2,268 research outputs found
Peroxisome Proliferator-Activated Receptor Delta: A Conserved Director of Lipid Homeostasis through Regulation of the Oxidative Capacity of Muscle
The peroxisome proliferator-activated receptors (PPARs), which are ligand-inducible transcription factors expressed in a variety of tissues, have been shown to perform key roles in lipid homeostasis. In physiological situations such as fasting and physical exercise, one PPAR subtype, PPARδ, triggers a transcriptional program in skeletal muscle leading to a switch in fuel usage from glucose/fatty acids to solely fatty acids, thereby drastically increasing its oxidative capacity. The metabolic action of PPARδ has also been verified in humans. In addition, it has become clear that the action of PPARδ is not restricted to skeletal muscle. Indeed, PPARδ has been shown to play a crucial role in whole-body lipid homeostasis as well as in insulin sensitivity, and it is active not only in skeletal muscle (as an activator of fat burning) but also in the liver (where it can activate glycolysis/lipogenesis, with the produced fat being oxidized in muscle) and in the adipose tissue (by incrementing lipolysis). The main aim of this review is to highlight the central role for activated PPARδ in the reversal of any tendency toward the development of insulin resistance
Clinical aspects of glucocorticoid sensitivity
Recent studies demonstrate that primary (hereditary) abnormalities in the glucocorticoid receptor gene make 6.6% of the normal population relatively 'hypersensitive' to glucocorticoids, while 2.3% are relatively 'resistant.' These abnormalities might explain why some individuals develop severe adverse effects during low dose glucocorticoid therapy, while others do not develop side effects even during long-term therapy with a much higher dose. Awareness of this heterogeneity in glucocorticoid sensitivity in the normal population might eventually allow the prediction of a 'safe' dose of glucocorticoid in individual patients. 'Resistance' to the beneficial clinical effects of glucocorticoid therapy in part of the patients with severe rheumatoid arthritis and asthma is probably rarely related to generalized primary (hereditary) glucocorticoid resistance. In the majority of patients this 'resistance' seems to be acquired and localized to the sites of inflammation, where it reflects high local cytokine production, which interferes with glucocorticoid action. Recognition of localized, acquired glucocorticoid resistance is of great importance indicating as alternative drug therapy with other immune-modulating drugs like cyclosporin and methotrexate. Chronic high dose glucocorticoid treatment in such patients is ineffective in alleviating symptomatology, while generalized side effects occur, reflecting the patient's normal systemic sensitivity to these drugs
Expression in hematological malignancies of a glucocorticoid receptor splice variant that augments glucocorticoid receptor-mediated effects in transfected cells
Glucocorticoids play an important role in the treatment of a number of
hematological malignancies, such as multiple myeloma. The effects of
glucocorticoids are mediated through the glucocorticoid receptor alpha,
the abundance of which can be modulated by alternative splicing of the
glucocorticoid receptor mRNA. Two splice variants of the glucocorticoid
receptor mRNA have been described: glucocorticoid receptor beta, which
reportedly has a dominant negative effect on the actions of the
glucocorticoid receptor alpha, and glucocorticoid receptor P, of which the
effects are unknown. In this study, we have investigated the expression
levels of these two splice variants at the mRNA level in multiple myeloma
cells and in a number of other hematological tumors. Although the
glucocorticoid receptor beta mRNA was, if at all, expressed at very low
levels, considerable amounts (up to 50% of the total glucocorticoid
receptor mRNA) glucocorticoid receptor P mRNA was present in most
hematological malignancies. In transient transfection studies in several
cell types and in multiple myeloma cell lines, the glucocorticoid receptor
P increased the activity of the glucocorticoid receptor alpha. These
results suggest that the relative levels of the glucocorticoid receptor
alpha and the glucocorticoid receptor P may play a role in the occurrence
of glucocorticoid resistance in tumor cells during the treatment of
hematological malignancies with glucocorticoids
Studies of Complex Biological Systems with Applications to Molecular Medicine: The Need to Integrate Transcriptomic and Proteomic Approaches
Omics approaches to the study of complex biological systems with potential applications to molecular medicine are attracting great interest in clinical as well as in basic biological research. Genomics, transcriptomics and proteomics are characterized by the lack of an a priori definition of scope, and this gives sufficient leeway for investigators (a) to discern all at once a globally altered pattern of gene/protein expression and (b) to examine the complex interactions that regulate entire biological processes. Two popular platforms in “omics” are DNA microarrays, which measure messenger RNA transcript levels, and proteomic analyses, which identify and quantify proteins. Because of their intrinsic strengths and weaknesses, no single approach can fully unravel the complexities of fundamental biological events. However, an appropriate combination of different tools could lead to integrative analyses that would furnish new insights not accessible through one-dimensional datasets. In this review, we will outline some of the challenges associated with integrative analyses relating to the changes in metabolic pathways that occur in complex pathophysiological conditions (viz. ageing and altered thyroid state) in relevant metabolically active tissues. In addition, we discuss several new applications of proteomic analysis to the investigation of mitochondrial activity
Five patients with biochemical and/or clinical generalized glucocorticoid resistance without alterations in the glucocorticoid receptor gene
Cortisol resistance (CR) is a rare disease characterized by a generalized
reduced sensitivity of end-organs to the actions of glucocorticoids (GCs)
Differential hormone-dependent transcriptional activation and -repression by naturally occurring human glucocorticoid receptor variants
The molecular mechanisms underlying primary glucocorticoid resistance or
hypersensitivity are not well understood. Using transfected COS-1 cells as
a model system, we studied gene regulation by naturally occurring mutants
of the glucocorticoid receptor (GR) with single-point mutations in the
regions encoding the ligand-binding domain or the N-terminal domain
reflecting different phenotypic expression. We analyzed the capacity of
these GR variants to regulate transcription from different promoters,
either by binding directly to positive or negative glucocorticoid-response
elements on the DNA or by interfering with protein-protein interactions.
Decreased dexamethasone (DEX) binding to GR variants carrying mutations in
the ligand-binding domain correlated well with decreased capacity to
activate transcription from the mouse mammary tumor virus (MMTV) promoter.
One variant, D641V, which suboptimally activated MMTV promoter-mediated
transcription, repressed a PRL promoter element containing a negative
glucocorticoid-response element with wild type activity. DEX-induced
repression of transcription from elements of the intercellular adhesion
molecule-1 promoter via nuclear factor-kappaB by the D641V variant was
even more efficient compared with the wild type GR. We observed a general
DEX-responsive AP-1-mediated transcriptional repression of the
collagenase-1 promoter, even when receptor variants did not activate
transcription from the MMTV promoter. Our findings indicate that different
point mutations in the GR can affect separate pathways of gene regulation
in a differential fashion, which can explain the various phenotypes
observed
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