Citations

OBJECTIVE—To determine the contribution of liver and viscera to splanchnic cortisol production in humans. RESEARCH DESIGN AND METHODS—D4 cortisol was infused intravenously; arterial, portal venous, and hepatic venous blood was sampled; and liver and visceral fat were biopsied in subjects undergoing bariatric surgery. RESULTS—Ratios of arterial and portal vein D4 cortisol/cortisoltotal (0.06 ± 0.01 vs. 0.06 ± 0.01) and D4 cortisol/D3 cortisol (1.80 ± 0.14 vs. 1.84 ± 0.14) did not differ, indicating that no visceral cortisol production or conversion of D4 cortisol to D3 cortisol via 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) occurred. Conversely, ratios of both D4 cortisol to cortisoltotal (0.05 ± 0.01; P < 0.05) and D4 cortisol to D3 cortisol (1.33 ± 0.11; P < 0.001) were lower in the hepatic vein than in the portal vein, indicating production of both cortisol and D3 cortisol by the liver. The viscera did not produce either cortisol (−8.1 ± 2.6 μg/min) or D3 cortisol (−0.2 ± 0.1 μg/min). In contrast, the liver produced both cortisol (22.7 ± 3.90 μg/min) and D3 cortisol (1.9 ± 0.4 μg/min) and accounted for all splanchnic cortisol and D3 cortisol production. Additionally, 11β-HSD-1 mRNA was approximately ninefold higher (P < 0.01) in liver than in visceral fat. Although 11β-HSD-2 gene expression was very low in visceral fat, the viscera released cortisone (P < 0.001) and D3 cortisone (P < 0.01) into the portal vein. CONCLUSIONS—The liver accounts for all splanchnic cortisol production in obese nondiabetic humans. In contrast, the viscera releases cortisone into the portal vein, thereby providing substrate for intrahepatic cortisol production.

SummaryBoth genetic and environmental factors contribute to autoimmune disease development. Previously, we evaluated genetic factors in a humanized mouse model of Hashimoto's thyroiditis (HT) by immunizing human leucocyte antigen DR3 (HLA-DR3) and HLA-DQ8 transgenic class II-knock-out non-obese diabetic (NOD) mice. DR3+ mice were susceptible to experimental autoimmune thyroiditis (EAT) induction by both mouse thyroglobulin (mTg) and human (h) Tg, while DQ8+ mice were weakly susceptible only to hTg. As one environmental factor associated with HT and tested in non-transgenic models is increased sodium iodide (NaI) intake, we examined the susceptibility of DR3+ and/or DQ8+ mice to NaI-induced disease. Mice were treated for 8 weeks with NaI in the drinking water. At 0·05% NaI, 23% of DR3+, 0% of DQ8+ and 20% of DR3+DQ8+ mice had thyroid destruction. No spleen cell proliferation to mTg was observed. Most mice had undetectable anti-mTg antibodies, but those with low antibody levels usually had thyroiditis. At 0·3% NaI, a higher percentage of DR3+ and DR3+DQ8+ mice developed destructive thyroiditis, but it was not statistically significant. However, when DR3+ mice had been depleted of CD4+CD25+ regulatory T cells prior to NaI treatment, destructive thyroiditis (68%) and serum anti-mTg antibodies were exacerbated further. The presence of DQ8 molecules does not alter the susceptibility of DR3+DQ8+ mice to NaI-induced thyroiditis, similar to earlier findings with mTg-induced EAT. Susceptibility of DR3+ mice to NaI-induced EAT, in both the presence and absence of regulatory T cells, demonstrates the usefulness of HLA class II transgenic mice in evaluating the roles of environmental factors and immune dysregulation in autoimmune thyroid disease.

Abstract Benzoquinone ansamycin antibiotics such as geldanamycin (GA) bind to the NH2-terminal ATP-binding domain of heat shock protein (Hsp) 90 and inhibit its chaperone functions. Despite in vitro and in vivo studies indicating promising antitumor activity, derivatives of GA, including 17-allylaminogeldanamycin (17-AAG), have shown little clinical efficacy as single agents. Thus, combination studies of 17-AAG and several cancer chemotherapeutics, including cisplatin (CDDP), have begun. In colony-forming assays, the combination of CDDP and GA or 17-AAG was synergistic and caused increased apoptosis compared with each agent alone. One measurable response that results from treatment with Hsp90-targeted agents is the induction of a heat shock factor-1 (HSF-1) heat shock response. Treatment with GA + CDDP revealed that CDDP suppresses up-regulation of HSF-1 transcription, causing decreased levels of stress-inducible proteins such as Hsp27 and Hsp70. However, CDDP treatment did not prevent trimerization and nuclear localization of HSF-1 but inhibited DNA binding of HSF-1 as shown by chromatin immunoprecipitation. Melphalan, but not camptothecin, caused similar inhibition of GA-induced HSF-1–mediated Hsp70 up-regulation. 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt cell survival assays revealed that deletion of Hsp70 caused increased sensitivity to GA (Hsp70+/+ IC50 = 63.7 ± 14.9 nmol/L and Hsp70−/− IC50 = 4.3 ± 2.9 nmol/L), which confirmed that a stress response plays a critical role in decreasing GA sensitivity. Our results suggest that the synergy of GA + CDDP is due, in part, to CDDP-mediated abrogation of the heat shock response through inhibition of HSF-1 activity. Clinical modulation of the HSF-1–mediated heat shock response may enhance the efficacy of Hsp90-directed therapy. [Mol Cancer Ther 2008;7(10):3256–64]

Abstract Aberrant activation of the androgen receptor (AR) by the ErbB2/ErbB3 heterodimer contributes to the development of hormone resistance in prostate cancer. EBP1, an ErbB3-binding protein, acts as an AR corepressor. As EBP1 is decreased in preclinical models of hormone-refractory prostate cancer, we studied the expression of EBP1 in human prostate cancer. We found that the expression of the EBP1 gene was significantly decreased in prostate cancer tissues compared with benign prostate at both mRNA and protein levels. Restoration of EBP1 expression in the hormone-refractory LNCaP C81 cell line led to an amelioration of the androgen-independent phenotype based on established biological criteria and a reduction in the expression of a cohort of AR target genes. The ability of the ErbB3 ligand heregulin (HRG) to stimulate growth and AKT phosphorylation of hormone-refractory prostate cancer cells was abolished. Abrogation of EBP1 expression by short hairpin RNA in hormone-dependent LNCaP cells, which undergo apoptosis in response to HRG, resulted in HRG-stimulated cell growth. Restoration of EBP1 expression decreased the tumorigenicity of C81 xenografts in female mice, whereas elimination of EBP1 expression enhanced the ability of LNCaP cells to grow in female mice. Our data support a role for EBP1 in the development of hormone-refractory prostate cancer via inhibition of both AR- and HRG-stimulated growth and present a novel strategy for treating androgen-refractory prostate cancer. [Mol Cancer Ther 2008;7(10):3176–86]

ABSTRACT Introduction Testosterone replacement therapy has been used in the treatment of sexual dysfunction; however, its use remains controversial, and the effectiveness and long-term health implications are unknown. Aim To evaluate the association between sex hormone serum levels, erectile function, and sexual drive in a population-based sample of men. Methods A stratified random sample of men residing in Olmsted County, Minnesota, completed a questionnaire containing questions from the Brief Male Sexual Function Inventory (BMSFI), and participated in a clinical exam, which included serum hormone measurements. Main Outcome Measures Levels of sexual drive (libido) and erectile function as assessed by the BMSFI and serum testosterone, bioavailable testosterone, and estradiol measurements. Results Out of 414 men, 294 had a regular sexual partner and androgen measurements at the 14th year of follow-up. Total testosterone and erectile function were significantly correlated even after adjustment for age (r = 0.12, P = 0.04). Conversely, total testosterone was not significantly correlated with sex drive (r = 0.08, P = 0.17). Bioavailable testosterone was significantly correlated with both erectile function and sex drive (r = 0.16, P = 0.01 and r = 0.20, P = 0.001, respectively). However, these associations disappeared after age adjustment (r = 0.04 and r = 0.09). Conclusions These cross-sectional results suggest the relationship between sex hormones and sexual function is complex, and that the age-related decline in sexual function may be due to age-related declines in levels of bioavailable testosterone rather than total testosterone levels.

Altitude exposure has been associated with loss of appetite and weight loss in healthy humans; however, the endocrine factors that contribute to these changes remain unclear. Leptin and glucagon-like peptide-1 (GLP-1) are peptide hormones that contribute to the regulation of appetite. Leptin increases with hypoxia; however, the influence of hypoxia on GLP-1 has not been studied in animals or humans to date. We sought to determine the influence of normobaric hypoxia on plasma leptin and GLP-1 levels in 25 healthy humans. Subjects ingested a control meal during normoxia and after 17 h of exposure to normobaric hypoxia (fraction of inspired oxygen of 12.5%, simulating approximately 4100 m). Plasma leptin was assessed before the meal, and GLP-1 was assessed premeal, at 20 min postmeal, and at 40 min postmeal. We found that hypoxia caused a significant elevation in plasma leptin levels (normoxia, 4.9 ± 0.8 pg·mL–1; hypoxia, 7.7 ± 1.5 pg·mL–1; p < 0.05; range, –16% to 190%), no change in the average GLP-1 response to hypoxia, and only a small trend toward an increase in GLP-1 levels 40 min postmeal (fasting, 15.7 ± 0.9 vs 15.9 ± 0.7 pmol·L–1; 20 min postmeal, 21.7 ± 0.9 vs 21.8 ± 1.2 pmol·L–1; 40 min postmeal, 19.5 ± 1.2 vs. 21.0 ± 1.2 pmol·L–1 for normoxia and hypoxia, respectively; p > 0.05 normoxia vs hypoxia). There was a correlation between SaO2 and leptin after the 17 h exposure (r = 0.45; p < 0.05), but no relation between SaO2 and GLP-1. These data confirm that leptin increases with hypoxic exposure in humans. Further study is needed to determine the influence of hypoxia and altitude on GLP-1 levels.