Hepatic 11β-hydroxysteroid Dehydrogenase Type Research Articles

Population Target-Mediated Pharmacokinetic/Pharmacodynamic Modeling to Evaluate SPI-62 Exposure and Hepatic 11β-Hydroxysteroid Dehydrogenase Type 1 (HSD-1) Inhibition in Healthy Adults.

SPI-62 is a small-molecule 11β-hydroxysteroid dehydrogenase type 1 (HSD-1) inhibitor exhibiting complicated nonlinear pharmacokinetics (PK) in human. Previously, we developed a target-mediated drug disposition (TMDD) model to characterize the substantial nonlinear PK of SPI-62. The aim of the current analysis was to perform population PK/PD analysis to further link SPI-62 exposure (i.e., PK) with its response (i.e., inhibition of hepatic HSD-1 activity) to gain a quantitative understanding of the SPI-62 dose-exposure-response relationship. PK and PD data from the first-in-human (FIH) clinical trials, including single ascending dose (SAD) and multiple ascending dose (MAD) studies, were used for model development. During the model development process, the final model selection was based on biological and physiological plausibility, goodness-of-fit plots, stability of parameter estimates, and objective function value. The nonlinear-mixed effect modeling (NONMEM) software was used for both the implementation of the PK/PD model and model simulation. SPI-62 plasma levels and hepatic HSD-1 inhibition over time following various dose regimens were simulated. The final model was a two-compartment TMDD model component for SPI-62 and an inhibitory Imax model component for hepatic HSD-1 activity. The TMDD-hepatic PD model that we established adequately characterized all remarkable PK and PD behaviors of SPI-62, such as extremely low plasma exposures following the first low doses, nonlinear PK turned into linear PK after repeated low doses, and substantial and long-lasting hepatic HSD-1 inhibition following low doses. SPI-62 was estimated to bind to the target with a second-order association rate constant (Kon) of 8.43 nM-1h-1 and first-order dissociation rate constant (Koff) value of 0.229 h-1, indicating that SPI-62 binds rapidly to, and dissociates slowly from, its pharmacological target. The estimated target capacity (Rtot) of 5460 nmol corresponds to approximately 2.2 mg of SPI-62, which comports well with the dose range in which PK nonlinearity is prominent. Model simulation results reveal that a 6 mg once-daily regimen can lead to long-lasting and substantial hepatic HSD-1 inhibition. A population TMDD-PD model that explains SPI-62 nonlinear PK and hepatic HSD-1 inhibition following different dose regimens in healthy adults was successfully established. Our simulation results provide a solid foundation for model-informed development of SPI-62.

Effects of long-snake moxibustion on the HPA axis and liver 11β-HSD1 expression in rats with kidney yang deficiency: 长蛇灸对肾阳虚大鼠HPA轴及肝脏11β-HSD1的影响

ObjectiveTo observe the effects of long-snake moxibustion on the hypothalamic-pituitary-adrenocortical (HPA) axis and hepatic 11β-hydroxy steroid dehydrogenase type 1 (11β-HSD1) expression in rats with kidney yang deficiency to provide a basis for later in-depth exploration of the action mechanism of long-snake moxibustion on such rats. MethodsFifteen SPF-grade, male, SD rats were randomly divided into a blank control group, a model group, and a long-snake moxibustion treatment group, with five rats in each group. Hydrocortisone powder (30 mg/kg) was administered by gavage at a volume of 10 mL/kg to prepare the rat model of kidney yang deficiency. After successful modeling, the rats in the long-snake moxibustion treatment group underwent long-snake moxibustion treatment every other day (along the governor vessel from Dazhui (GV14) to Shenshu(BL23), for a period of 14 days. The remaining two groups were secured in the same way as the long-snake moxibustion treatment group, although they did not receive any treatment. The body weight, rectal temperature, and spontaneous activity count of the rats, as well as serum levels of corticotropin releasing hormone (CRH) and corticosterone (CORT) were detected by ELISA before modeling, after modeling, and after treatment. The amount of 11β-HSD1 protein in rat liver was determined by immunohistochemistry and Western blot analysis. ResultsCompared with the rats in the blank control group, those in the model group exhibited a significant decrease in the trend of body weight growth and in rectal temperature (P <0.05), as well as a slight yet non-significant decrease in spontaneous activity count (P >0.05); compared with the rats in the model group, the rats in the treatment group exhibited a significant increase in rectal temperature (P <0.05) and in spontaneous activity count (P <0.05). Moreover, after 14 days of treatment, compared with the rats in the blank, the rats in the model group exhibited a significant decrease in serum CORT content (P <0.05) and in the expression of 11β-HSD1 in the liver (P <0.05), as well as a slight yet non-significant decrease in serum CRH content (P >0.05); compared with the rats in the model group, the rats in the treatment group exhibited a significant increase in serum CRH content (P <0.05) and in the expression of 11β-HSD1 in the liver (P <0.05), as well as a slight yet non-significant increase in serum CORT content (P >0.05). ConclusionLong-snake moxibustion can increase the rectal temperature and spontaneous activity count of rats with kidney yang deficiency, improve the function of the HPA axis, and increase the expression of 11β-HSD1 in the liver.

Altered lipid partitioning and glucocorticoid availability in CBG-deficient male mice with diet-induced obesity.

To evaluate how deficiency in corticosteroid-binding globulin (CBG), the specific carrier of glucocorticoids, affects glucocorticoid availability and adipose tissue in obesity. C57BL/6 (WT) and CBG-deficient (KO) male mice were fed during 12 weeks with standard or hyperlipidic diet (HL). Glucocorticoid availability and metabolic parameters were assessed. Body weight and food intake were increased in KO compared with WT mice fed a standard diet and were similar when fed a HL diet. Expression of CBG was found in white adipose tissue by immunochemistry, real-time PCR, and Western blot. In obesity, the subcutaneous depot developed less in KO mice compared with WT, which was associated with a minor adipocyte area and peroxisome proliferator-activated receptor-γ expression. Conversely, the epididymal depot displayed higher weight and adipocyte area in KO than in WT mice. CBG deficiency caused a fall of hepatic 11β-hydroxysteroid dehydrogenase type 2 expression and an increase in epidymal adipose tissue, particularly in HL mice. Deficiency in CBG drives lipid partitioning from subcutaneous to visceral adipose depot under a context of lipid excess and differentially modulates 11β-hydroxysteroid dehydrogenase type 2 expression.

High Sucrose Intake Ameliorates the Accumulation of Hepatic Triacylglycerol Promoted by Restraint Stress in Young Rats.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder. Stress promotes the onset of the NAFLD with a concomitant increment in the activity of the hepatic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1). However, the interaction between the stress and a carbohydrate-enriched diet for the development of NAFLD in young animals is unknown. In the present study, we evaluated the impact of chronic stress on the hepatic triacylglycerol level of young rats fed or not with a high sucrose-diet. For doing this, 21-day old male Wistar rats were allocated into 4 groups: control (C), chronic restraint stress (St), high-sucrose diet (S30), and chronic restraint stress plus a 30 % sucrose diet (St + S30). Chronic restraint stress consisted of 1-hour daily session, 5 days per week and for 4 weeks. Rats were fed with a standard chow and tap water (C group) or 30 % sucrose diluted in water (S30 group). The St + S30 groups consumed less solid food but had an elevated visceral fat accumulation in comparison with the St group. The St group showed a high level of serum corticosterone and a high activity of the hepatic 11β-HSD-1 concomitantly to the augmentation of hepatic steatosis signs, a high hepatic triacylglycerol content, and hepatic oxidative stress. Conversely, the high-sucrose intake in stressed rats (St + S30 group) reduced the hepatic 11β-HSD-1 activity, the level of serum corticosterone, and the hepatic triacylglycerol content. Present findings show that a high-sucrose diet ameliorates the triacylglycerol accumulation in liver promoted by the restraint stress in young male rats.

Hepatic 11β-hydroxysteroid dehydrogenase type 1 activity in obesity and type 2 diabetes using a novel triple tracer cortisol technique.

Dysregulation of 11β-hydroxysteroid dehydrogenase (11β-HSD) enzyme activities are implicated in the pathogenesis of obesity and insulin resistance. The aim of the study was to determine whether hepatic 11β-HSD type 1 (11β-HSD-1) enzyme activity differs in people with and without obesity and type 2 diabetes. We measured hepatic 11β-HSD-1 activity in the overnight fasted state in 20 lean non-diabetic participants (LND), 21 overweight/obese non-diabetic participants (OND) and 20 overweight/obese participants with type 2 diabetes (ODM) using a non-invasive approach. One mg doses of [9,12,12-(2)H3]cortisol (D cortisol) and [4-(13)C]cortisone ([(13)C]cortisone) were ingested, while [1,2,6,7-(3)H]cortisol ([(3)H] cortisol) was infused intravenously to enable concurrent measurements of first-pass hepatic extraction of ingested D cortisol and hepatic conversion of ingested [(13)C]cortisone to C13 cortisol derived from the ingested cortisone (a measure of 11β-HSD-1 activity in the liver) using an isotope dilution technique. One-way ANOVA models and Kruskal-Wallis tests were used to test the hypothesis. Plasma D cortisol and C13 cortisol concentrations were lower in OND than in LND (p < 0.05) over 6 h of the study. There was no difference (p = 0.15) in C13 and D cortisol concentrations between OND and ODM and between LND and ODM for the same study period. Hepatic conversion of [(13)C]cortisone to C13 cortisol was similar between groups. Hepatic conversion of [(13)C]cortisone to C13 cortisol did not differ between the groups studied. We conclude that hepatic 11β-HSD-1 activity is similar in individuals who are overweight/obese or who have type 2 diabetes.

Elevated hepatic 11β-hydroxysteroid dehydrogenase type 1 induces insulin resistance in uremia

Insulin resistance and associated metabolic sequelae are common in chronic kidney disease (CKD) and are positively and independently associated with increased cardiovascular mortality. However, the pathogenesis has yet to be fully elucidated. 11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyzes intracellular regeneration of active glucocorticoids, promoting insulin resistance in liver and other metabolic tissues. Using two experimental rat models of CKD (subtotal nephrectomy and adenine diet) which show early insulin resistance, we found that 11βHSD1 mRNA and protein increase in hepatic and adipose tissue, together with increased hepatic 11βHSD1 activity. This was associated with intrahepatic but not circulating glucocorticoid excess, and increased hepatic gluconeogenesis and lipogenesis. Oral administration of the 11βHSD inhibitor carbenoxolone to uremic rats for 2 wk improved glucose tolerance and insulin sensitivity, improved insulin signaling, and reduced hepatic expression of gluconeogenic and lipogenic genes. Furthermore, 11βHSD1(-/-) mice and rats treated with a specific 11βHSD1 inhibitor (UE2316) were protected from metabolic disturbances despite similar renal dysfunction following adenine experimental uremia. Therefore, we demonstrate that elevated hepatic 11βHSD1 is an important contributor to early insulin resistance and dyslipidemia in uremia. Specific 11βHSD1 inhibitors potentially represent a novel therapeutic approach for management of insulin resistance in patients with CKD.

Pharmacokinetic–pharmacodynamic studies of the 11β‐hydroxysteroid dehydrogenase type 1 inhibitor MK‐0916 in healthy subjects

To characterize pharmacokinetic parameters of MK-0916 and its safety and tolerability in lean, healthy male subjects following single and multiple oral doses. To assess (by stable-isotope labelling) the in vivo inhibition of cortisone-to-cortisol conversion following oral MK-0916. Data are presented from two randomized, controlled, double-blind, rising-dose phase I studies. In the first study, subjects received single oral doses of 0.4-100 mg MK-0916 (n = 16). In the second study, subjects received 0.2-225 mg MK-0916 followed by daily doses of 0.2-100 mg for 13 days beginning on day 2 or day 15 (n = 80). Plasma and urine drug concentrations were measured for pharmacokinetic analysis. For pharmacodynamic analysis, concentrations of plasma [(13)C4]cortisol were measured by high-pressure liquid chromatography and tandem mass spectrometry following a single oral dose of 5 mg [(13)C4]cortisone. Doses ≥3 mg were rapidly absorbed (time at which maximal concentration was achieved in plasma, 1.1-1.8 h). Exposure (measured as the area under the concentration-time curve from 0 to 168 h) increased approximately in proportion to dose. Values for the maximal plasma concentration and the plasma concentration at 24 h increased in excess of dose proportionality at doses <6 mg and roughly in proportion to dose at doses >6 mg. In subjects dosed with 6 mg MK-0916 once daily for 14 days, the mean trough plasma concentration was 240 nm and in vivo cortisone-to-cortisol conversion was inhibited by 84%. The relationship between plasma MK-0916 and hepatic 11β-hydroxysteroid dehydrogenase type 1 inhibition was well represented by a simple Emax model with an IC50 of 70.4 nm. Exposure to MK-0916 was generally well tolerated. These findings indicate that 11β-hydroxysteroid dehydrogenase type 1 is effectively inhibited in human subjects by doses of MK-0916 that are well tolerated.

Liver Upregulation of Genes Involved in Cortisol Production and Action Is Associated with Metabolic Syndrome in Morbidly Obese Patients

Hepatic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity, which converts cortisone (inactive) to cortisol, is downregulated in obesity. However, this compensation fails in obese with metabolic abnormalities, such as diabetes. To further characterize the tissue-specific cortisol regeneration in obesity, we have investigated the mRNA expression of genes related to local cortisol production, i.e., 11β-HSD1, hexose-6-phosphate dehydrogenase (H6PDH) and cortisol action, glucocorticoid receptor (GR) and a cortisol target gene, phosphoenolpyruvate carboxykinase (PEPCK) in the liver, and visceral (VAT) and subcutaneous (SAT) adipose tissues from morbidly obese patients with and without metabolic syndrome (MS). Fifty morbidly obese patients undergoing bariatric surgery, 14 men (mean age, 41.3 ± 3.5years; BMI, 48.0 ± 3.6kg/m(2)) and 36 women (mean age, 44.6 ± 1.9years; BMI, 44.9 ± 1.2kg/m(2)), were classified as having MS (MS+, n = 20) or not (MS-, n = 30). Tissue mRNA levels were measured by real-time polymerase chain reaction. Hepatic mRNA levels of these genes were higher in obese patients with MS (11β-HSD1, P = 0.002; H6PDH, P = 0.043; GR, P = 0.033; PEPCK, P = 0.032) and positively correlated with the number of clinical characteristics that define the MS. The expression of the four genes positively correlated among them. In contrast to the liver, these genes were not differently expressed in VAT or SAT, when MS+ and MS- obese patients were compared. Coordinated liver-specific upregulation of genes involved in local cortisol regeneration and action support the concept that local hepatic hypercortisolism contributes to development of MS in morbidly obese patients.

Effects of menopause on hepatic 11β-hydroxysteroid dehydrogenase type 1 activity and adrenal sensitivity to adrenocorticotropin in healthy non-obese women

Menopause is associated with central obesity, dyslipidemia, hypertension and insulin resistance, which are also shown in the patients with excess of glucocorticoids. However, the interaction of hypothalamic–pituitary–adrenal (HPA) axis activity and menopause has not been fully understood. In this study, 55 healthy non-obese women were recruited, and then divided into two groups, premenopausal group (n = 24) and postmenopausal group (n = 31). HPA axis function was evaluated by using dexamethasone suppression test (DST; 0.25 mg), and adrenocorticotrophic hormone (ACTH)-stimulation test. Moreover, 25 mg cortisone acetate test was applied to evaluate the hepatic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity. We found that hepatic 11β-HSD1 activity and adrenal response to ACTH were increased in the postmenopausal group compared with the premenopausal group, whereas the negative feedback effect of dexamethasone did not show significant difference between pre- and postmenopausal women. These findings suggest that the adrenal sensitivity to ACTH and hepatic 11β-HSD1 activity are increased. The increased cortisol conversion and/or synthesis may be contributed to the dysmetabolic features in the postmenopausal women.

Hepatic glucose regulation and metabolism in adult sheep: effects of prenatal betamethasone

Fetal exposure to synthetic glucocorticoids in sheep results in increased fetal hepatic 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) and corticosteroid-binding globulin (CBG) protein levels and insulin resistance in postnatal life. The aim was to determine whether these changes persisted to adulthood and whether alterations in mediators of hepatic glucocorticoid and glucose regulation contributed to changes in metabolism. Pregnant ewes or their fetuses received either repeated intramuscular saline (MS, FS) or betamethasone injections (0.5 mg/kg; M4, F4) at 104, 111, 118, and 124 days of gestation (dG), or a single betamethasone injection at 104 dG followed by saline at 111, 118, and 124 dG (M1, F1). Offspring were catheterized at 2 and 3 yr of age and given an intravenous glucose challenge (0.5 mg/kg). Hepatic tissue was collected at 3.5 yr. At 2 yr of age, basal plasma insulin was elevated in M4 offspring and at 3 yr of age was elevated in F4 offspring. Basal insulin-to-glucose ratio was significantly elevated in M4 offspring at 2 yr of age and elevated in M1, M4, and F4 offspring at 3 yr of age. All betamethasone treatments resulted in significant increases in hepatic glucose-6-phosphatase (G-6-Pase) activity. Hepatic glucocorticoid receptor protein levels were not altered in M1 and M4 offspring but were increased in F1 and F4 offspring. Hepatic CBG protein levels were lower in F4 but not F1 offspring and were unchanged from control in M1 and M4 offspring. Prenatal betamethasone exposure results in elevated hepatic G-6-Pase activity in adulthood and may contribute to long-term changes in metabolism.

In-vivo quantification of hepatic 11β-hydroxysteroid dehydrogenase type I activity–a preliminary study

In-vivo quantification of hepatic 11β-hydroxysteroid dehydrogenase type I activity–a preliminary study

MRNA and enzyme activity of hepatic 11β-hydroxysteroid dehydrogenase type 1 are elevated in C57BL/KsJ-db/db mice

To evaluate the importance of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in insulin resistant diabetic C57BL/KsJ-db/db mice, we measured the activity and mRNA level of 11β-HSD1 in the liver of db/db mice and their heterozygote litter mates, db/+m mice. The blood glucose, plasma insulin, and corticosterone levels of db/db mice were significantly higher than those of db/+m mice. Despite hyperinsulinemia, the activity level of this enzyme was significantly higher in db/db mice, and the mRNA level of hepatic 11β-HSD1 was also significantly higher in db/db mice. Since hepatic 11β-HSD1 in vivo mainly functions as 11-keto-reductase and does not work as 11β-oxidase, these results suggest that the rate of hepatic conversion of 11-dehydrocorticosterone to corticosterone is increased in db/db mice, resulting in higher glucocorticoid activity in the liver. The increased hepatic corticosterone concentration due to the elevation of 11β-HSD1 and high plasma corticosterone concentration may antagonize the action of insulin and cause insulin resistance. These findings have a potentially important implication for relationships between increased hepatic 11β-HSD1 and insulin resistance in db/db mice. The present paper is the first to demonstrate the increased activities and mRNA level of hepatic 11β-HSD1 in db/db mice.