No abstract

The orphan nuclear receptor estrogen-related receptor (ERR) ␣ is a downstream effector of the transcriptional coactivator PGC-1␣ in the regulation of genes important for mitochondrial oxidative capacity. PGC-1␣ is also a potent activator of the transcriptional program required for hepatic gluconeogenesis, and in particular of the key gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK). We report here that the regulatory sequences of the PEPCK gene harbor a functional ERR␣ binding site. However, in contrast to the co-stimulating effects of ERR␣ and PGC-1␣ on mitochondrial gene expression, ERR␣ acts as a transcriptional repressor of the PEPCK gene. Suppression of ERR␣ expression by small interfering RNA leads to reduced binding of ERR␣ to the endogenous PEPCK gene, and an increase in promoter occupancy by PGC-1␣, suggesting that part of the ERR␣ function at this gene is to antagonize the action of PGC-1␣. In agreement with the in vitro studies, animals that lack ERR␣ show increased expression of gluconeogenic genes, including PEPCK and glycerol kinase, but decreased expression of mitochondrial genes, such as ATP synthase subunit ␤ and cytochrome c-1. Our findings suggest that ERR␣ has opposing effects on genes important for mitochondrial oxidative capacity and gluconeogenesis. The different functions of ERR␣ in the regulation of these pathways suggest that enhancing ERR␣ activity could have beneficial effects on glucose metabolism in diabetic subjects by two distinct mechanisms: increasing mitochondrial oxidative capacity in peripheral tissues and liver, and suppressing hepatic glucose production.Nuclear receptors mediate the effects of many hormonal and dietary signals. These receptors bind to specific genomic sequences, recruit coactivators or corepressors of transcription, and regulate accordingly the expression of genes important for a wide range of biological processes, including development, reproduction, and metabolism (for reviews, see Refs. 1 and 2 and references therein). The estrogen-related receptor (ERR) 2 ␣ is a nuclear receptor with high sequence similarity to the estrogen receptors, and the founding member of a small family of orphan receptors that also includes ERR␤ and ERR␥ (3, 4). Despite their similarity to estrogen receptors, ERRs are not activated by estrogens or other known natural agonists (reviewed in Refs. 5 and 6). Structural studies of ERR␣ and ERR␥ indicate that these receptors can achieve a transcriptionally active conformation in the absence of a ligand, and suggest that ERR activity may not be subject to regulation by small lipophilic molecules (7,8). As an alternative mechanism of regulation, ERR␣ activity is controlled by the availability of specific coactivators that act as protein ligands (9 -11). Notably, the transactivation function of ERR␣ is weak in many cells where other nuclear receptors are active, and is greatly enhanced by expression of the transcriptional coactivators PGC-1␣ or PGC-1␤ (9 -11). PGC-1␣ not only activates the transcriptional function of ERR␣ bu...

BackgroundLymphedema management programs have been shown to decrease episodes of adenolymphangitis (ADLA), but the impact on lymphedema progression and of program compliance have not been thoroughly explored. Our objectives were to determine the rate of ADLA episodes and lymphedema progression over time for patients enrolled in a community-based lymphedema management program. We explored the association between program compliance and ADLA episodes as well as lymphedema progression.Methodology/Principal FindingsA lymphedema management program was implemented in Odisha State, India from 2007–2010 by the non-governmental organization, Church's Auxiliary for Social Action, in consultation with the Centers for Disease Control and Prevention. A cohort of patients was followed over 24 months. The crude 30-day rate of ADLA episodes decreased from 0.35 episodes per person-month at baseline to 0.23 at 24 months. Over the study period, the percentage of patients who progressed to more severe lymphedema decreased (P-value  = 0.0004), while those whose lymphedema regressed increased over time (P-value<0.0001). Overall compliance to lymphedema management, lagged one time point, appeared to have little to no association with the frequency of ADLA episodes among those without entry lesions (RR = 0.87 (0.69, 1.10)) and was associated with an increased rate (RR = 1.44 (1.11, 1.86)) among those with entry lesions. Lagging compliance two time points, it was associated with a decrease in the rate of ADLA episodes among those with entry lesions (RR = 0.77 (95% CI: 0.59, 0.99)) and was somewhat associated among those without entry lesions (RR = 0.83 (95% CI: 0.64, 1.06)). Compliance to soap was associated with a decreased rate of ADLA episodes among those without inter-digital entry lesions.Conclusions/SignificanceThese results indicate that a community-based lymphedema management program is beneficial for lymphedema patients for both ADLA episodes and lymphedema. It is one of the first studies to demonstrate an association between program compliance and rate of ADLA episodes.