rate was increased by phenobarbital at age of 14 days and in adult animals. Measurements of serum corticosterone and corticosterone production by adrenal glands in vitro confirmed earlier reports showing that during perinatal period increased level of circulating corticosterone can be associated with minor or transient changes in adrenal cortex activity. It is concluded that changes in liver corticosterone metabolism are likely to play an important role in regulation of glucocorticoid activity perinatally when the responsiveness of pituitary-adrenal system to environmental stimuli is decreased.

Sex-linked specificity of the hepatic metabolism of steroids in rats. Mass fragmentography as a method for the assay of hydrogenated metabolites of corticosterone in the liver.

A method is described for the separation, identification and quantitation of endogenous hydrogenated metabolities of corticosterone in rat liver Corticosterone, 5α- and 5β-dihydrocorticosterone, 3α,11β,21-trihydroxy-5α-pregnane-3,20-dione, 3β,11β,21-trihydroxy-5α-pregnane-3,20-dione, 3α,11β,21-trihydroxy-5β-pregnane-3,20-dione, 3β,11β,21-trihydroxy-5α-pregnane-3,20-dione, 5α-pregnane-3α,11β,20α,21-tetrol, 5α-pregnane-3α,11β,20β,21-tetrol and 5α-pregnane-3β,11β,20β,21-tetrol are specifically quantitated in one analysis by mass fragmentography all as their O-methyloxime pertrimethylsilyl derivatives. A pronounced difference in the amounts of these nine metabolites between male and female adult rats was found, while in newborn rats only the two tetrahydro-compounds bearing a 5α-hydrogen were detected in both sexes. On the other hand 3α,11β,1 5α,21-tetrahydroxy-5α-pregnan-20-one was detected only in the adult female as its second prominent metabolite of corticosterone. Corticosterone metabolites being biochemical markers of the sex-linked differentiation of the hepatocytes, their mass fragmentographic assay is proposed as a tool for the quantitative analysis of this type of gene expression.