Sexually Dimorphic Effects of Maternal Nutrient Reduction on Expression of Genes Regulating Cortisol Metabolism in Fetal Baboon Adipose and Liver Tissues

Maternal nutrient reduction (MNR) during fetal development may predispose offspring to chronic disease later in life. Increased regeneration of active glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in metabolic tissues is fundamental to the developmental programming of metabolic syndrome, but underlying mechanisms are unknown. Hexose-6-phosphate dehydrogenase (H6PD) generates NADPH, the cofactor for 11β-HSD1 reductase activity. CCAAT/enhancer binding proteins (C/EBPs) and the glucocorticoid receptor (GR) regulate 11β-HSD1 expression. We hypothesize that MNR increases expression of fetal C/EBPs, GR, and H6PD, thereby increasing expression of 11β-HSD1 and reductase activity in fetal liver and adipose tissues. Pregnant MNR baboons ate 70% of what controls ate from 0.16 to 0.9 gestation (term, 184 days). Cortisol levels in maternal and fetal circulations increased in MNR pregnancies at 0.9 gestation. MNR increased expression of 11β-HSD1; H6PD; C/EBPα, -β, -γ; and GR in female but not male perirenal adipose tissue and in male but not female liver at 0.9 gestation. Local cortisol level and its targets PEPCK1 and PPARγ increased correspondingly in adipose and liver tissues. C/EBPα and GR were found to be bound to the 11β-HSD1 promoter. In conclusion, sex- and tissue-specific increases of 11β-HSD1, H6PD, GR, and C/EBPs may contribute to sexual dimorphism in the programming of exaggerated cortisol regeneration in liver and adipose tissues and offsprings’ susceptibility to metabolic syndrome.Although central obesity, genetic susceptibility, aging, sedentary lifestyle, and stress are recognized as important contributing factors to development of diabetes and metabolic syndrome, it is now understood that an adverse intrauterine environment resulting from poor maternal nutrition, stress, or overexposure to glucocorticoids can lead to developmental programming of these conditions in later life (1). Maternal nutrient reduction (MNR) affects a significant portion of the population in the developing world, but it is much less an issue in developed countries where maternal smoking, pregnancy-induced hypertension, and placental insufficiency or other placental pathologies may all result in restriction of intrauterine growth restriction. To survive these adverse conditions, the fetus has to make adaptive alterations in the expression patterns of genes involved in glucose and insulin metabolism. Permanent changes to these genes may predispose the fetus to the development of metabolic syndrome in later life, an adaptation often referred to as the “thrifty phenotype hypothesis” (2–7).Excess cortisol is associated with metabolic syndrome (8). Increased glucocorticoid activity in these tissues also is proposed as a key mechanism underlying the developmental programming of metabolic syndrome (9). Increased expression of glucocorticoid receptor (GR) expression is observed in hepatic, renal, and adipose tissues after developmental programming in several animal species (9,10), although other reports indicate no change (11). Although circulating levels of glucocorticoids are not changed in patients with obesity and metabolic syndrome (12,13), increased local regeneration of biologically active glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in the major metabolic tissues has been suggested to play a pivotal role in the pathogeneses of metabolic syndrome (14). The reductase activity of 11β-HSD1 regenerates cortisol (humans)/corticosterone (rodents) from their biologically inactive metabolites cortisone/11-dehydrocorticosterone, thus amplifying the actions of glucocorticoids (15). Such local hypercortisolism is believed to cause metabolic and other complications in metabolic syndrome (8,16,17). A key role for 11β-HSD1 in metabolic syndrome is supported by findings that 11β-HSD1^−/− mice are protected from developing metabolic syndrome (18,19), whereas selective overexpression of 11β-HSD1 in adipose or liver tissue, the two major tissues expressing 11β-HSD1 in the body, leads to a metabolic syndrome phenotype (20,21). MNR has been shown to cause a persistent increase in 11β-HSD1 expression in the visceral adipose or liver tissues in a number of animal models (9,22). However, evidence of overexpression of 11β-HSD1 in developing fetal liver and adipose tissue in response to the challenge of MNR in the fetal primate is lacking, although a persistent postnatal increase of 11β-HSD1 expression was observed in the liver and subcutaneous adipose tissues in the common marmoset after prenatal exposure to dexamethasone (23). Because the baboon shares 96% genomic homology with humans (24), characterizing the effect of MNR on 11β-HSD1 expression in the liver and adipose tissues in a fetal primate model would improve understanding of human development and aid translation of developmental programming during human development.Despite considerable evidence of a role for 11β-HSD1 in the pathogenesis of developmental programming of metabolic syndrome, the mechanism that increases 11β-HSD1 expression during developmental challenges is unknown. 11β-HSD1 is among the target genes that are regulated by the CCAAT/enhancer binding proteins (C/EBPs) and GR (25,26). We hypothesize that the challenge of nutrient restriction to the developing fetus results in a persistent increase of C/EBP and GR expression in the major glucocorticoid-sensitive tissues, such as liver and fat, and as a consequence, downstream genes including 11β-HSD1 are up-regulated, leading to a feed-forward production of cortisol and expression of glucocorticoid-target genes in these cells. 11β-HSD1 is a bidirectional enzyme capable of both reductase and oxidase activity (15). The reductase activity of 11β-HSD1 regenerating cortisol/corticosterone depends on the availability of the cofactor NADPH, derived from the enzymatic activity of hexose-6-phosphate dehydrogenase (H6PD) (27). Thus parallel increases of H6PD and 11β-HSD1 may be a prerequisite for the reductase activity of 11β-HSD1.To address these hypotheses, we studied the effect of 70% maternal ad libitum food intake from 0.16 gestation (term, 184 days) to 0.9 gestation on the expression of 11β-HSD1, H6PD, GR, and C/EBP, which are central to the peripheral generation of cortisol in fetal adipose tissue, as well as the mineralocorticoid receptor (MR) that may also mediate the effects of cortisol (28) and its targets phosphoenolpyruvate carboxykinase 1 (PEPCK1) and peroxisome proliferator-activated receptor γ (PPARγ), which are essential for hepatic energy metabolism and adipocyte differentiation (29,30).     

A Pilot Study on the Safety and Efficacy of Generic Mycophenolate Agent as Conversion Maintenance Therapy in Stable Liver Transplant Recipients

Purpose

The patent covering mycophenolate mofetil (MMF) in Korea has expired and, thus, several generic MMF agents are now commercially available. The supply of Cellcept (Roche Korea) was interrupted at the end of 2011, so it was inevitable that a generic MMF would be used instead. During this period, we performed a prospective pilot study to examine the safety and efficacy of a generic mycophenolate agent (Myconol: Hanmi Pharmaceutical, Seoul Korea) for use as conversion maintenance therapy in stable liver transplantation (OLT) recipients.

Methods

OLT recipients, who were treated with MMF on an outpatient basis from January 2012 to March 2012, attended follow-up interviews conducted. The patients had undergone OLT ≥ 2 years before the study, had tolerated Cellcept, and showed stable liver function. Fifty-three patients were followed up for more than 3 months after conversion to the same dose of Myconol.

Results

After conversion to Myconol, 6 patients (11.3%) experienced new side effects, which disappeared when they reverted to Cellcept (n = 5) or stopped taking Myconol medication (n = 1). The side effects associated with Myconol included gastrointestinal symptoms (indigestion and diarrhea; n = 3), skin eruptions (n = 1), pruritus (n = 1), and insomnia (n = 1). The mean mycophenolic acid levels were 1.71 ± 0.88 μg/mL for Cellcept and 1.83 ± 0.91 μg/mL for Myconol, which showed a strong correlation (r² = 0.92, P < .001).

Conclusions

Myconol showed similar pharmacokinetics to those of Celcept, but a small proportion of patients experienced agent-specific side effects; therefore, patients should be closely monitored when taking Myconol. Also, further studies, with a greater number of patients, are required to identify the full spectrum of drug-associated side effects.     

Comparison of Peritoneal Dialysis and Hemodialysis After Kidney Transplant Failure

Background

Patients with a failed kidney transplant represent a unique chronic kidney disease population that is increasing in number and is at high risk of morbidity and mortality. Among transplant-naïve patients, those treated with peritoneal dialysis (PD) show an early survival advantage compared with those treated with hemodialysis (HD). But any advantage of PD after allograft failure is unknown. The aim of this study was to investigate the clinical outcomes of patients with failed allografts according to the type of dialysis modality.

Method

We reviewed medical records of patients who initiated dialysis after kidney transplant failure from November 1982 to May 2011. Demographics features, clinical data, and survival outcomes were compared between PD and HD patients who had experienced allograft failure.

Results

The 182 patients with failed allografts showed the most common cause to be chronic rejection. The median duration of function before allograft failure was 74.0 months. After allograft failure, 145 (79.7%) patients returned to HD and 37 (20.3%) to PD. Twenty-three patients (12.6%) died over the median 69.1 months duration of follow-up. During the observation period, 16 HD (11%) and 7 PD (8.9%) patients died. The survival rates of PD patients at 1 year were 91.2% and 84.4%, respectively, at 1 and 3 years, and those of HD patients 94.8% and 88.9%. There was no significant difference in the survivals of the 2 groups.

Conclusions

The study suggests that the outcome of patients starting PD after kidney transplant failure was similar to those starting HD. Therefore, PD can be regarded to be a good treatment option for patients returning to dialysis after kidney transplant failure.